Alzheimer's treatment and prevention

[modocmodoc]

Add this one..

Abstract

Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters (SERT) to increase the synaptic concentrations of serotonin. Beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) is responsible for amyloid β plaque formation. Hence it is an interesting target for Alzheimer's disease (AD) therapy. This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named 'Fetzima' with BACE-1 and SERT. Fetzima is chemically known as levomilnacipran. The study has explored a possible link between the treatment of Depression and AD. 'Autodock 4.2' was used for docking study. The free energy of binding (ΔG) values for 'levomilnacipran-SERT' interaction and 'levomilnacipran-BACE1' interaction were found to be -7.47 and -8.25 kcal/mol, respectively. Levomilnacipran was found to interact with S438, known to be the most important amino acid residue of serotonin binding site of SERT during 'levomilnacipran-SERT' interaction. In the case of 'levomilnacipran-BACE1' interaction, levomilnacipran interacted with two very crucial aspartic acid residues of BACE-1, namely, D32 and D228. These residues are responsible for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain. Hence, Fetzima (levomilnacipran) might act as a potent dual inhibitor of SERT and BACE-1 and expected to form the basis of a future dual therapy against depression and AD. It is an established fact that development of AD is associated with Major Depressive Disorder. Therefore, the design of new BACE-1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial.


(PDF) Fetzima (levomilnacipran), A Drug for Major Depressive Disorder as a Dual Inhibitor for Human Serotonin Transporters and Beta-Site Amyloid Precursor Protein Cleaving Enzyme-1. Available from: https://www.researchgate.net/public...e_Amyloid_Precursor_Protein_Cleaving_Enzyme-1 [accessed Sep 10 2018].

 

[mr peabody]

Voacanga Africana found to protect brain cells from Alzheimer's

Salk scientists find that a plant used for centuries by healers of Sao Tome e Principe holds lessons for modern medicine.

For hundreds of years, healers in Sao Tome e Principe, an island off the western coast of Africa, have prescribed cata-manginga leaves and bark to their patients. These pickings from the Voacanga africana tree are said to decrease inflammation and ease the symptoms of mental disorders.

Now, scientists at the Salk Institute for Biological Studies have discovered that the power of the plant isnt just folklore: a compound isolated from Voacanga africana protects cells from altered molecular pathways linked to Alzheimer's disease, Parkinson's disease and the neurodegeneration that often follows a stroke.

What this provides us with is a source of potential new drug targets, says senior author Pamela Maher, a senior staff scientist in Salks Cellular Neurobiology Laboratory. The results were published this week in the Journal of Ethnopharmacology.

Antonio Currais, a research associate who works with Maher, was visiting family in his native Portugal when he crossed paths with Maria do Ceu Madureira, an ethnopharmacology researcher at the University of Coimbra. For the past twenty years, Madureira has been surveying the use of herbal medicine on the island. Currais and Maher had recently developed a series of tests to screen compounds for their potential use in treating neurodegenerative disorders and Currais saw the perfect chance to put the assay to the test. He began a collaboration with Madureiras team.

There was already a lot of descriptive information of particular plants that have potential effects on the nervous system, Currais says. We took that further to quantitatively document the real neuroprotective action of the compounds in these plants.

Currais and Maher began studying seven different extracts collected from five species of plants in Sao Tome e Principe. Three of the five had been reported by local healers to have effects on the nervous system and two were used as controls. The Salk research team put each sample through different assays, all conducted in living human and mouse cells, designed to test their potential impact against neurodegeneration.

One assay tested the ability of the plant extracts to protect cells against oxidative stress, a byproduct of metabolism that can cause DNA damage and has been linked to age-related neurodegeneration. Another tested anti-inflammatory properties of the compounds. A third test measured whether the samples could block the build-up of beta-amyloid peptides in neurons, which has been linked to Alzheimer's disease.

I was surprised at how potent they were, says Maher. I thought maybe we'd see a little bit of activity in some of the assays and then have to separate out individual components to see a more profound effect. But one sample in particular, Voacanga africana, performed exceptionally on all assays, even in its most dilute form.

When Currais and Maher isolated different components of the plant, they found that the anti-inflammatory and neuroprotective effects of the plant were mostly due to one molecule, called voacamine. The compound hasnt yet been tested in animal models but its performance in the assays suggests that it may have pharmaceutical potential for treating Alzheimer's, Parkinson's or stroke.

There are still a lot of potential sources of drugs in plants that are native to countries around the world and most of them haven't been tested to any extent, says Maher. You can't test everything, so the best way to approach plant research for drugs is to use the knowledge that's been around for thousands of years to help you pick and choose what to study with modern techniques. That way you're not just shooting in the dark.

Maher, Currais and Madureira are planning more follow up studies on voacamaine and also hope to apply their assays to more plants of interest.

Other researchers on the study were Chandramouli Chiruta and Marie Goujon-Svrzic of the Salk Institute for Biological Studies; Gustavo Costa, Tania Santos, Maria Teresa Batista, Jorge Paiva, and Maria do Ceu Madureira of the University of Coimbra.

Both the Portuguese and American researchers worked in full partnership with local institutions, traditional healers and communities in order to respectfully conduct research in the area of indigenous knowledge, assuring the intellectual property rights and the sharing of benefits that may arise as a result of the study of these local medicinal plants.

https://www.salk.edu/news-release/a...t-reveals-possible-treatment-for-aging-brain/

 

[Asclepius]

I recently saw where marijuana can actually protect the brain from injuries NFL football players commenly get called CTE (caused by repeated and numerous brain trauma received during competition). Oddly enough, it is a banned substance and NFL players are routinely fined and suspended for games and eventually kicked out of the league if they test positive enough times. However, I do feel eventually testing will get done, officially, and marijuana will be administered when indicated. Possibly, the NFL may even lead the charge in that direction, being they have a vested interest in protecting their players, and the "game" for that matter. I just hope testing gets done, however it gets done!

Ah here; It's common knowledge that scientific studies have proven that cannaibis contributes to cognitive defects when consumed/smoked over prolonged periods - lets stop shitting ourselves with this nonsense ffs.

 

[novaveritas]

Ah here; It's common knowledge that scientific studies have proven that cannaibis contributes to cognitive defects when consumed/smoked over prolonged periods - lets stop shitting ourselves with this nonsense ffs.

Put very simply Ah No.
They haven't proven it for cannabis or maybe they have proven it for the obscure drug of abuse 'cannaibis' so lets stop shitting ourselves with the idea that the science is in any way settled ffs.

Some of these studies are seriously fucked by bad design and confounding factors and others are weak, Perhaps the hypothesis could equally be thick fuckers often are keener on smoking cannabis and that correlation is not causation. What you think is common knowledge is common but it is not knowledge in terms of being true scientifically or otherwise. Retrospective studies are notoriously poor and lead to bias because the recruitment process is not rigorous and selects for problem users.
I will quote the disclaimers in one larger metastudies because I can't be bothered to write it out myself basically the problem is lack of baseline, lack of controls and poor design to avoid inclusion criteria bias.
There is no doubt that cannabis can cause cognitive impairment when the user is under the influence of the drug, there is also no doubt that it has a very long elimination half life, which is another confounding factor.

The extant evidence base draws on case control studies of recruited cannabis users and comparison subjects. These studies screen participants for potential confounding factors, such as alcohol and drug dependence, and compare them on neuropsychological test performance after a period of abstinence from cannabis. There are two commonly cited potential limitations of this approach. One is the absence of data on initial, precannabis-use neuropsychological functioning. It is possible that differences in test performance between cannabis users and controls are attributable to premorbid rather than cannabis-induced deficits. A second limitation is reliance on retrospectively reported quantity, frequency, duration, and age-of-onset of cannabis use, often inquired about years after initiation of heavy use.

In the same way schizophrenics are heavier smokers but heavy smoking doesn't cause schizophrenia.

Not all cannabis is the same, the cannabis that came out of the Nederweed phenomenon in the 1990's is high THC low CBD low THVC and is a different creature pharmacologically to more traditional varieties. Unfortunately the major consumption of cannabis in the west is now these high THC cultivars. A lot of the studies on neuroprotective effects of cannabis point towards CBD and other non THC components being as or more important than the THC content.

 

[DotChem]

Voacanga Africana found to protect brain cells from Alzheimers, Parkinsons and the neurodegeneration

.....When Currais and Maher isolated different components of the plant, they found that the anti-inflammatory and neuroprotective effects of the plant were mostly due to one molecule, called voacamine. The compound hasnt yet been tested in animal models but its performance in the assays suggests that it may have pharmaceutical potential for treating Alzheimers, Parkinsons or stroke.....

This confirm previous studies. Turns out Voacamine is a potent Cannabinoid CB1 receptor antagonist .. The first natural product CB1 antagonist discovered

Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664820/

2.32. Voacamine and Analogues

Voacamine, 3,6-oxidovoacangine, and 5-hydroxy-3,6-oxidovoacangine are the indole alkaloids isolated from methanolic extract of root bark of Voacanga africana, a tropical African tree. Several compounds have been isolated and screened for the cannabinoid activity in Aequorin/GPCR cell-based Ca²⁺ functional assay using CP55,940 or rimonabant as a positive control for cannabinoid receptors ligands [111]. These compounds exhibited potent CB₁ receptor antagonist activity in a concentration-dependent manner compared to rimonabant, whereas the other coexisting alkaloids, such as voacangine, vobasine, and tabersonine, fail to exhibit any CB receptor mediated activity. This was the first study showing that naturally occurring alkaloids are also source of CB₁ receptor antagonists and this could be further evaluated for cannabimimetic activity and potential therapeutic benefits.

 

[Asclepius]

Stress, high blood pressure, diet and exercise and genetic predisposition(no rocket-science)...most importantly - emotional health and environment. All contributing factors to consider.
(many journal articles, with details, on prevention)

Like I posted ( or alluded to in one of many glorifyication posts/threads) in Cannabis discussion, or the like - no trajectory of overconsumption yields ANY benefits. It's taboo to say it but its factually accurate and if you don't like that, then that in itself, doesnt change the situation.

If you're looking for a 'cure' there is none, yet - it is far too complex an issue atm.

If you are afraid of developing it; then look after your health and well being (phsysiological, emotional); no guarantees but you will reap the benefits.

No one is perfect; we will all be compost someday but to prevent early deterioration, in this short time; involves realistic behaviour and attitude.



http://www.utas.edu.au/wicking/preventing-dementia

*Ignore the twee uni vids...but...

 

[Hikeboy3000]

Let’s not forget about nicotine, one of the only drugs that’s scientifically proven to increase memory and attention.

MECHANISM OF THE EFFECTS OF NICOTINE ON ALZHEIMER’S DISEASE
Baolu Zhao, Institute of Biophysics, Academia Sinica, Beijing, China. Contact e-mail: [email protected]
Background: Epidemiology shows that nicotine preventing and therapeutic effects on Alzheimer’s disease (AD), but the mechanism is not clear. Methods: We studied the mechanism of the effect nicotine on AD in cell and animal systems, by ESR (electron spin resonance techniques), SRXRF (Synchrotron radiation X-ray fluorescence analysis),immunohistochemistry staining, RT-PCR, siRNA and other techniques. Results: We found nicotine was an effective antioxidant; Nicotine treatment decreases the intracellular copper and zinc in senile plaques; Nicotine could mediated the metal homeo- stasis by using SH-SY5Y cells overexpressing APP; Nicotine effectively in- hibited apoptosis in hippocampal cultures and increase of caspase activity induced by Ab; Nicotine suppressed Ab-induced accumulation of free radi- cal and increase of intracellular Ca2?. Nicotine inhibited mitochondria swell- ing and cytochrome c release from the mitochondria. The density of Ab immunoreactivity decreased about 60% in hippocampus and the protein level of Ab aggregation significantly reduced after nicotine administration in hip- pocampus and cortex of the transgenic AD mouse. Nicotine prevents the activation of NF-kB and C-Myc by inhibiting the activation of MAPKs. The activity of iNOS and the production of NO were downregulated by nicotine treatment. RNA interference experiments showed that the above nicotine-mediated process requires a7 nAChR. Conclusions: Our results suggest that nicotine is beneficial in retarding the neurodegenerative diseases AD. These data provide a mechanistic base for the potential development of selected a7 nAChR agonists or iNOS inhibitors used for treating AD.



https://www.ncbi.nlm.nih.gov/pubmed/10796667

 

[Coolwhip]

Ah here; It's common knowledge that scientific studies have proven that cannaibis contributes to cognitive defects when consumed/smoked over prolonged periods - lets stop shitting ourselves with this nonsense ffs.

And it's common knowledge that those defects correct themselves very shortly after cessation of use. Even when talking about long term use that started in adolescence the gap that remains shortly after cessation is barely significant. And for it to be detectable at all requires chronic heavy use.

I mean, no shit you shouldn't stay stoned all day every day on high TCH low CBD strains, but even if you do a 2 weeks after stopping you won't test any different than the general population. There's barely any research in this regard concerning high CBD strains. And there is nothing showing that regular, moderated, cannabis use begun in adulthood can't be a part of a healthy lifestyle.

 

[mr peabody]

Analysis of Voacanga africana reveals possible treatment for the aging brain

Salk scientists find that a plant used for centuries by healers of Sao Tome e Principe holds lessons for modern medicine.

For hundreds of years, healers in Sao Tome e Principe, an island off the western coast of Africa, have prescribed cata-manginga leaves and bark to their patients. These pickings from the Voacanga africana tree are said to decrease inflammation and ease the symptoms of mental disorders.

Now, scientists at the Salk Institute for Biological Studies have discovered the power of the plant isnt just folklore: a compound isolated from Voacanga africana protects cells from altered molecular pathways linked to Alzheimers disease, Parkinsons disease and the neurodegeneration that often follows a stroke.

What this provides us with is a source of potential new drug targets, says senior author Pamela Maher, a senior staff scientist in Salks Cellular Neurobiology Laboratory. The results were published this week in the Journal of Ethnopharmacology.

Antonio Currais was visiting family in his native Portugal when he crossed paths with Maria do Ceu Madureira, an ethnopharmacology researcher at the University of Coimbra. For 20 years, Madureira has been surveying the use of herbal medicine on the island. Currais and Maher had recently developed a series of tests to screen compounds for their potential use in treating neurodegenerative disorders and Currais saw the perfect chance to put the assay to the test. He began a collaboration with Madureiras team.

Sao Tome e Principe Sum Pontes and San Veronica healers collect the Voacanga africana plant for
their patients. In assays, the plant showed to be potent in reducing inflammation, oxidative
stress and amyloid-beta peptides (typically associated with Alzheimers disease).

There was already a lot of descriptive information of particular plants that have potential effects on the nervous system, Currais says. We took that further to quantitatively document the real neuroprotective action of the compounds in these plants.

Currais and Maher began studying seven different extracts collected from five species of plants in Sao Tome e Principe. Three of the five had been reported by local healers to have effects on the nervous system and two were used as controls. The Salk research team put each sample through different assays, all conducted in living human and mouse cells, designed to test their potential impact against neurodegeneration.

One assay tested the ability of the plant extracts to protect cells against oxidative stress, a byproduct of metabolism that can cause DNA damage and has been linked to age-related neurodegeneration. Another tested anti-inflammatory properties of the compounds. A third test measured whether the samples could block the build-up of beta-amyloid peptides in neurons, which has been linked to Alzheimer?s disease.

I was surprised at how potent they were, says Maher. I thought maybe wed see a little bit of activity in some of the assays and then have to separate out individual components to see a more profound effect. But one sample in particular, Voacanga africana, performed exceptionally on all assays, even in its most dilute form.

When Currais and Maher isolated different components of the plant, they found that the anti-inflammatory and neuroprotective effects of the plant were mostly due to one molecule, called voacamine. The compound hasnt yet been tested in animal models but its performance in the assays suggests that it may have pharmaceutical potential for treating Alzheimers, Parkinsons or stroke.

There are a lot of potential sources of drugs in plants native to countries around the world, and most of them havent been tested, says Maher. You cant test everything, so the best way to approach plant research for drugs is to use the knowledge thats been around for thousands of years to help you pick and choose what to study with modern techniques. That way youre not just shooting in the dark.

Maher, Currais and Madureira are planning more follow up studies on voacamaine and also hope to apply their assays to more plants of interest.

Other researchers on the study were Chandramouli Chiruta and Marie Goujon-Svrzic of the Salk Institute for Biological Studies; Gustavo Costa, Tania Santos, Maria Teresa Batista, Jorge Paiva, and Maria do Ceu Madureira of the University of Coimbra.

Both the Portuguese and American researchers have worked in full partnership with local institutions, traditional healers and communities in order to respectfully conduct research in the area of indigenous knowledge, assuring the intellectual property rights and the sharing of benefits that may arise as a result of the study of these local medicinal plants.

https://www.salk.edu/news-release/a...t-reveals-possible-treatment-for-aging-brain/

-----

Compound from the West African tree Voacanga africana may protect the brain

Antonio Currais, Chandramouli Chiruta, Marie Goujon-Svrzic, Gustavo Costa, Tania Santos

The leaves and bark of the Voacanga africana tree may hold potential to ward off Alzheimer’s Disease.

Altered molecular pathways are partly responsible for neurodegeneration typical of Alzheimer’s Disease. A compound extracted from the leaves and bark of an African tree – the Voacanga Africana, has been used in folk medicine for centuries, and scientists at the Salk Institute for Biological Studies (California, USA) identified that extracts of Voacanga africana performed exceptionally on assays (human and mouse cells) that tested the effects against neurodegeneration. Voacanga Africana extract was effective at protecting cells against oxidative stress, showed anti-inflammatory properties, was capable of blocking the build-up in brain neurons of beta-amyloid peptides characteristic of Alzheimer's disease. The study authors report that:

“Our study identifies the alkaloid voacamine as a major compound in Voacanga africana with potent neuroprotective activities in these assays.”

https://www.worldhealth.net/news/compound-african-tree-may-protect-brain/

 

[Limpet_Chicken]

Anyone know the structure of voacamine? Given the plant in question and it's close relatives, guessing maybe some multicyclic indolic structure, like ibogaine?

 

[vecktor]

Anyone know the structure of voacamine? Given the plant in question and it's close relatives, guessing maybe some multicyclic indolic structure, like ibogaine?

it is the indolic dimer derived from voacangine and cleavamine.
Voacamine is not a major alkaloid of Voacanga Africana, and the referenced work is somewhat suspect.
V

when did the forum software and bullshit cloud protection on bluelight become so shit?

 

[DotChem]

.. and the referenced work is somewhat suspect.

"extract of Voacanga Africana" contains Tabersonine in addition to Voacamine and Voacangine. Tabersonine is actually the major alkaloid in some parts of V. Africana (the seeds in particular but also leaves and bark). It has been shown to inhibit beta-amyloid plaques formation.. probably that is the effect of Tabersonine they were seeing..
Tabersonine inhibits amyloid fibril formation and cytotoxicity of Aβ(1-42).

 

[Limpet_Chicken]

Not familiar with cleavamine. The synthesis of voacamine looks like something you might find if you were to record the dreams of a lot of organic chemists, and looked at the content of their nightmares

Could be worse though, I feel really sorry for the poor buggers who had to discover the structure of, and then undertake the total synthesis of palytoxin, or maitotoxin. (palytoxin is a marine polyether biotoxin, a long chain shaped multicyclic thing, and with more than 10 to the 21'st power stereoisomers, one of them being palytoxin, second only to the similar marine toxin maitotoxin as being the second most potent toxin of nonproteinaceous nature known to man. Disrupts sodium ion gradients, along with other ionic gradients, and is an extraordinarily potent cardiotoxin due to being a highly powerful inducer of vasoconstriction in cardiac vessels. It binds Na+/K+-ATPase, and turns it into a nonselective cation channel, which it locks in the open conformation, causing the cellular ion gradient in all cell types to be completely destroyed, induces haemolysis, massive cardiac vasoconstriction, and capable of killing within minutes. As well as being a generalized cytotoxin to any cellls expressing Na+/K+-ATPase.

 

[vecktor]

The voacamine paper is very suspect on many levels and probably should be filed under junk. I dont think this journal has a great reputation for thorough peer review.
I suspect like dotchem suggested they discovered tabersonine or something very similar had anti amyloid effects (Not that it is for certain that amyloid causes alzheimers. Amyloid could be caused by alzheimers, ask Eli Lily about that hypothesis and how much of a money pit it is) they then misidentified it and then went down this strange rabbit hole with voacamine.

I am not being unreasonable in suggesting caution with this paper, here are some of the more obvious problems with the paper which undermine the claims.

Biosynthesis
Voacamine is a dimeric indole alkaloid and is probably derived from condensing voacangine (the right hand part in the drawing above) and a cleavamine type alkaloid, however as drawn in the paper and in wikipedia the absolute orientation of the voacangine part in voacamine is the wrong enantiomer, voacangine is naturally occuring as one enantiomer (-) absolute stereochemistry but in the paper and the structure on wikipedia has the (+) form of voacangine joined to the cleavamine. That seems just a bit unlikely, If you believe that structure, then you must also believe the plant makes one enantiomer of voacangine then inverts two stereo centers for absolutely no reason, then joins it to the cleavamine type alkaloid to make voacamine instead of just using the abundant voacangine enantiomer. hmmmm
Voacamine is much more common in closely related South American plants it seems it is a minor constituent in most Voacanga africana specimens. Voacamine from South American sources is optically active.

Chemical Analysis and identification of voacamine as the active:

Extract B from Voacanga africana bark (400 mg) was dissolved in a minimal amount of 1:1 MeOH/CH2Cl2, adsorbed on silica gel, then loaded onto a wet (CH2Cl2) column and purified by flash chromatography using 2?10% MeOH/CH2Cl2 as an eluent. This gave 30 mg ( 7.5% ) of pure voacamine and 150 mg ( 37.5% ) of an inseparable mixture of voacamine with other compounds

So there was a bunch of other compounds. very strange that HPLC didn't separate and lead to identification of the other alkaoids, but then look at the paper at the HPLC trace, and the fraction collection, no baseline separation of peaks, a massively wandering baseline or something huge eluting, and a very strange choice of 330nm UV detection. That is not HPLC in my book unless the H is for hopeless rather than high.

Mass spectrometry:
The exact mass is off for voacamine, C43H52N4O5 is 704.3937 M+H should be 705.4016 they have 705.4067 in the mass spectra and no peaks for the 13C isotope M+1 M+2 peaks. yet in the ID data they claim "calculated 705.4010; found 705.3962 " but nowhere is there a 705.3962 peak in the mass spectra presented as proof.

Whilst Orbitraps are strange beasts compared to TOF they should be good out to 4 decimal places probably 5 decimals if set up for accuracy, they shouldn't be wrong at the 3rd decimal place and they definately should see the 13C isotopic peaks the (M+1) +H should be about 40% of M+H with voacamine but it is missing entirely. Perhaps the experienced Orbitrapper from the Salk institute can explain, exactly how a half million dollar machine cannot see a peak that is 40% of the base peak which has to be there unless the plant grew on a different planet. The machine should also see M+2+H but for some odd reason it doesn't.

 

[DotChem]

^ That makes sense. The natural Voacangine isolated from V. Africana is optically active. So assuming Voacamine is biosynthesized from a condensation of Voacangine and Cleavamine, then yes the structure in that paper as well as that shown on Voacamine wiki page depict the "wrong" isomer ie the unnatural Voacangine enantiomer.. assuming! since we don't know that for sure: it could be biosynthesized de nuevo! It is actually the major alkaloid (~9% of TA) even in Voacanga Africana bark with Voacangine at ~6% TA depending on the season the bark is harvested .. kind of complex: the composition of the alkaloid varies according to the season so in some samples Vocangine is highest and in other Voacamine and in yet others Tabersonine..

But keep in mind though, lots of papers (dealing mostly with the biology rather than the chemistry) of Iboga alkaloids depict the "wrong" enantiomers even for well established structures like Ibogaine. So I guess it may be a honest mistake. Someone having fun with chemdraw should edit the structure on Voacamine wiki).
Another thing, afaik there is still no definitive answer as to the stereochemistry of the C16 carbon linking the 2 molecules. Some authors depict the (R)-16 and others the (S). Best paper below from Japan that provides an answer but it is a solution (NMR-NOE) derived structure. A definitive answer would be to solve the crystal structure of Voacamine and close all debates. But I guess, there is no money to be made pursuing the compound. Interesting though, Voacamine is the first natural alkakoid reported as potent cannabinoid CB1 receptor antagonist:

​

Discovery of indole alkaloids with cannabinoid CB1 receptor antagonistic activity
Kitajima M et al

​

Bioorg Med Chem Lett. 2011 Apr 1;21(7):1962-4. ​

Abstract

: Three indole alkaloids, voacamine (1), 3,6-oxidovoacangine (2), and a new alkaloid, 5-hydroxy-3,6-oxidovoacangine (3), isolated from Voacanga africana were found to exhibit potent cannabinoid CB1 receptor antagonistic activity. This is the first example of CB1 antagonists derived from natural alkaloids.
​

​

 

[DotChem]

...however as drawn in the paper and in wikipedia the absolute orientation of the voacangine part in voacamine is the wrong enantiomer..

​

But keep in mind though, lots of papers (dealing mostly with the biology rather than the chemistry) of Iboga alkaloids depict the "wrong" enantiomers even for well established structures like Ibogaine... ​

Here is one paper depicting totally "wrong" enantiomeric structures of natural Ibogaine Ibogamine and Catharantine from a "synthetic chemistry" paper for Pete's sake!! and claiming "Enantioselective synthesis of Iboga Alkaloids and Vinblastine via rearrangement of quaternary ammonium!!

 

[S.J.B.]

Here is one paper depicting totally "wrong" enantiomeric structures of natural Ibogaine Ibogamine and Catharantine from a "synthetic chemistry" paper for Pete's sake!! and claiming "Enantioselective synthesis of Iboga Alkaloids and Vinblastine via rearrangement of quaternary ammonium!!

This is more a case of disingenuousness than error, I would say. They synthesized the unnatural enantiomers in the paper but seemingly didn't want to acknowledge that, so they switched all the structures in that scheme. The reviewers shouldn't have let them get away with that.

 

[mr peabody]

Cannabis shown to reverse cognitive decline and fight Alzheimer’s

Cannabis has the reputation of impairing memory, attention and motivation, especially in young people. But what if it could actually protect the brain and prevent neurodegenerative disorders like Alzheimer’s and other types of dementia from developing?

Although cannabis has been used for its medicinal properties for many thousands of years, scientific research into the plant and its derivatives (pioneered by the Beckley Foundation and others) has only recently started to acknowledge and investigate some of its health benefits. Among many therapeutic applications, results gathered over the last decade have unveiled some extremely promising brain-protective and restorative properties.

The effects of cannabis are caused by chemical compounds produced by the plant known as cannabinoids. These include tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabinoid-like molecules – called endocannabinoids – occur naturally in the brain, and are involved in a diverse range of processes including appetite, energy regulation, and sleep. Indeed, cannabinoid receptors are some of the most abundant receptors found in the body.

The endocannabinoid system develops gradually throughout childhood and is most active during adolescence, but as we age, its activity declines. Compelling evidence suggests this may be one of the root causes of some of the detrimental aspects of normal and pathological aging. One possibility seems particularly worth exploring – that supplementing the aging endocannabinoid system with exogenous plant cannabinoids may mitigate some of the damage that occurs in the brain as we grow older.

Recent experimental research seems to support this notion. In a study published last year, THC – the molecule in cannabis responsible for its psychoactive effects – was found to reverse age-related cognitive decline in old mice. The study also found that THC increased the number of connections between brain cells in the hippocampus, a brain region which plays a key role in memory.

THC, administered on consecutive days, significantly increased the speed at which
mature and old mice completed a maze task

This is not an isolated report; several other studies have found that THC-like substances improve memory and cognition in rodents. The positive effects of cannabis and cannabinoids on sleep and appetite, and on reducing stress and anxiety, may constitute other indirect ways in which these substances can ward off cognitive decline.

Perhaps even more profound is the implication that cannabinoids may treat more serious age-related disorders such as Alzheimer’s Disease. Despite the diagnosis of Alzheimer’s in millions of people every year, there is yet no definitive treatment for the condition. The disease involves accumulation of the toxic protein amyloid-beta (Aβ) in the brain. The insoluble Aβ plaques also cause further damage when the bodies own inflammatory response attacks cells in an attempt to clear them, leading to further death of brain tissue.

The idea that a component of cannabis – a natural, easily-grown substance with a known, positive safety profile – could be used to treat a disease which is afflicting more and more people in an aging population is a very attractive one.

Though the science is still at an early stage, pre-clinical research is promising. A study using neuronal cell cultures that had been genetically altered to over-produce Aβ – effectively a test-tube model of Alzheimer’s Disease – found that by adding increasing doses of THC, less of the toxic protein accumulated, and cells were less likely to die. These findings are also reflected in animal studies, which found that cannabinoids similar to THC and CBD improved cognition and decreased cellular damage in a mouse model of the disease.

THC increased survival of Aβ-producing neurones (left), and decreased the
accumulation of Aβ (right) in a dose-dependent manner

There are various proposed mechanisms for the neuroprotective effect of cannabinoids in degenerative disorders such as Alzheimer’s. Symptoms of these diseases are partially a result of the body’s own immune system overreacting to diseased neurones. In chronic brain diseases, excessive immune response to neurones can further damage them, a process known as pathological neuroinflammation. The endocannabinoid system is involved in regulating the inflammatory response by inducing changes in pro-inflammatory proteins, limiting possible damage caused by their over-activation.

Another potential mechanism via which cannabinoids may exert their neuroprotective effects could be through inhibiting excitotoxicity. If neurones activate for too long and too often (excitation), they become damaged (toxicity). Damaged neurones then release chemicals that further activate and damage neurones near them, creating a positive feedback loop of spreading cellular damage. Activation of the cannabinoid system by endocannabinoids decreases the release of these potentially harmful molecules, limiting the spread of damage from an initial injury. By introducing plant cannabinoids in addition to those naturally produced by the body, it may be possible to boost these effects and further minimise brain damage.

Cannabis derivatives hold great medical potential – not only for the treatment of neurodegenerative diseases such as Alzheimer’s, but for epilepsy, addiction, pain, and a host of other conditions. Unfortunately, this potential is limited by anti-scientific laws and policies. Cannabis is currently on Schedule I of the UN’s global drug conventions; of ‘little or no therapeutic value’, despite the overwhelming amount of evidence to the contrary. This strict legal scheduling means that research into the plant is severely underfunded and limited by bureaucratic restrictions which do little to quell recreational use of cannabis, but which do prevent doctors prescribing it to patients.

We are actively campaigning to reform the current system of drug legislation, and hope that both UK and global policy will soon change to reflect the scientific evidence. The Beckley Foundation and other research groups are dedicated to fully unravelling the therapeutic benefits of cannabis and other psychoactive compounds – something that everyone will benefit from.

http://beckleyfoundation.org/2018/06...ne-alzheimers/

 

[S.J.B.]

Cannabis shown to reverse cognitive decline and fight Alzheimer’s

I'm sure the Beckley Foundation is doing good work but that's a disingenuous, clickbait headline.

 

[mr peabody]

Researchers Identify Virus and Two Types of Bacteria as Major Causes of Alzheimer’s

A worldwide team of senior scientists and clinicians have come together to produce an editorial which indicates that certain microbes, a specific virus and two specific types of bacteria, are major causes of Alzheimer’s Disease. Their paper, which has been published online in the highly regarded peer-reviewed journal, Journal of Alzheimer’s Disease, stresses the urgent need for further research – and more importantly, for clinical trials of anti-microbial and related agents to treat the disease.

This major call for action is based on substantial published evidence into Alzheimer’s. The team’s landmark editorial summarises the abundant data implicating these microbes, but until now this work has been largely ignored or dismissed as controversial – despite the absence of evidence to the contrary. Therefore, proposals for the funding of clinical trials have been refused, despite the fact that over 400 unsuccessful clinical trials for Alzheimer’s based on other concepts were carried out over a recent 10-year period.

Opposition to the microbial concepts resembles the fierce resistance to studies some years ago which showed that viruses cause certain types of cancer, and that a bacterium causes stomach ulcers. Those concepts were ultimately proved valid, leading to successful clinical trials and the subsequent development of appropriate treatments.

Professor Douglas Kell of The University of Manchester’s School of Chemistry and Manchester Institute of Biotechnology is one of the editorial’s authors. He says that supposedly sterile red blood cells were seen to contain dormant microbes, which also has implications for blood transfusions.

“We are saying there is incontrovertible evidence that Alzheimer’s Disease has a dormant microbial component, and that this can be woken up by iron dysregulation. Removing this iron will slow down or prevent cognitive degeneration. We can’t keep ignoring all of the evidence,” Professor Douglas Kell said.

Professor Resia Pretorius of the University of Pretoria, who worked with Douglas Kell on the editorial, said “The microbial presence in blood may also play a fundamental role as causative agent of systemic inflammation, which is a characteristic of Alzheimer’s disease – particularly, the bacterial cell wall component and endotoxin, lipopolysaccharide. Furthermore, there is ample evidence that this can cause neuroinflammation and amyloid-β plaque formation.”

The findings of this editorial could also have implications for the future treatment of Parkinson’s Disease, and other progressive neurological conditions.

Abstract

Microbes and Alzheimer’s Disease

We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even though treatment based on it might slow or arrest AD progression. We refer to the many studies, mainly on humans, implicating specific microbes in the elderly brain, notably herpes simplex virus type 1 (HSV1), Chlamydia pneumoniae, and several types of spirochaete, in the etiology of AD. Fungal infection of AD brain has also been described, as well as abnormal microbiota in AD patient blood. The first observations of HSV1 in AD brain were reported almost three decades ago]. The ever-increasing number of these studies (now about 100 on HSV1 alone) warrants re-evaluation of the infection and AD concept.

AD is associated with neuronal loss and progressive synaptic dysfunction, accompanied by the deposition of amyloid-β (Aβ) peptide, a cleavage product of the amyloid-β protein precursor (AβPP), and abnormal forms of tau protein, markers that have been used as diagnostic criteria for the disease. These constitute the hallmarks of AD, but whether they are causes of AD or consequences is unknown. We suggest that these are indicators of an infectious etiology. In the case of AD, it is often not realized that microbes can cause chronic as well as acute diseases; that some microbes can remain latent in the body with the potential for reactivation, the effects of which might occur years after initial infection; and that people can be infected but not necessarily affected, such that ‘controls’, even if infected, are asymptomatic.

https://neurosciencenews.com/microbes-alzheimers-neurology-3826/