INFLAMMATION | +50 articles

[mr peabody]

Psychedelics as anti-inflammatory agents*

by Thomas Flanagan & Charles Nichols | 13 Aug 2018

Serotonin receptor agonists have recently emerged as promising new treatment options for a variety of disorders. The recent success of these agonists, also known as psychedelics, like psilocybin for the treatment of anxiety, depression, obsessive-compulsive disorder (OCD), and addiction, has ushered in a renaissance in the way these compounds are perceived in the medical community and populace at large. One emerging therapeutic area that holds significant promise is their use as anti-inflammatory agents. Activation of 5-HT2A receptors produces potent anti-inflammatory effects in animal models of human inflammatory disorders at sub-behavioural levels. This review discusses the role of the 5-HT2A receptor in the inflammatory response, as well as highlight studies using the 5-HT2A agonist (R)-DOI to treat inflammation in cellular and animal models. It also examines potential mechanisms by which 5-HT2A agonists produce their therapeutic effects. Overall, psychedelics regulate inflammatory pathways via novel mechanisms, and may represent a new and exciting treatment strategy for several inflammatory disorders.

Psychedelics produce a potent blockade of the inflammation produced by TNF-α in cell and animal models of inflammation. Because of TNF-α’s controversial role in asthma and (R)-DOI’s impact on numerous factors contributing to the differentiation of multiple immune cells, we believe that the effects of 5-HT2A receptor activation likely extend far beyond the mere blockade of TNF-α signalling. Given the select nature by which (R)-DOI only blocks sub-sets of pro-inflammatory mediator expression, psychedelics may modulate histone modifications and epigenetic signalling for their therapeutic effects. In asthma, an interplay between the acetylation and de-acetylation states of histones in inflammatory genes has been well documented. Furthermore, histone de-acetylase (HDAC) inhibitors have been shown to reduce eosinophilic inflammation and AHR in mouse models of asthma. It is certainly plausible that 5-HT2A receptor activation modulates histone acetylation and methylation patterns to promote the expression of anti-inflammatory genes and repress the expression of pro-inflammatory genes. Only recently has it been establishes that 5-HT2A receptor activity can alter epigenetic factors.

The remaining questions regarding psychedelics and inflammation include:

1. Do 5-HT2A agonists have more pronounced effects in some cell types more than others?

2. Does 5-HT2A receptor activation modulate differentiation of immune-related cells to more anti-inflammatory phenotypes?

3. What are the effects of chronic administration of a 5-HT2A agonist in peripheral tissues to treat immune-related disorders?

It is tempting to speculate on the nature of 5-HT2A receptor activation in other inflammatory disorders. Because 5-HT2A receptor activation impacts the expression of several key inflammatory mediators and the variety of effects we have observed in animal models of inflammation, we believe that psychedelics may be of therapeutic value to a wide range of inflammatory disorders in humans. With regard to therapeutic aspects of psychiatric disorders like depression, putative suppression of neuroinflammation by psychedelics may play a key role in the long-term stability of the reported anti-depressant effects after a single treatment. Another putative component may be stimulation of neurogenesis. For example, the psychotropic ingredient of the Amazonian tea ayahuasca can stimulate hippocampal neurogenesis, which has been shown to reduce depression-like behaviours.

Although the use of sub-behavioural levels of psychedelics remains to be validated as an effective therapeutic strategy for inflammation in humans, the data from cellular and animal models is promising, and these agents represent small molecule, highly bioavailable, inexpensive and steroid sparing treatments for inflammatory-related diseases like asthma, atherosclerosis, inflammatory bowel disease, and rheumatoid arthritis. One possible barrier to the development of psychedelics for use in the clinic is that the majority are scheduled and controlled substances in the United States and several other countries. Nevertheless, drugs that activate the 5-HT2A receptor and that have been shown to produce psychedelic effects in humans have already been FDA approved (e.g. lorcaserin). Although the results we discuss here are promising, more research is needed to fully unlock their therapeutic potentials, and to discover the molecular mechanisms underlying their effects.

*From the article here :

Psychedelics as anti-inflammatory agents - PubMed

Serotonin (5-hydroxytryptamine, 5-HT)_2A receptor agonists have recently emerged as promising new treatment options for a variety of disorders. The recent success of these agonists, also known as psychedelics, like psilocybin for the treatment of anxiety, depression...

www.ncbi.nlm.nih.gov

 

[mr peabody]

Treating Neurodegenerative Disorders with Cannabinoids

Cornerstone Wellness | 17 Sep 2014

Neuroinflammation is known to play a significant role in essentially all neurodegenerative processes. Diseases such as Alzheimer’s, Multiple Sclerosis (MS), Huntington’s Disease, and Parkinson’s Disease all involve hyperactive microglia, which are the live-in macrophages of the brain, spinal cord, and central nervous system. Macrophages are immune cells that capture and dissolve foreign substances, germs, and cancer cells within the body. The microglia in the brain and spinal cord form the first line of immune defense in the central nervous system. Unfortunately, in the case of aforementioned diseases, these cells have become overactive causing them to secrete excess substances, such as cytokines (cell signals that regulate cell group growth and response), glutamate, and harmful free radicals. This excessive production of chemicals causes inflammation, which leads to further cell death.

Cannabis and the family of chemicals it produces are known to act on two major cell receptor types named CB1 and CB2 respectively. The CB1 receptor is most commonly found in neurons throughout the brain. The psychedelic effects of cannabis come from this receptor’s function, which re-wires the way neurons signal each other. The CB2 receptor on the other hand, is found throughout the body, especially within the immune system cells. The effects of activating the CB2 receptor are more myriad, but within the immune system specifically four groups of effects have been identified:

1. Induction of apoptosis or forced cell death
2. Suppression of cell proliferation
3. Induction of regulatory T cells
4. Inhibition of pro-inflammatory cytokine/chemokine production and increase in anti-inflammatory cytokines

The last of these effects is the basis upon exploring using cannabinoids to halt the progress of neurodegenerative disorders. The idea is that if cannabinoids can prevent excess production of cytokine, inflammation will decrease, and the resultant cell death around that inflammation will not occur. This would go a long measure toward slowing progression of neuro-inflammatory diseases. However, it is important to note that tempering inflammation would still not allow the brain to recover to its pre-disease state and slow neural damage would inevitably continue to occur. Likewise, modern medicine currently utilizes a variety of treatments in these diseases as more or less palliative care.

Based on these observations, research groups worldwide have been testing specific cannabinoids and other CB2 agonists with various models of neuro-inflammatory disease, generally in rodents.

The following is a general review of effects noticed, grouped by disease:

Alzheimer’s Disease – In Alzheimer’s cannabidiol has been shown to “reduce the transcription and expression of pro-inflammatory molecules in the hippocampus of an in-vivo model of induced neuroinflammation”. The hippocampus is the part of the brain that controls conversion of memory from short to long-term and controls spatial navigation. In Alzheimer’s, it’s one of the first areas of the brain to suffer damage and why patients have memory problems. Another agonist, which has the name SR141716A, also prevents amnesia induced by certain peptides, so these both promise a future in treating the disease.

Parkinson’s Disease – In this disease, the agonist WIN55,212-2 has been shown to protect mouse neurons from the neurotoxin MPTP, which is the chemical which leads to the death of dopaminergic neurons and causes Parkinson’s Disease.

Multiple Sclerosis – Although the cause of MS is unclear, researchers have determined that both genetic susceptibility and environmental trigger play a role. Some patients develop their symptoms of MS after contracting a virus. Likewise, testing rodents injected with a virus that intentionally lead to animal models of MS provided ground to investigate the effects that CB2 agonists might have on MS in humans. As is, cannabis concentrate is already prescribed under the name Sativex to alleviate neuropathic pain, spasticity, and overactive bladder symptoms associated with MS. Although some agonists did increase symptoms, several, including THC, delayed onset and reduced severity of symptoms. Three agonists, WIN55,212-2, ACEA, and JWH-015 were shown to improve motor function by attenuating microglia and immune cell infiltration into the spinal cord.

Exactly how these effects are achieved is still unknown. Although it is presumed that the effects of the CB2 agonists (any molecules that can activate CB2 receptors, including cannabinoids) stem from CB2 receptor activation, other theories have been proposed. One research group at the University of Bari has explored the extra-cannabinoid receptor binding activity of cannabidiol (CBD). Researchers there found that CBD can surprisingly communicate with the nucleus of the cell directly through interaction with nuclear hormone receptors. There are several possible chemical pathways through which cannabinoids can achieve their effects, beyond CB2 receptors. Further research will illuminate these pathways.​

https://cornerstonecollective.com/ho...der-treatment/

 

[mr peabody]

Expression of GLUT3 on activated T cells. GLUT3 (green) is localized on the cell surface, the mitochondria (violet)
and the nucleus (blue) were also shown.

How Sugar Promotes Inflammation

University of Würzburg | Neuroscience News | 22 Mar 2022

Excessive glucose consumption directly promotes the pathological function of certain cells within the immune system. Calorie-reduced diets can have beneficial effects on the immune system and have autoimmune diseases.

People who consume sugar and other carbohydrates in excess over a long period of time have an increased risk of developing an autoimmune disease. In affected patients, the immune system attacks the body’s own tissue and the consequences are, for example, chronic inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, type 1 diabetes and chronic inflammation of the thyroid gland.

New targets for therapy

The underlying molecular mechanisms that promote autoimmune diseases are multilayered and complex. Now, scientists at the Julius Maximilians University of Würzburg (JMU) have succeeded in deciphering new details of these processes.

Their work support the notion that excessive consumption of glucose directly promotes the pathogenic functions of certain cells of the immune system and that, conversely, that a calorie-reduced diet can have a beneficial effect on immune diseases.

Based on these findings, they also identified new targets for therapeutic interventions: A specific blockade of glucose-depended metabolic processes in these immune cells can suppress excessive immune reactions.

Dr. Martin Väth is responsible for the study, which has now been published in the journal Cell Metabolism. He is a junior research group leader at the Institute of Systems Immunology—a Max Planck research group under the umbrella of JMU that focuses on the interplay of the immune system with the organism. Collaborators from Amsterdam, Berlin, Freiburg and Leuven were also involved in this study.

Glucose transporter with a side job

Martin Väth explains that “immune cells need large amounts of sugar in the form of glucose to perform their tasks. With the help of specialized transporters at their cell membrane, they can take up glucose from the environment.”

Together with his team, Väth has showed that a specific glucose transporter—scientifically named GLUT3—fulfills additional metabolic functions in T cells besides the generating energy from sugar.

In their study, the scientists focused on a group of cells of the immune system that have not been known for very long: T helper cells of type 17, also called Th17 lymphocytes, which play an important role in regulating (auto-) inflammatory processes.

“These Th17 cells express lots of GLUT3 protein on their cell surface,” Väth explains. "Once taken up, glucose is readily converted to citric acid in the mitochondria before it is metabolized into acetyl-coenzyme A (acetyl-CoA) in the cytoplasm. Acetyl-CoA is involved in numerous metabolic processes, including the biosynthesis of lipids."

However, acetyl-CoA fulfills additional functions in inflammatory Th17 cells. Väth and his team showed that this metabolic intermediate can also regulate the activity of various gene segments. Thus, glucose consumption has a direct influence on the activity of proinflammatory genes.

According to the researchers, theses new findings pave the way for the development of targeted therapy of autoimmune diseases. For example, blocking GLUT3-dependent synthesis of acetyl-CoA by the dietary supplement hydroxycitrate, which is used to treat obesity, can mitigate the pathogenic functions of Th17 cells and reduce inflammatory-pathological processes.

The so-called “metabolic reprogramming” of T cells opens new possibilities to treat autoimmune diseases without curtailing protective immune cell functions.

How Sugar Promotes Inflammation - Neuroscience News

Excessive glucose consumption directly promotes the pathological function of certain cells within the immune system. Calorie-reduced diets can have beneficial effects on the immune system and have autoimmune diseases.

neurosciencenews.com

 

[mr peabody]

Therapeutic potential of 5-MeO for cancer "very promising"

by Dr. Attila Szabo | Frontiers In Imunology | 14 Jul 2015

Research on the therapeutic potential of 5-MeO for cancer is still in the early stages, but the few studies that have been done are very promising. It has been shown to exert powerful anti-cancer and anti-inflammatory effects through the modulation of innate and adaptive immune processes. Its regulatory effect on the sigma-1 receptor, which plays a significant role in cancer, is especially interesting.

Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-kB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes.

This emerging field also offers promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies.

In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine, and 3,4-methylenedioxy-methamphetamine will be discussed from a perspective of molecular immunology and pharmacology.

Special attention is given to the functional interaction of serotonin and sigma-1 receptors and their cross-talk with toll-like and RIG-I-like pattern-recognition receptor-mediated signaling. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer’s disease.

Since both NF-kB and type I IFN signaling contribute to the transcriptional regulation of genes that are involved in cellular proliferation and survival, and many psychedelics exhibit in vitro anti-cancer potential through 5-HTRs, these compounds could be promising candidates in novel therapies of cancer.

Thus, as a target for future pharmacological investigations, DMT emerges as a potent and promising candidate in novel therapies of peripheral and CNS autoimmune diseases (such as Multiple Sclerosis or Amyotrophic Lateral Sclerosis) and cancer.

Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500993/​

 

[mr peabody]

Researchers unlock the profound anti-inflammatory properties of cannabis*

by Mark Taylor | Benzinga | Aug 23 2019

A new study deciphers for the first time the cannabis plant's biological blueprint for producing two molecules with anti-inflammatory properties.

That study, which is published in the August 2019 issue of the journal Phytochemistry delineates for the first time the biosynthesis pathway outside of the actual cannabis sativa plant that allows reproduction of the molecules cannflavin A and cannflavin B.

Those cannflavins belong to the class of plant flavonoids, plant chemicals found in almost all fruits and vegetables, known as flavones, which occur in several plant lineages.

The study shows the medicinal versatility of the cannabis plant: Beyond the intoxicating ingredient THC and therapeutic oils that often contain cannabidiol (CBD), there exist many other specialized metabolites requiring further research.

The researchers at Guelph University in Ontario, Canada, unlocked the blueprint for producing the cannflavins, which were discovered in a 1985 study and were found to display “potent anti-inflammatory activity in various animal cell models.”

The new information in the Phytochemistry study opens a pathway to figure how to engineer plant metabolism to make medicine from the cannflavin A and B enzymes.

Tariq Ahktar, lead author and assistant professor of plant biochemistry at Guelph's Department of Molecular and Cellular Biology, told Weedmaps News that “for almost 30 years nobody touched these molecules or worked extensively on them. We thought it was a good time to look at these very promising molecules more closely.”

Ahktar said his laboratory utilizes plant chemistry and genomics to determine how plants produce certain molecules and compounds that have medicinal or industrial uses.

He said the cannaflavins A and B were discovered in the United Kingdom more than 30 years ago by researcher Marilyn Barrett. Her study also introduced the name cannflavin. Barrett's research showed that cannflavins A and B have nearly 30 times the power of aspirin to inhibit inflammation in cells.

Yet that discovery is just the beginning. Ahktar explained that the two cannflavins are present in cannabis in very low amounts.

“So if you want to gain the anti-inflammatory benefits, you would have to consume copious amounts of cannabis, which is both unlikely and impractical,” he said, "necessitating the need to reproduce the molecules outside of the cannabis plant."

He said cannflavins are “definitely encouraging news” for people suffering from acute and chronic pain, who have few effective alternatives to opioids, which work by blocking the brain's pain receptors. These cannflavins appear to take a different path by attacking cells that encourage inflammation, a primary cause of much pain.

Ahktar said that for decades American and Canadian researchers have been unable to research the medicinal properties of cannabis because of prohibitions against the cultivation and sale of the plant, still considered illegal by the U.S. federal government. Ahktar said his team has demonstrated a biochemical pathway for commercial producers to allow the production of cannflavins A and B from yeast, bacteria, plants, or other means.

“That way you don't have to grow huge fields of cannabis to obtain the benefits,” he said, noting that the Guelph researchers have patented the genes and licensed their research to Toronto-based Anahit International Corp., to biosynthesize those molecules.

The ability to “hack” other plants or microorganisms to produce their medicinal compounds offers great potential benefits to science and industry. Dr. Jeff Chen, Director of the University of California, Los Angeles (UCLA) Cannabis Research Initiative, spoke at the July 2019 Microscopes and Machines conference in Los Angeles about using biosynthesis as an alternative that is more scalable, consistent and continuous than plant farming to produce cannabinoids and other beneficial compounds.

Chen cautioned that science has a long way to go to find the most efficient method of producing the cannabinoids and other beneficial compounds. Patients, however, haven't been waiting.

Ahktar said he spoke with many patients who used cannabis successfully to treat a range of conditions and swore it improved their pain levels and reduced inflammation.

“Now that we have a mechanism for reproducing this, we can start producing it and performing side by side comparisons with existing pain relievers and test their relative efficacy,” he said.

The study comes amid an ongoing opioid crisis in the United States. According to the U.S. Centers for Disease Control and Prevention (CDC), U.S. healthcare providers prescribed more than 214 million prescriptions for opioid pain in 2016, with an estimated 11 million people misusing prescription opioids that year. More than two-thirds of the 63,632 drug overdose deaths in 2016 involved prescription or illicit opioids. From 1999 to 2017, almost 218,000 people died in the United States from overdoses related to prescription opioids.

Gregory Gerdeman, chief scientific officer for the St. Petersburg, Florida-based medicinal cannabis cultivator 3 Boys Farm and a neuroscientist who has studied the effects of cannabis on the brain for 22 years, said the takeaway from the study is that herbal cannabis takes a multifaceted approach to combating inflammation and that it may offer a greater therapeutic value than the THC or CBD alone.

“It also may point to potential drug development,” Gerdeman said. “I believe in herbal cannabis as a medicine. I think it already offers a very promising strategy for replacing opioids. We now know how the plant synthesizes cannflavins A and B and we're living in an age in which pharmaceutical companies are creating genetically modified cannabis that could allow drug factories to reproduce these molecules outside of the cannabis plant. This study shows how the science of cannabis as a medicine is being taken seriously today in the medical and pharmaceutical worlds. It was not that way in 1997 or even in 2007.”

He called cannabis the “queen of medicinal plants,” adding, “We have many secrets yet to learn from her.”

Gerdeman cautioned, however, that the Canadian study did not explore the precise role of cannflavins A and B in fighting inflammation or the molecules' potential therapeutic effects.

“The assertion from a 30-year-old study that these cannflavins offer anti-inflammatory effects 30 times the strength of aspirin requires much more research and study to validate. It would be premature to say that using isolated cannflavins as a drug would be desirable or without safety concerns.”

*From the article here :

Researchers Unlock What Gives Cannabis its Anti-Inflammatory Qualities

A new study deciphers for the first time the cannabis plant's biological blueprint for producing two molecules thought to have anti-inflammatory properties, a discovery that could pave the way for...

news.weedmaps.com

 

[mr peabody]

D’Or Institute

Inflammation, neurodegeneration and 5-MeO-DMT

D’Or Institute for Research and Education | Neuroscience News | 9 Oct 2017

A new study reveals psychedelic substances may have a neuroprotective role when it comes to inflammation. Researchers also report psychedelics can alter signaling pathways associated with neuroplasticity. .

A new study has identified changes in signaling pathways associated with neural plasticity, inflammation and neurodegeneration triggered by a compound from 5-MeO-DMT.

"For the first time we could describe psychedelic related changes in the molecular functioning of human neural tissue," said Stevens Rehen, study leader, Professor of Federal University of Rio de Janeiro (UFRJ) and Head of Research at D'Or Institute for Research and Education (IDOR).

Though recent studies have demonstrated that psychedelic substances, such as LSD, MDMA and ayahuasca, hold therapeutic potential with possible anti-inflammatory and antidepressant effects, the lack of appropriate biological tools has been shown as a critical limitation for the identification of molecular pathways targeted by psychedelics in the brain.

In order to unveil the effects of 5-MeO-DMT, Vanja Dakic (IDOR) and Juliana Minardi Nascimento (IDOR) have exposed cerebral organoids, which are 3D cultures of neural cells that mimic a developing human brain, to a single dose of the psychedelic.

By employing mass spectrometry-based proteomics to analyze cerebral organoids, they found that 5-MeO-DMT altered the expression of nearly one thousand proteins. Then, they mapped which proteins were impacted by the psychedelic substance and their role in the human brain.

Researchers found that proteins important for synaptic formation and maintenance were upregulated, among them, proteins related to cellular mechanisms of learning and memory, key components of brain functioning.

On the other hand, proteins involved in inflammation, degeneration and brain lesion were downregulated, suggesting a potential neuroprotective role for the psychedelic substance.

"Results suggest that classic psychedelics are powerful inducers of neuroplasticity, a tool of psychobiological transformation that we know very little about," said Sidarta Ribeiro, Director of the Brain Institute of Federal University of Rio Grande do Norte (UFRN) and coauthor of the study.

http://neurosciencenews.com/psychede...inibrain-7690/​

 

[mr peabody]

Tryptamines: Endogenous regulators of inflammation and tumor immunity?*

by Attila Szabo | Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary | 14 Jul 2015

Tryptamines are members of a large family of monoamine alkaloids that are widespread in nature and abundant in all the three Kingdoms of life (plants, fungi, and animals). Their main feature is a common indole ring, a backbone that is structurally related to the amino acid tryptophan. This tryptamine backbone designates many biologically active compounds, such as psychedelics and neurotransmitters (91). To date, our knowledge about the immunomodulatory capacity of tryptamines is quite scarce. DMT is the only member of the family that has been investigated so far.

DMT is related to the neurotransmitter serotonin, the hormone melatonin, and other psychedelic tryptamines, such as bufotenin and psilocin. It is a naturally occurring indole alkaloid that is ubiquitous in plants, such as Diplopterys cabrerana and Psychotria viridis, which are used for the preparation of sacramental psychoactive brews including yage and ayahuasca. In addition to its ubiquitous presence in plant species, DMT has also been detected in animal tissues and is considered to be an endogenous trace amine. The milestones of DMT research were laid down by Szara and Axelrod who reported first the psychoactive effects and occurrence of this compound in the human brain. This led to the hypothesis that DMT is an endogenous hallucinogen, and later it was proposed to be a neurotransmitter or neuromodulator. DMT was shown to act as an agonist at several serotonin receptors including 5-HT1A, 5-HT2A, and 5-HT2C as well as at sigmar-1.

The vast majority of the initial research into the reasons for the presence of psychoactive tryptamines in the human body has sought their involvement in mental illness. Until now, very little has been known about the function of DMT in cellular and general physiological processes, and the emphasis of research mostly aimed the understanding of its psychedelic properties. Recently, we and others demonstrated that DMT has the capability to modulate immune responses in in vitro human primary cell cultures. In these studies, DMT was shown to act as a non-competitive inhibitor of indoleamine 2,3-dioxygenase (IDO) and as a strong inducer of anti-tumor cytotoxic activity in the co-cultures of human PBMCs and a glioma cell line. Furthermore, DMT and its analog 5-MeO-DMT were found to exert potent anti-inflammatory activity through the sigmar-1 in human monocyte-derived dendritic cell (moDC) cultures. MoDCs are key cell types of the mammalian immune system connecting and orchestrating innate and adaptive immune responses as professional antigen-presenting cells (APCs). DMT or 5-MeO-DMT treatment of LPS, polyI:C or pathogen-activated human primary moDCs resulted in a significant inhibition of the secretion of the inflammatory cytokines, IL-1β, IL-6, TNFα, and the chemokine CXCL8/IL-8. In contrast, secreted levels of the anti-inflammatory IL-10 increased markedly following in vitro DMT/5-MeO-DMT administration. DMT and 5-MeO-DMT exhibited the effective inhibitory potential at the level of adaptive immune responses (T helper cell 1 and 17 priming by moDCs), as well. These are in line with previous findings showing the immunomodulatory potential of ayahuasca in humans mostly affecting the number and ratio of lymphocyte subpopulations. Notably, the number of circulating NK cells, a cell type involved in anti-viral and anti-cancer immune responses, increased significantly. The anti-cancer activity of ayahuasca has already been reviewed in a paper by Schenberg. However, it is important to keep in mind that ayahuasca is a complex decoction that, besides DMT, contains several other components according to the admixture plants used in the making process. Furthermore, ayahuasca can be administered in various ways (single-time, long-term, etc.), thus one should be particularly careful with the study design and interpretation of the data. Nevertheless, ayahuasca consumption in a highly controlled clinical setting emerges as a very promising model for investigating the possible immunomodulatory effects of DMT in humans. Importantly, it is possible that the observed anti-inflammatory and immunosuppressive effects may counteract with the anti-cancer activity, therefore further investigations are needed to elucidate the complex in vivo consequences of DMT administration.

The mentioned studies demonstrate and propose new biological roles for DMT, which may act as a systemic endogenous regulator of inflammation and immune homeostasis. According to these new results, DMT and 5-MeO-DMT possess the capability to inhibit the polarization of human moDC-primed CD4+ T helper cells toward the inflammatory Th1 and Th17 effector subtypes in inflammatory settings. This is of particular importance, since Th1 and Th17 cells and the cytokines they secrete are key players in the etiology and symptomatology of many chronic inflammatory and autoimmune diseases of the CNS and other tissues. Moreover, the mobilization of innate immune mechanisms is also well established in many psychiatric and neurological disorders. Thus, as a target for future pharmacological investigations, DMT emerges as a potent and promising candidate in novel therapies of peripheral and CNS autoimmune diseases (such as multiple sclerosis or amyotrophic lateral sclerosis) and cancer.

*From the article here :

Frontiers | Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities

Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory...

www.frontiersin.org

 

[mr peabody]

UMass Medical School researchers explain why cannabis may relieve intestinal inflammation*

by Jim Fessenden | UMass Medical School Communications | 13 Aug 2018

Reports from cannabis users that the drug reduces the symptoms of inflammatory bowel disease (IBD) may finally be explained by new research from UMass Medical School and the University of Bath showing that endocannabinoids help control and prevent intestinal inflammation in mice.

This is the first time scientists have reported a biological mechanism to explain why some users have reported beneficial effects from cannabis on inflammatory conditions such as ulcerative colitis and Crohn’s disease. Researchers hope their findings will lead to the development of drugs and treatments for gut disorders, which affect millions of people around the world and are caused when the body’s immune defenses mistakenly attack the lining of the intestine.

The findings appear in the Journal of Clinical Investigation.

“There’s been a lot of anecdotal evidence about the benefits of cannabis, but not a lot of science to back it up,” said Beth McCormick, Director of the UMass Center for Microbiome Research. “For the first time, we have an understanding of the molecules involved in the process and how endocannabinoids and cannabinoids control inflammation. This gives clinical researchers a new drug target to explore to treat patients who suffer from inflammatory bowel diseases, and perhaps other diseases, as well.”

The researchers discovered that gut inflammation is regulated by two important processes that are constantly in flux and responding to changing conditions in the intestinal environment. The first process, identified in previous scientific research, promotes an aggressive immune response in the gut that destroys dangerous pathogens, but which can also damage the lining of the intestine when immune cells attack indiscriminately.

The second pathway, turns off the inflammation response via special molecules transported across the epithelial cells lining the gut by the same process already known to remove toxins from these cells in the intestine cavity. Crucially, this response requires a naturally-produced molecule called an endocannabinoid, which is very similar to cannabinoid molecules found in cannabis.

If the endocannabinoid isn’t present, inflammation isn’t kept in balance and it can run unchecked, as the body’s immune cells attack the intestinal lining.

Dr. McCormick and colleagues believe that because cannabis use introduces cannabinoids into the body, these molecules could help relieve gut inflammation, as the naturally produced endocannabinoids normally would.

“We need to be clear that while this is a plausible explanation for why users have reported cannabis relieves symptoms of IBD, we have so far only evaluated this in mice and have not proven this experimentally in humans. We hope that these findings will help us develop new ways to treat bowel diseases in humans” said Randy Mrsny, PhD, professor of pharmacy and pharmacology at the University of Bath.

*From the article here :
https://www.umassmed.edu/news/news-...cannabis-may-relieve-intestinal-inflammation/​

 

[mr peabody]

DMT and 5-MeO-DMT found to modulate inflammatory responses through the sigma-1 receptor

Attila Szabo, Attila Kovacs, Ede Frecska, Eva Rajnavolgyi

The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands, DMT, its derivative 5-MeO-DMT and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cells (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses.

Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1b, IL-6, TNFa and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.

Introduction

The term sigma receptor dates back historically to the sigma/ opioid receptor described by Martin et al. and reported to mediate the psychotropic effects of N-allylnormetazocine (NANM). It was originally thought to be an opioid receptor due to its modulation by NANM that could be antagonized by naloxone, a universal opioid antagonist. Later, Su and colleagues clarified the pharmacological features of the ligand-binding site and the name was changed to ‘sigma receptor’ differentiating it from the sigma/opioid receptor. According to its tissue expression profile and ligand selectivity the receptor was subsequently classified to the sigma-1 and sigma-2 receptor subtypes (sigmar-1/2). In the last two decades several clinical studies demonstrated the importance of sigmar-1 in many diseases ranging from cancer, pain and addiction to different psychiatric and neurological disorders among them Major depression, Alzheimer’s disease, schizophrenia, and stroke.

Early studies showed that sigmar-1 is expressed not only in distinct regions of the CNS but also in immune cells. It was shown to regulate cell differentiation and survival by acting as a chaperone at the mitochondria-associated endoplasmic reticulum membrane. Murine studies also demonstrated that the specific activation of sigmar-1 resulted in immunosuppression, and in vivo decreased lymphocyte activation and proliferation. Sigma-1 receptor ligands possess potent immuno-regulatory properties via increasing the secretion level of anti-inflammatory IL-10, and suppressing IFNc and GM-CSF expression. These important studies showed that sigmar-1 may cause significant alterations in immune functions.

The endogenous ligands for sigmar-1 involve neurosteroids, dehydro-epiandrosterone (DHEA), and naturally occuring indole alkaloids/tryptamines, such as DMT and its closely related analogue 5-MeO-DMT. Psychedelic indole alkaloids are widespread in nature and abundant in plants, which are used in preparation of sacramental psychoactive decoctions such as yage and ayahuasca. DMT and 5-MeO-DMT have also been detected in animal tissues; furthermore, DMT is considered as an endogenous trace amine neurotransmitter that regulates brain physiology. It has recently been shown that DMT is a natural ligand for sigmar-1, and its administration was reported to influence the number of circulating lymphocytes in humans, but the exact mechanism has not been uncovered yet. In the light of these findings it is tempting to speculate that DMT and 5-MeO-DMT may have impact on inflammatory responses through sigmar-1.

In this study we aimed to investigate the effects of DMT and 5-MeO-DMT-mediated activation of sigmar-1 on human primary moDC functions under inflammatory conditions as compared to resting state. To our best knowledge this is the first study reporting that dimethyltryptamines are potent anti-inflammatory agents, which have the capacity to modulate the functions of moDCs in a sigmar-1-dependent manner. Our results envision that dimethyltryptamines targeted to the sigmar-1 receptor could emerge as promising candidates for future pharmacological therapies in chronic inflammatory and autoimmune conditions of the CNS or peripheral tissues. We also propose a new biological role for DMT, which, through the sigmar-1 of myeloid immune cells, may act as an endogenous regulator of inflammation and immune homeostasis.

Discussion

Psychedelic trypamines are members of the indole alkaloid family, the largest and most common class of alkaloids in the Animal and Plant Kingdoms. DMT and bufotenine, the metabolic product of 5-MeO-DMT in mammals, have been detected in animal and human blood, urine, cerebrospinal fluid, brain, intestine and many other tissues suggesting that these compounds may have important biological roles other than their psychotropic and neuromodulatory properties.

The orphan receptor sigmar-1 has been shown to regulate many physiological processes inculding cell survival and proliferation. The expression of sigma receptors is not limited to the brain as high level expression was detected in mammalian liver, kidney, gut and other tissues as well. Sigmar-1 has also been detected in immune cells mediating strong immunosuppressive and anti-inflammatory effects. It has recently been reported that DMT is an endogenous ligand for sigmar-1, and its agonistic activity may be expanded to analogues, such as the methoxy derivative 5-MeO-DMT. However, very little is known about the physiological functions of dimethyltryptamines in human and the emphasis of contemporary research is mostly related to understanding its psychedelic properties and to our best knowledge, the biological effects of DMT via sigmar-1 has not been investigated yet. In this study we adressed the question whether sigmar-1 is expressed in human primary myeloid cells, and if so, what is its functional role in human physiology. According to our results, sigmar-1 is expressed in human monocytes and its expression is increasing during the differentiation process to macrophages and dendritic cells.

These results demonstrated for the fist time that DMT and 5-MeO-DMT have the capability to inhibit the polarization of human moDC-primed CD4+T helper cells towards inflammatory Th1 and Th17 effector lymphocytes in infectious/inflammatory settings. This is of particular importance, since Th1 and Th17 cells and the cytokines they secrete are key players in the etiology and symptomatology of many chronic inflammatory and autoimmune diseases of the CNS and other tissues. Moreover, the mobilization of innate immune mechanisms is also well established in many psychiatric and neurological disorders. In neuropsychiatric research it is an increasingly accepted hypothesis that a number of diseases affecting large populations, such as Alzheimer’s, Parkinson’s disease, Major depression are caused by chronic inflammation of the central nervous system. High-resolution whole genome-wide association studies found significant correlations between gene polymorphisms of innate immune receptors and the frequency of late onset Alzheimer’s disease (AD). Since blood-derived monocytes were shown to be able to translocate to the CNS, our results could expand the role of moDCs to a more global context by suggesting their regulatory role under autoimmune or infectious inflammatory conditions in the brain.

We conclude that the function of dimethyltryptamines may extend the central nervous system activity and may play a more universal role in immune regulation. Here we demonstrate for the first time that DMT and 5-MeO-DMT have potent immunomodulatory effects on the functional activities of human dendritic cells operating through the sigma-1 receptor. We also show that DMT-mediated sigmar-1 activation can interfere with both innate and adaptive immune responses. On the one hand, it strongly decreases the levels of pro-inflammatory cytokines and chemokines such as IL-1b, IL-6, TNFa and IL8, while upregulates the production of the anti-inflammatory cytokine IL-10. On the other hand, DMT and 5-MeO-DMT pre-treatment of pathogen-activated moDCs abolishes their capacity to initiate adaptive immune responses mediated by inflammatory Th1 and Th17 cells. These findings greatly expand the biological role of dimethyltryptamines, which may act not only as neuromodulators or psychedelics, but also as important regulators of both innate and adaptive immunity. Thus, the DMT-sigmar-1 axis emerges as a promising candidate for novel pharmacotherapies of chronic inflammatory and autoimmune diseases.

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0106533&type=printable​

 

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Psychedelics and Immunomodulation

by Dr. Attila Szabo | Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

Classical psychedelics are psychoactive substances that have been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation and cell survival by activating NF-κB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have been shown to play crucial roles in numerous immunological processes. This emerging field offers promising treatment modalities for various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer.

Scientific investigations concerning the possible immunological effects of psychedelics date back to the 1970s, but the biomedical Renaissance of psychedelic research began only a decade ago. An important antecedent was the identification of neuro-immune communication in mammals that has greatly expanded the domain of physiological activity of psychoactive substances. Since immune cells were found to also express many types of neurotransmitter receptors, an entirely new aspect was added to the biomedical paradigm. Early neuroimmunologists considered the immune and nervous systems as separate parts, but a crucial conceptual leap led to the emergence of the modern approach. This new concept represents neuroimmune communication as an integrated physiological entity, with the immune and nervous systems being its two aspects.

In the last two decades, several neurotransmitter receptors involved in the pharmacology of psychedelics have been identified as being crucial in many immunological processes pointing to novel therapeutic avenues. Classical psychedelics have been shown to exert strong anti-cancer and anti-inflammatory effects through the modulation of innate and adaptive immune processes. Two models have been proposed to address the possible biochemical dynamics of these interactions. On the one hand, (i) regulation may occur through the alteration of the cytokine-pattern of activated cells. The anti-inflammatory cytokines, IL-10 and TGFβ, and pro-inflammatory cytokines, TNFα and IFNγ, seem to be key players in this regulation. On the other hand, (ii) a complex intracellular cross-talk of pattern-recognition receptors (PRRs), serotonin, and sigma-1 receptors might be involved in the immunomodulatory process. While PRRs were shown to be crucial for innate and adaptive host defense, their inappropriate activation has been associated with autoimmunity and inflammatory diseases. Psychedelics, by modulating the activity of 5-HT1, 5-HT2, and sigmar-1 receptors, are potent anti-inflammatory agents.

https://pdfs.semanticscholar.org/0967/3ff5caa5ddaa6f2abcbabc161f8ea779ba61.pdf​

 

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Psychedelics modulate innate and adaptive inflammatory responses through the Sigma-1R receptor

Attila Szabo, Attila Kovacs, Ede Frecska, Eva Rajnavolgyi

The orphan receptor Sigma-1R is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models.

Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via Sigmar-1R that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the Sigma-1R receptor.

http://publichealthwell.ie/journal/p..._complete=true​

 

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Psychedelics as anti-inflammatory agents

by Shane O'Connor | Psychedelic Science Review | 14 Nov 2019

A look into the less discussed therapeutic aspect of psychedelics: the anti-inflammatory effect.

In recent years, compounds that act as agonists (aka activators) at the serotonin 2A receptor (5-HT2A) have emerged as a prominent therapy for several disorders including depression, obsessive-compulsive disorder (OCD), anxiety, and addiction. The recently discovered therapeutic effect of psychedelic agonists has led to a reevaluation in the way these compounds are perceived in the medical sphere and amongst the general population at large.

One recently identified therapeutic characteristic of psychedelics that holds notable promise is their anti-inflammatory effect. This article explores the anti-inflammatory effect of psychedelics – thought to be mediated through 5-HT2A activation – and how this effect pertains to disorders of the central nervous system (CNS) and other, more recently identified indications.

Inflammation and depression

Inflammation is generally defined as an endogenous repair or host defense mechanism in response to a biological or physical insult. The inflammatory response aims to eliminate invading agents and facilitate healing. This response not only initiates an acute defense against damaging agents but also contributes to the renewal of normal tissue functioning following a harmful occurrence. Within minutes to hours of a biological insult, the body initiates an innate immune response. This response acts by recruiting immune cells to injury sites and promotes inflammation through cytokine release. Some of these cytokines include Tumour Necrosis Factor – Alpha (TNF-α) and Interleukin 6 (IL-6).

Researchers have established that inflammation plays a vital role in the pathophysiology underlying psychiatric disorders such as depression. For example, the introduction of the pro-inflammatory cytokines TNF-α and IL-1β into healthy animal subjects generates behaviors similar to social withdrawal. A meta-analysis examining the connection between inflammation and response to depression treatment found that antidepressants lower IL-6 levels, regardless of treatment outcome. Furthermore, the same analysis found that increased TNF-α levels are associated with treatment resistance and that treatment non-responders display higher baseline inflammation levels.

Psychedelics and the 5-HT2A receptor

Where do psychedelics fit into this inflammation scenario? Several psychedelic compounds such as psilocybin, initiate the psychedelic state through the activation of 5-HT2A. Activation of this receptor is thought to acutely reset resting-state functional connectivity (RFSC) to healthy networks to rapidly alleviate depression.

However, some research groups posit that the long-lasting effects of psychedelic-assisted therapy are a result of reduced neuroinflammation. 5-HT2A activation is thought to mediate this reduction in neuroinflammation. However, to build a case for this claim, the focus must shift from the CNS to more peripheral locals.

Peripheral Insights

While HT2A is found in high densities extensively throughout the CNS, it is also present in peripheral tissues. These include but are not limited to, endothelial, muscle, endocrine, and immune tissues. The selective 5-HT2A agonist and psychedelic compound (R)-2,4-dimethoxy-4-iodoamphetamine ((R)-DOI) demonstrated a potent anti-inflammatory effect when administered on rat aortic smooth muscle cells. Several 5-HT2A agonists have demonstrated significant anti-inflammatory characteristics, including lysergic acid diethylamide (LSD). However, (R)-DOI was effective at levels in the low picomolar range (IC50 concentrations 10–20 pM).

This low IC50 means that (R)-DOI has an anti-inflammatory effect at doses far below that needed to produce behavioral effects. Furthermore, (R)-DOI was effective in significantly attenuating TNF-α induced inflammation and reduced levels of inflammatory cytokine IL-6. These results may provide an insight into the long-lasting antidepressant effects observed in psychedelic-assisted therapy, as dysregulated TNF-α and IL-6 are associated with the onset and symptomatology of depression (Figure 1).

Figure 1 - Studies have shown that increased levels of inflammatory cytokines contribute to the development
of depression. These effects are due to disturbed neuronal synaptic plasticity and disturbances in the levels of
different neurotrophic factors, in particular, BDNF.

Other indications for psychedelics and inflammation

Interestingly, one biotech company has identified a potential therapeutic effect of (R)-DOI for indications outside of the realm of neuropsychiatric disorders, but still involving inflammatory mechanisms.

Eleusis, a clinical-stage life science company, recently funded a study that examined the effect of (R)-DOI in treating cardiovascular disease. Leading the study was Dr. Charles Nichols, son of professor emeritus of pharmacology at Purdue University, David Nichols. Using (R)-DOI, Nichols and his team observed a reduction in aorta inflammation and a decrease in overall and HDL cholesterol levels. The vascular study showed physiological without any psychological effects (this is important because mice given a psychedelic can sometimes show behavior consistent with psychosis).

Nichols told Endpoints news in a recent interview, “Translated into the clinic in humans, it would be as if someone was obese, had diabetes, had high cholesterol, and was able to take a low dose of this drug at a sub-behavioral level and really treat several different aspects of the complications of being obese.” He went on to add that the study was translatable to a clinical trial, and was optimistic of drug development within 10 to 20 years.

Eleusis has also begun examining the potential therapeutic benefits of (R)-DOI in the treatment of asthma. Early studies demonstrated the prevention of inflammation associated with acute allergic asthma in a mouse model. Treatment with (R)-DOI significantly reduced pulmonary inflammation and improved airway function.

Summary of psychedelics and inflammation

Science has only relatively recently begun understanding the significance of inflammation in the pathophysiology of neuropsychiatric disorders. The same is true for the role of 5-HT2A agonists in treating the same class of disorders. Much of the current research concerning the therapeutic action of 5HT2A agonists centers around disorders of the CNS (e.g., depression), with short-term amelioration of symptoms thought to stem from changes in the functional connectivity between specific brain regions.

The recent literature outlined in this article posits that the long-term changes observed following psychedelic-assisted therapy may be a result of the anti-inflammatory actions of the compounds. Moreover, this anti-inflammatory effect may be exploited to treat entirely new indications, such as asthma and cardiovascular diseases. However, the reader must recognize that much of the data presented here are still in very early preclinical stages. Nevertheless, it is not unreasonable to think that in 10-20 years, the anti-inflammatory potential of psychedelics will be unlocked, allowing for their use in a multitude of age-related diseases.

Psychedelics as Anti-Inflammatory Agents

A look into the less discussed therapeutic aspect of psychedelics: the anti-inflammatory effect.

psychedelicreview.com

 

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Psychedelic (R)-DOI stymies Asthma development*

Genetic Engineering & Biotechnology News | 10 Feb 2015

Scientists at the Louisiana State University Health New Orleans School of Medicine have found that the psychedelic drug, (R)-DOI, prevents the development of allergic asthma in a mouse model. The effects are potent and effective at a concentration 50-100 times less than would influence behavior. The research (“Serotonin 5-HT2 receptor activation prevents allergic asthma in a mouse model”) appears in the American Journal of Physiology-Lung Cellular and Molecular Physiology.

The team looked at the effects of (R)-DOI, a serotonin 5-hydroxytryptamine (5-HT)2A receptor agonist which contains serotonin, a molecule known to be tied to inflammation, but not asthma.

“We have previously established that activation of serotonin 5-hydroxytryptamine (5-HT)2A receptors has potent anti-inflammatory activity in primary cultures of vascular tissues and in the whole animal in vasculature and gut tissues,” the authors wrote in the American Journal of Physiology - Lung Cellular and Molecular Physiology.

These drugs, while their neurological effects have been researched extensively, identified its role in asthma development—a discovery, lead researcher Charles Nichols, PhD, an Associate Professor of Pharmacology and Experimental Therapeutics at the LSU Health New Orleans School of Medicine, believes could pave the way for breakthrough inhalers and medications.

“These drugs are known only for their effects in the brain,” notes Charles Nichols, Ph.D., associate professor of pharmacology and experimental therapeutics. “What we have demonstrated for the first time is that they are also effective in treating physiological diseases outside of the brain, a completely new and exciting role for this class of drug. Not only is this a significant breakthrough in the field of study of serotonin and psychiatric drugs, but it is a breakthrough in the field of asthma as well. We have identified an entirely new anti-inflammatory mechanism for the treatment of asthma in the clinic that could someday be administered in an inhaler or a daily pill.”

Previously, Dr. Nichols' lab found that activation of the serotonin receptor 5-HT2A with psychedelics produces powerful anti-inflammatory activity in tissues of the blood vessels and gut. Building on that, the researchers identified a drug they believed would be effective against the inflammatory disease asthma. They found that administration of (R)-DOI blocked pulmonary inflammation, mucus hyperproduction, airways hyperresponsiveness, and turned off certain key genes in the lung involved in immune response that together blocked the development of allergic asthma in their mouse model.

“Our results highlight a likely role of the 5-HT2 receptors in allergic airways disease and suggest that 5-HT2 receptor agonists may represent an effective and novel small molecule-based therapy for asthma,” write the investigators.

According to the National Heart, Lung, and Blood Institute, asthma is a chronic lung disease that inflames and narrows the airways. Asthma causes recurring periods of wheezing, chest tightness, shortness of breath, and coughing. Asthma affects people of all ages, but it most often starts during childhood. In the U.S., more than 25 million people are known to have asthma.

“Overall, given the recent interest and success using these drugs for psychiatric therapies in the clinic, our research at LSU Health New Orleans is the first to show that they have potential to heal the body as well as the mind,” notes Dr. Nichols.

*From the article here :

Mind-altering Drug Stymies Asthma Development

Psychedelic drug prevents the development of allergic asthma in a mouse model.

www.genengnews.com

 

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The impact of psychedelics on inflammation

by Alexander Lekhtman | LUCID News | 8 Jul 2020

This article accompanies “Eleusis Draws on Research Into Psychedelics To Develop New Medicines for Inflammation,” and details the company’s research on how psychedelic medicines could improve immunity.

A long time researcher of psychedelic substances is on the forefront of investigating how these materials may be used to reduce inflammation and support the immune system.

These investigations may provide new opportunities for scientists to develop more effective treatments for diseases impacted by inflammation such as Alzheimer’s disease and cancer.

Charles Nichols, professor of pharmacology at LSU, is examining how the substituted amphetamine 2,5-Dimethoxy-4-iodoamphetamine, also known as DOI, affects immune function.

The psychedelic effects of DOI have been compared to LSD, but unlike that material, it is not a Schedule 1 substance in the U.S.

First synthesized by Alexander Shulgin, a radioactive iodine-125 form of DOI for PET imaging was first developed in the lab of Nichol’s father, David E. Nichols.

Charles Nichols and his research team found that by triggering the serotonin receptor 5-HT2A, DOI affects the tumor necrosis factor, a cell signaling protein or cytokine that regulates the immune cells.

Tumor necrosis factor, also known as TNF-alpha, is involved in systemic inflammation which is implicated in Alzheimer’s disease, cancer and other ailments.

Other substances that trigger the 5-HT2A serotonin receptor, including TCB-2 and LSD, have also been found to inhibit TNF-alpha, with DOI being the most active.

Nichols notes that psychedelic substances that impact serotonin receptors appear to work differently from existing treatments for inflammation. He says that presently available anti-inflammatories take three different forms: NSAIDs like ibuprofen or aspirin, corticosteroids like hydrocortisone, and biologic anti-inflammatories like antibodies.

Nichols says these drugs all have harmful side-effects that may even be fatal, and don’t treat all diseases.

“Psychedelics do not act through any of these mechanisms, but instead very potently prevent inflammation through blockade of specific cellular inflammatory pathways contributing to disease,” says Nichols. “They are not immunosuppressant in nature, and as such are predicted to have less adverse side-effects.”

In addition to triggering serotonin receptors and affecting TNF-alpha, Nicols says that DOI also affects the activity of nuclear factor-kB (NF-kB), a protein that controls cytokine and other inflammatory responses.

“There are profound effects to both prevent and treat pre-existing symptoms of asthma, and vascular inflammation associated with cardiovascular disease that we have published, and are currently working on additional disease models,” says Nichols of his work with NF-kB.

“These are complex inflammatory diseases involving more than TNF-alpha, so we believe that the anti-inflammatory effects are multifaceted and affect multiple pathways in several different tissue types.”

Cautious investigations for a range of possible treatments

Nichols is now the chair of the scientific advisory board for Eleusis Ltd., a London-based life sciences company founded in 2013. Eleusis is sponsoring Nichols’ research into a new substance called ELE-02 which is part of the ELE series of compounds.

Part of the chemical class of substituted phenethylamines, which includes LSD, the ELE compounds also bind to serotonin receptors and trigger an anti-inflammatory response without a psychoactive effect. The ELE compounds are currently being investigated by Eleusis as a possible treatment for eye inflammation.

Does research into the anti-inflammatory properties of psychedelic substances have the potential to develop treatments for diseases like COVID-19? Nichols cautions that there is presently insufficient information to determine if this might be true.

“We have found that psychedelics are not immunosuppressants, and only target subsets of pathways that together are able to treat disease pathology,” says Nichols.

“We have found that psychedelics are not therapeutic for inflammation associated with several disease models. Therefore, the therapeutic potential for psychedelics for a particular inflammatory-related condition will have to be evaluated on a disease-by-disease basis.”

Investigating DMT

Nichols says that investigations into N,N-Dimethyltryptamine, also known as DMT, also shows promise for new treatments. He says that studies show that DMT interacts with the sigma-1 receptor which impacts both the central nervous system and immune cells. "Triggering this receptor has significant impacts on immunity and inflammation," says Nichols.

Attila Szabo, a National Institutes of Health Distinguished Investigator, studies DMT and its derivative, 5-MeO-DMT, both naturally-occurring in the body. He examines how these substances interact with the sigma-1 receptor when stimulated by E. Coli or influenza.

Szabo found that these interactions reduced levels of inflammatory cytokines, while increasing levels of anti-inflammatory proteins. They also reduce activity of T-cells, which regulate inflammation.

Szabo notes that since the endogenous levels of these tryptamines, or those produced inside the body, are quite low in mammals, more research is needed to verify the physiological significance of these findings and how they can be applied to fight disease.

“One of the possible mechanisms is that the levels of endogenous tryptamines can be massively increased at the site of infection or inflammation. due to local cellular stress responses,” says Szabo. "These molecules may achieve concentrations sufficiently high enough to be able to influence immune or inflammatory responses.”

Like Szabo, Nichols is cautious about the need for more research. “I think the jury is still out on sigma-1 receptors,” says Nichols. “Existing investigations with DMT have not been translated, to my knowledge, to any relevant animal models of human inflammatory disease for validation. Certainly more research needs to be performed in this area to better define the potential.”

Impact of mood and motions on immunity

The psychoactive effects of psychedelics may also be relevant to immunity. Psychedelics produce altered states that can affect a person’s mood, emotional, or spiritual health in complex ways.

“It has been well known for years that the environment and experiences of an individual can influence the immune system,” says Nichols. “The immune system is highly complex, and its activity can be modulated by the brain, the gut, the food we eat, etc.”

Nichols points to the hypothalamic–pituitary–adrenal axis or HPA axis, which is a neuroendocrine system. It controls our reactions to stress and regulates many functions including mood, emotion, and the immune system. Studies have shown that MDMA and psilocybin can help alleviate disorders like PTSD, depression and anxiety, which are associated with dysfunction in the HPA axis.

According to Nichols, clinical studies investigating MDMA and psilocybin could also look at their impact on inflammation.

“It’s quite conceivable that MDMA and psilocybin-mediated reductions in stress and anxiety, and normalization of HPA axis function, would result in a strengthened immune system,” says Nichols. “Clinical studies using MDMA and psilocybin that incorporate the measurement of inflammatory biomarkers may address this.”

Researcher Charles Nichols Studies the Impact of Psychedelic Substances on Inflammation - Lucid News

Critical research sponsored by the Eleusis Benefit Corporation could lead to new drugs for Alzeimers and Retinal Disease

www.lucid.news

 

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Will psychedelic drugs replace inhalers to treat Asthma?

The asthma-fighting properties of psychedelics*

Psychedelic Newswire | 21 Aug 2020

The medical community has long been interested in psychedelics for their anti-inflammatory properties, but the stigma associated with these substances, together with the prohibitive laws in force, have made the therapeutic exploitation of psychedelics a difficult undertaking. Recent interest has allowed Eleusis Ltd., a psychedelics company, to investigate the different psychedelics in order to find out which ones have potent anti-inflammatory attributes.

The researchers looked at about 21 psychedelics which target a specific serotonin receptor (5-HT2A). When this receptor is activated, anti-inflammatory effects are observed in asthmatics.

The researchers found that a group of psychedelics called 2C-H had the ability to regulate inflammation without triggering the behavioral effects linked to the intake of psychedelics like LSD.

To understand how the psychedelics work, the Eleusis research team created a rat model instead of using mice as is the norm in the research community. This change was motivated by the realization that mice have the ability to metabolize psychedelics so fast that it becomes difficult to study the anti-inflammatory effects of the substance administered. Rats were chosen because they have a slower rate of metabolizing psychedelics.

The research team found that there was no correlation between how potent a psychedelic is and its anti-inflammatory properties. For example, LSD is a potent psychedelic, but it didn’t exhibit strong anti-inflammatory abilities in the asthmatic rats despite triggering the behavioral attributes which show that someone is under the influence of the substance.

The team concluded that the cellular systems responsible for the behavioral effects of psychedelics are different from those which trigger anti-inflammatory effects.

Eleusis isn’t the only entity studying psychedelics. Johns Hopkins University for instance secured $17m last year to set up a psychedelics research center to investigate these substances’ effects on the brain, mood and learning, and memory. The team at the Johns Hopkins center are also doing research on whether psilocybin can be used to treat Alzheimer’s and other neurological disorders.

Eleusis decided to begin by developing ocular drugs to target the serotonin receptor. This method of administering drugs through the eyes is a desirable one because it allows the patient to get the therapeutic effects of the psychedelic drug without having to experience the behavioral effects that accompany that drug. The company plans to develop additional drugs in the coming future to combat the inflammatory tendencies triggered by other diseases. All that will depend on how the clinical phase of this project pans out.

*From the article here :

Eleusis Sheds Light on the Asthma-Fighting Properties of Psychedelics - PsychedelicNewsWire (PNW)

The medical community has always had keen interest in psychedelics, such as LSD, for their anti-inflammatory properties. However, the stigma associated with these substances, together with the prohibitive laws in force, have made the therapeutic exploitation of psychedelics a difficult...

www.psychedelicnewswire.com

 

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Psychedelic drug 5-MeO-DMT induces rapid changes in inflammatory markers

by Eric Dolan | PsyPost | Dec 15 2019

In addition to reducing symptoms of depression, the psychedelic drug 5-MeO-DMT appears to cause changes in inflammatory biomarkers, according to preliminary research published in the journal Psychopharmacology.

“5-MeO-DMT is a very unique and interesting molecule which certainly deserves further scientific attention,” said study author Malin Uthaug, a PhD candidate at Maastricht University in the Netherlands.

“As it is a rather unexplored area, I’ve been researching the effects of the fast-acting psychedelic substance for the past 2-3 years as part of my doctoral work at Maastricht University. This study is the second published study on the topic from my dissertation, which I will defend during the spring 2020.”

To examine the effects of inhalation of vaporized synthetic 5-MeO-DMT on stress and inflammatory immune functions, Uthaug and her colleagues tested 11 participants before they consumed the drug, after they consumed the drug, and 7 days later.

The participants completed assessments of depression, anxiety, stress, life satisfaction, ego dissolution, mindfulness, and altered states of consciousness. They also provided the researchers with saliva samples, allowing them to check inflammatory biomarkers such as cortisol.

The researchers found that participants tended to have higher mindfulness rating of non-judgment and reduced symptoms of depression directly after the 5-MeO-DMT session, as well at the 7-day follow-up.

However, five of the 11 participants reported adverse effects after consuming the psychedelic, such as feeling scared and confused, and three participants reported adverse effects in the week after the session.

“This suggests that adverse events from the psychedelic experience are tolerable but challenging and occur in a sizeable fraction of 5-MeO-DMT users,” the researchers said.

Uthaug and her colleagues also found that 5-MeO-DMT increased levels of cortisol while reducing levels of another inflammatory biomarker, interleukin-6 (IL-6).

“This study illustrates for the first time the immunomodulatory potential of 5-MeO-DMT, alongside with replications of previous findings of improvement of affect as well as mindfulness related capacities after use in a naturalistic setting,” Uthaug told PsyPost.

The changes in inflammatory biomarkers, however, were unrelated to ratings of mental health or the psychedelic experience.

“There are yet some unanswered questions with regard to 5-MeO-DMT. One of them is; what happens in the brain after ingestion? Addressing this research gap through an imaging study is important not only to enhance the current literature on the topic, but can also help to better understand the brain and so too human consciousness,” Uthaug added.

“Bear in mind that findings of this study are not conclusive, but rather warrant further clinical investigations of 5-MeO-DMT, specifically through the intramuscular route of administration for the reasons highlighted by Alexander Sherwood et al., 2019.”

Psychedelic drug 5-MeO-DMT induces rapid changes in inflammatory markers

In addition to reducing symptoms of depression, the psychedelic drug 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) appears to cause changes in inflammatory ...

www.psypost.org

 

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Scientists use psychedelics to discover an anti-inflammatory pharmacophore

by Barb Bauer, MS | Psychedelic Science Review | 4 Sep 2020

Integrating several tests into a SAR, scientists have identified the compound 2C-H as a structural basis of the anti-inflammatory response in rats.

The news surrounding psychedelic research these days is full of clinical trials on compounds including psilocybin, MDMA, DMT, and LSD. Scientists and psychologists are slowly teasing out the details of the pharmacology and therapeutic applications of these compounds. Psychedelic science has arguably created its own field of expertise for generating, applying, and sharing the empirical information it generates.

A recent study takes an interesting turn, examining inflammatory response using several psychedelics, rats, histopathology, and cellular functional assays. As a consequence, the findings have downstream impacts that spill into scientific disciplines other than psychedelics.

Background

The researchers conducting this study, Flanagan et al., were looking for a pharmacophore for anti-inflammatory activity in rats. They chose to use psychedelics to help them find one because of two previous observations made by researchers: 1) some psychedelics have potent anti-inflammatory properties2 and 2) the anti-inflammatory effects don’t seem to correlate with behavior changes.

The latter observation implies there are two different mechanisms at work. Therefore, by using the 5-HT2A receptor (5-HT2AR) in their study (the one responsible for psychedelic effects), the researchers hypothesized they could segregate the psychedelic compounds based on their ability to cause an anti-inflammatory effect. And, maybe they could observe if there were separate pathways for the behavioral and anti-inflammatory effects.

Study design

The study tested 21 drugs that are agonists of 5-HT2AR. They represented the three primary chemical classes of psychedelics, phenylalkylamines, ergolines, and tryptamines.

Flanagan et al. created a rat model (which they validated in the study) to screen the compounds for causing allergic asthma. The did this by sensitizing and exposing the animals over time to chicken ovalbumin via injection. The rats were then exposed to each drug dissolved in saline at a dose of 0.5 mg/kg. The aerosol mixture was administered with a nebulizer. After exposure, the rat’s lungs were removed and fixed for histological examination.

Using human HEK293 cells expressing 3-HT2AR, the researchers conducted downstream Gαq-mediated calcium flux assays. With this test, the researchers wanted to see if the anti-inflammatory effects of some psychedelics involved mobilizing intracellular calcium.

Some findings of the study

The researchers assembled a structure-activity relationship (SAR) for the compounds and test data. Analysis of the SAR revealed several significant findings, five of which are summarized below.​

1. Overall, the data indicated that activating 5-HT2AR is “necessary and sufficient for the anti-asthma effects of psychedelics” in rats.​
2. The compound 2C-H (2,5-dimethoxyphenethylamine) represents the pharmacophore for anti-inflammatory activity. This means that 2C-H has the chemical characteristics essential for the anti-inflammatory response via 5-HT2A​
3. The researchers identified how modifications to the psychedelic compound’s chemical structure could either enhance or reduce its anti-inflammatory activity. Figure 1 below illustrates the findings from the SAR analysis.​
4. The data indicated that a psychedelic compound’s ability to prevent asthmatic symptoms does not involve activating calcium mobilization in cells downstream from 5-HT2A.​
5. Integrating their results with behavioral studies in the literature, the authors hypothesized that the anti-inflammatory effects of a particular psychedelic would be at a lower dose than what is needed to produce behavioral effects.​

Figure 1: Image illustrating the findings from the SAR. The phenylalkylamine compounds center around the 2C-H pharmacophore. LSD is at the center of the ergolines and DMT (the least modified tryptamine) is at the center of the tryptamines. The researchers measured each compound’s efficacy by its ability to prevent airway hyperresponsiveness (AHR) in the test animals.

Significance of the study results

Creating SARs and identifying pharmacophores present significant advancements that benefit many scientific disciplines. The findings of this study by Flanagan et al. have significant implications in several research areas, including immunology and psychedelics.

Among other applications, scientists can take this information and use it to design anti-inflammatory drugs that don’t have the behavioral effects of psychedelics. The SAR also expands the knowledge base regarding the serotonin 5-HT2A receptor, which is critical for psychedelic researchers.

Scientists Use Psychedelics to Discover an Anti-Inflammatory Pharmacophore

Psychedelics have helped scientists identify anti-inflammatory molecular features, called pharmacophores.

psychedelicreview.com

 

[mr peabody]

This is why cannabis is so effective at easing inflammation

by Mary Schumacher | Chicago Tribune | 8 Sep 2020

While inflammation is the cause of many maladies, it’s also sometimes the remedy. It accounts for back pain, arthritis flare ups, headaches, bowel disorders and even an increase in heart disease. Alzheimer’s is yet another affliction associated with inflammation. And cannabis? It’s a known anti-inflammatory.

As studies show, not only does cannabis have a positive effect in taming inflammation and a myriad ailments associated with inflammation, the entourage effect created by the combination of cannabinoids, including THC, gives a person an even better result. When this synergy takes place, inflammation is greatly relieved, and thus so are the diseases and pains that go with it.

Buyer beware: Make sure you know what you’re using.

Quality and longevity of life are sincere goals of most humans, and accomplishing those goals takes a level of fitness that is somewhat lacking in the average American lifestyle. Many people unable to exercise or stretch for their health aren’t capable because of inflamed joints or other painful inflammations that hinder activity.

Because cannabis works as an anti-inflammatory, it could very easily be the ticket to better health and wellness all around. If the joint pain isn’t in the way and the mindset is elevated to a can-do level, the world opens up a bit and the first steps toward holistic health have been taken.

Cannabis has been studied for the relief of inflammatory bowel diseases like Crohn's and one study showed that the anti-inflammation properties are to be thanked. Although the initial purpose of the study to seek complete Crohn's remission wasn't achieved, it was found that 10 out of 11 patients treated had "clinical, steroid free benefits."

Steroids and other anti-inflammatory pharmaceuticals have many side effects. For steroids, immune system efficiency can go down and muscle weakness may occur among other problematic possibilities. For NSAIDs, the most common over the counter anti-inflammatory, prolonged use can result in stomach pain and eventually to ulcers.

One thing cannabis is short on is side effects. Sure there’s dry mouth, increased hunger, an enhancement of the senses and, oh yeah, a substantial reduction in inflammation, but aren’t most of those things part of the point? It’s no wonder that so many patients use cannabis for chronic pain, inflammatory bowel disease and even Alzheimer’s.

The Fresh Toast is a daily lifestyle platform with a side of cannabis. For more information, visit www.thefreshtoast.com.

This is how cannabis effectively eases inflammation

Cannabis has a positive effect in taming inflammation and a myriad of ailments associated with swelling.

www.chicagotribune.com

 

[mr peabody]

Depression and anxiety share several symptoms and common risk factors, and are often treated with the same drugs.

Depression linked with inflammation*

European College of Neuropsychopharmacology | Neuroscience News | 15 Sep 2020

Depression and anxiety have different biochemical links to inflammation and lipid metabolism. Those with depression have greater levels of inflammation and different types and amounts of lipids in their blood compared to those with anxiety. The metabolites associated with depression were linked to the severity of symptoms. Higher levels of lipids associated with depression detected in a person’s blood correlated with more severe symptoms.

Anxiety and depression are often linked and assumed to be closely related, but now research has shown for the first time that depression and anxiety have different biochemical associations with inflammation and lipid (fat) metabolism. This indicates that different, more targeted treatments may be possible to treat anxiety and depression. This work is presented at the ECNP Congress.

Depression and anxiety share several symptoms, have common risk factors, and often they are treated with the same drugs. Over 50% of patients with depression (Major Depressive Disorder) also have a history of anxiety. Nevertheless, psychiatrists classify them as different disorders, although until now it has been difficult to identify biochemical evidence for this.

Scientists from the Netherlands study used blood samples from 304 people with depression, 548 with anxiety, 531 with both depression and anxiety, 807 with remitted disorders, and 634 healthy controls. Using a nuclear magnetic resonance detector they tested for associations between 40 metabolites found in blood and symptoms of depression, and symptoms of anxiety (such as panic, pathological worry, etc.).

“We have two main findings,” said Hilde de Kluiver, of Amsterdam UMC. “Firstly, we found that the depressed group showed evidence of greater inflammation which was not seen in the anxious group. We also found that the depressed group had very different amounts and types of lipid in their blood. For example, depressed people had high levels of triglycerides, but lower levels of omega-3-fatty acids. In contrast, those people who had anxiety disorder had a lipid composition very similar to the healthy control group.

"We also found that those metabolites associated with depression were also associated with the severity of the depression: in other words, if you had more of a lipid associated with depression, your depression tended to be worse.”

In recent years, depression has been associated with disturbances in the body’s immune system and metabolism, and previous researchers have shown that depressed people tend to have different biochemical markers to those of healthy people. However, no such analysis of such a wide set of markers has been undertaken for anxiety. This work shows, for the first time, that the immune system and lipid metabolism changes in depressed people but not in anxious people.

The researchers hope that these findings will lead to better treatments. “Our group is now planning to test whether depressed people with altered inflammation might respond to treatment with anti-inflammatory drugs,” said Hilde de Kluiver.

Commenting, Dr Philippe Nuss (Hôpital Saint-Antoine, Paris) said “This is an important finding for several reasons. First it identifies easy-to-measure blood biomarkers characterising a subtype of depression whose underlying mechanism is specific and will probably need an appropriate treatment. It also emphasises the fact that mental disorders should be seen in a whole body perspective where major regulatory physiological systems such as immunity and lipid metabolism are involved. In addition, both immunity and lipids are strongly involved in brain metabolism. It is thus not surprising that Ms de Kluiver’s work shows that the severity of depression is greater in patients with more impaired biomarkers.”

*From the article here :

Depression, Not Anxiety, Linked With Inflammation and Metabolic Change - Neuroscience News

Depression and anxiety have different biochemical links to inflammation and lipid metabolism. Those with depression have greater levels of inflammation and different types and amounts of lipids in their blood compared to those with anxiety. The metabolites associated with depression were linked...

neurosciencenews.com

 

[mr peabody]

UC Berkeley scientists propose radical new theory that AD memory loss and cognitive
dysfunction are due to a leaky barrier between the blood stream and the brain.

Drugs that quell brain inflammation found to reverse dementia

UC Berkeley | Neuroscience News | Dec 29 2019

Older mice given anti-inflammatory medication were better able to learn new tasks and became almost as adept at learning as mice half their age.

Drugs that tamp down inflammation in the brain could slow or even reverse the cognitive decline that comes with age. In a publication appearing today in the journal Science Translational Medicine, University of California, Berkeley, and Ben-Gurion University scientists report that senile mice given one such drug had fewer signs of brain inflammation and were better able to learn new tasks, becoming almost as adept as mice half their age.

“We tend to think about the aged brain in the same way we think about neurodegeneration: Age involves loss of function and dead cells. But our new data tell a different story about why the aged brain is not functioning well: It is because of this “fog” of inflammatory load,” said Daniela Kaufer, a UC Berkeley professor of integrative biology and a senior author, along with Alon Friedman of Ben-Gurion University of the Negev in Israel and Dalhousie University in Canada. “But when you remove that inflammatory fog, within days the aged brain acts like a young brain. It is a really, really optimistic finding, in terms of the capacity for plasticity that exists in the brain. We can reverse brain aging.”

The successful treatment in mice supports a radical new view of what causes the confusion and dementia that often accompany aging. More and more research shows that, with age, the filtration system that prevents molecules or infectious organisms in the blood from leaking into the brain — the so-called blood-brain barrier — becomes leaky, letting in chemicals that cause inflammation and a cascade of cell death. After age 70, nearly 60% of adults have leaky blood- brain barriers, according to Friedman’s magnetic resonance imaging (MRI) studies.

An accompanying paper by the two researchers and Dan Milikovsky of Ben-Gurion University shows that the inflammatory fog induced by a leaky blood-brain barrier alters the mouse brain’s normal rhythms, causing microseizure-like events — momentary lapses in the normal rhythm within the hippocampus — that could produce some of the symptoms seen in degenerative brain diseases like Alzheimer’s disease. Electroencephalograms (EEGs) revealed similar brain wave disruption, or paroxysmal slow wave events, in humans with epilepsy and with cognitive dysfunction, including Alzheimer’s and mild cognitive impairment (MCI).

Together, the papers give doctors two biomarkers — leaky barriers detectable by MRI and abnormal brain rhythms detectable by EEG — that can be used to flag people with blood-brain barrier problems, as well as a potential drug to slow or reverse the consequences.

“We now have two biomarkers that tell you exactly where the blood-brain barrier is leaking, so you can select patients for treatment and make decisions about how long you give the drug,” said Kaufer, a member of UC Berkeley’s Helen Wills Neuroscience Institute. “You can follow them, and when the blood-brain barrier is healed, you no longer need the drug.”

Blood-brain barrier

Scientists have long suspected that a leaky blood-brain barrier causes at least some of the tissue damage after brain injury and some of the mental decline that comes with age. But no one knew how.

In 2007, however, Friedman and Kaufer linked these problems to a blood protein, albumin. In 2009, they showed that when albumin leaks into the brain after trauma, it binds to the TGF-β (TGF-beta) receptor in brain cells called astrocytes. This triggers a cascade of inflammatory responses that damage other brain cells and neural circuits, leading to decreased inhibition and increased excitation of neurons and a propensity toward seizures.

They also showed in mice that blocking the receptor with an antihypertension drug, losartan, prevented the development of epilepsy after brain trauma. Epilepsy is a frequent consequence of concussions like those sustained by soldiers from roadside bombs.

Subsequent studies revealed leakiness in the barrier after stroke, traumatic brain injury and football concussions, solidly linking albumin and an overexcited TGF-β receptor to the damage resulting from these traumas.

In their new studies, Kaufer and Friedman showed that introducing albumin into the brain can, within a week, make the brains of young mice look like those of old mice, in terms of hyperexcitability and their susceptibility to seizures. These albumin-treated mice also navigated a maze as poorly as aged mice.

“When we infused albumin into the brains of young mice, we recapitulated aging of the brain: the gene expression, the inflammatory response, resilience to induced seizures and mortality after seizures, performance in a maze. And when we recorded their brain activity, we found these paroxysmal slow wave events,” Kaufer said. “And all were specific to the site we infused. So, doing this is sufficient to get an aged phenotype of this very young brain.”

When they genetically engineered mice so that they could knock out the TGF-β receptor in astrocytes after they’d reached old age, the senile mouse brains looked young again. The mice were as resistant to induced seizures as a young mouse, and they learned a maze like a young mouse.

Serendipitously, a Palo Alto, California, medicinal chemist, Barry Hart, offered to synthesize a small-molecule drug that blocks the TGF-β receptor in astrocytes only, and that could traverse the blood-brain barrier. When they gave the drug, called IPW, to mice in doses that lowered the receptor activity level to that found in young mice, the brains of the aged mice looked younger, too. They showed young brain-like gene expression, reduced inflammation and improved rhythms — that is, reduced paroxysmal slow wave events — as well as reduced seizure susceptibility. They also navigated a maze or learned a spatial task like a young mouse.

In analyzing brain tissue from humans, Kaufer found evidence of albumin in aged brains and increased neuroinflammation and TGF-β production with age. Friedman developed a special type of MRI imaging — dynamic contrast-enhanced (DCE) imaging — to detect leakage in the blood-brain barrier and found more leakage in people with greater cognitive dysfunction.

"Altogether, the evidence points to a dysfunction in the brain’s blood filtration system as one of the earliest triggers of neurological aging," Kaufer said.

Kaufer, Friedman and Hart have started a company to develop a drug to heal the blood-brain barrier for clinical treatment and hope that the drug will help reduce brain inflammation — and, thus, permanent damage — after stroke, concussion or traumatic brain injury, and eventually help older adults with dementia or Alzheimer’s disease who have demonstrated leakage of the blood-brain barrier.

“We got to this through the back door — we started with questions about plasticity having to do with the blood-brain barrier, traumatic brain injury and how epilepsy develops,” Kaufer said. “But after we’d learned a lot about the mechanisms, we started thinking that maybe in aging it is the same story. This is new biology, a completely new angle on why neurological function deteriorates as the brain ages.”

Drugs that quell brain inflammation reverse dementia - Neuroscience News

Older mice given anti-inflammatory medication were better able to learn new tasks and became almost as adept at learning as mice half their age.

neurosciencenews.com