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GSK3 Beta, an enzyme I’ve come to love

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Neuroprotection

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Apr 18, 2015
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sorry for this long post, but it’s a big topic and I hope at least some of you can make sense of it. I’ll provide studies in the next post since that’s easier for me due to my blindness. GSK3 is a serine/threonine kinase That phosphorylates a massive range of cellular substrates but got its name after being first discovered as a negative regulator of glycogen synthesis. GSK3 is unusual in that it’s constitutionally active and is regulated by a wide range of upstream enzymes/Signals, most of which inhibit its activity. examples of these include the CAMP/PKA, PI3K/PKB and PKC signalling cascades amongst many others.

Relevance to neuroscience:

Recently, GSK3, more specifically, insufficient inhibition of its activity in the brain has been linked to a wide range of psychiatric disturbances including depression, schizophrenia and most notably, bipolar disorder. bipolar, especially the manic phase is of greatest interest, as this is where GSK3 has been found to be the most active. furthermore, the well-known mood stabiliser lithium is thought to be a direct inhibitor of GSK3. additionally, lithium as well as much more potent and selective GSK3 inhibitors were found to Block hyperactivity in animals induced either by amphetamine or knockout of the dopamine transporter. they also block psychostimulant reward, sensitisation and conditioned place preference in many animal studies. actually, in human trials, lithium blocked the energising/activating as well as euphoric effects of dextroamphetamine but did not interfere with the ability of dextroamphetamine to induce psychosis.

How does GSK3 work in neurons?:

The answer to that is, no one is really sure. however, this is changing rapidly, and perhaps the most important discoveries surround the role of this protein in synaptic plasticity. basically, GSK3 targets and modifies a wide range of presynaptic and postsynaptic proteins; including vesicles, transport proteins, ion channels, receptors and neuronal microtubules. From the research I have done, it appears that GSK3 tunes the activity and intrinsic excitability of Neurons and the circuits in which they reside. GSK3 perhaps best known for its role in synaptic LTD, something it achieves by triggering the internalisation or degradation of AMPA or GABAA receptors or blocking the transport proteins that normally deliver them to the surface of the synapse. however, this is a region specific effect and in some cases GSK3 can enhance Ampa receptor activity. nevertheless, GSK3 is vital for NMDA receptor-mediated LTD whilst inhibition of GSK3 is an absolute requirement for LTP to occur. personally, I think the inhibition of GABAA receptor function bye GSK3 should be studied in more detail as I feel that this probably sharpens neuronal activity and is relevant to mania.

GSK3, How I went from hating to admiring it. given my fascination with neuronal survival and dislike of anything that possibly kills neurons, GSK3 appeared to be the ultimate enemy. this was for several reasons. Firstly, its inhibitors were shown to be neuroprotective and neuroregenerative in a wide range of disease models. secondly, GSK3 is actually inhibited by practically all neuronal survival and growth pathways including those I mentioned above. it didn’t help that I’ve read blogs, articles and watched a video championing inhibitors of this enzyme as a breakthrough cure for diabetes and CNS disorders. All this lead me to see GSK3 as a hideous disease causing protein that served only to damage the brain. I couldn’t have been more wrong. firstly, correlation doesn’t equal causation. Yes, GSK3 can trigger neuronal in yes, GSK3 can trigger neuronal apoptosis, but a recent article I read, actually proposed that the kinase activity was not responsible for neuronal death, But rather, other structural sites on the protein May interact with mitochondrial death pathways. note that the kinase activity is necessary in mood regulatory, mood elevating and synaptic regulatory activity of this protein. secondly, GSK3 is actually vital for proper memory function and encoding as well as appropriate neuronal development. in the adult brain, it reportedly acts as a strong protector against seizure onset and epileptaGenesis by weakening excitatory cynaptic strength. last but not least, GSK3 is absolutely necessary for expression of dopamine related behaviours and inhibiting it can block the pleasurable and energising effects of psychostimulants. The postsynaptic D2 Receptor relies on indirect activation of GSK3 via inhibition of PKB in order to generate its well known effects on locomotion, mood, memory, behaviour and Gene expression. surprisingly, it’s been discovered that even the D1 receptor, which, in theory should inhibit GSK3 actually needs GSK3 activity in order to generate typical behavioural effects.

What’s wrong with GSK3 inhibition:
In my opinion, nothing at all, so long as it is only a temporary solution. for those suffering from intractable mania/depression, traumatic brain injury and possibly addiction, GSK3 inhibition is a promising starting point. however, this must not be a long-term solution to any psychiatric disorder. This is because at least from what I’ve heard, mood stabilisers which inhibit GSK3 zap the joy out of peoples lives and leave them emotionally apathetic and empty. not surprising when you consider the role of the enzyme in dopamine receptor downstream actions. once researchers fully comprehend The downstream targets of GSK3, Focus should be turned to The interactions of GSK3 structural motifs with cell death pathways in neurons. it is these interactions that should then be targeted for inhibition, rather than solely targeting the kinase Domain.
 
Skorpio said:
Why do you dislike apoptosis? Do you want cancer?

Speaking of cancer. GSK3beta is pretty involved in a few branches of wnt signaling.
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It’s not really apoptosis in general that I dislike, but rather indiscriminate/Unnecessary neuronal apoptosis/necrosis that can occur when non damaging conditions arise in the brain. for example, prolonged hypoglycaemia is known to trigger massive neuron death despite the fact no physical damage actually occurs to the neurons initially. rather, it is as if the neurons, facing unusual conditions undergo apoptosis as an innate and frantic response that does more damage and no good. of course, that doesn’t mean neuronal apoptosis isn’t required, it clearly is, and is vital for proper brain development.
What I hope from future research is the ability to manipulate neuron activity greatly without triggering unnecessary neuron death. I hope this would allow drugs like psychostimulants to become much safer in the long-term.
 
Neuroprotection said:
It’s not really apoptosis in general that I dislike, but rather indiscriminate/Unnecessary neuronal apoptosis/necrosis that can occur when non damaging conditions arise in the brain. for example, prolonged hypoglycaemia is known to trigger massive neuron death despite the fact no physical damage actually occurs to the neurons initially. rather, it is as if the neurons, facing unusual conditions undergo apoptosis as an innate and frantic response that does more damage and no good. of course, that doesn’t mean neuronal apoptosis isn’t required, it clearly is, and is vital for proper brain development.
What I hope from future research is the ability to manipulate neuron activity greatly without triggering unnecessary neuron death. I hope this would allow drugs like psychostimulants to become much safer in the long-term.
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Profound hypoglycemia starves cells of atp and generally generates toxicity due to the failure to maintain a calcium gradient. The apoptosis is in response to this. If the cells are apoptosing before they lose viability, i would expect that pathway to not completely generalize to all programs of apoptosis.
 
Skorpio said:
Profound hypoglycemia starves cells of atp and generally generates toxicity due to the failure to maintain a calcium gradient. The apoptosis is in response to this. If the cells are apoptosing before they lose viability, i would expect that pathway to not completely generalize to all programs of apoptosis.
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Yes, that’s correct, it is uncontrolled calcium influx that damages/kills neurons under many circumstances, ranging from physical traumatic brain injury to Energy depletion or severe seizure activity. however, according to studies I have read, disturbed calcium gradient alone does not usually seriously damage or kill neurons. instead, apoptosis or necrosis is triggered before the cells have a chance to recover. this is why inhibitors of the mitochondrial death pathway like NIM811 show very strong protection against certain types of neuronal death particularly against secondary brain injury or that triggered by energy failure. interestingly, NIM811 blocked neuronal death and prevented cognitive impairments caused by hypoglycaemia despite failing to block the activation of aggressive calcium-dependent proteolytic enzymes like Calpain.
You may be wondering how this links with psychostimulants. well, we’ve all heard about free radicals from dopamine autoxidation or calcium overload from excessive glutamate receptor stimulation playing a role in amphetamine and cocaine like stimulant neurotoxicity. of course, damage by free radicals is direct and can kill all types of cells in sufficient quantities. antioxidants are about the best but by no means ideal solution We currently have, though in reality, the perfect solution would be direct increase of specialised antioxidant enzyme expression in the brain. however, from what I’ve read, The largest component of stimulant short and long-term neuronal damage and resultant memory impairment or psychosis onset comes from excessive calcium entering through excess glutamate receptor activation. note that dopamine receptors actually work and generate most of their behavioural affects by altering the function of glutamate and it’s receptors. The problem is, most of the positive effects of psychostimulants also rely on this pathway and an animal studies, lowering the amount of glutamate in the brain or blocking glutamate receptors blocks psychostimulant effects. of course, in animal studies, researchers generally look for locomotor activity or conditioned place preference, though I do still wonder if any rewarding affects of the stimulant drug remain when these approaches are taken. it probably doesn’t, i’ve actually read reports of people trying to employ more effective neuroprotective strategies like very high dose NAC or calcium channel blockers and they claim it ruined their drug experience by suppressing the reward whilst leaving the uncomfortable stimulation intact. I feel amphetamine use is another situation where uncoupling changes in ion gradients from cell death pathways May be beneficial.
 
Neuroprotection said:
animal studies
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Look for progressive ratio tests. Those do a decent job of demonstrating how much animals "value" a drug. Basically they press a lever and get the drug but each time they have to press it more. The main point measured is when the animal stops.

Definately a lot of studies about amphetamine and its rewarding/addictive qualities out there, and some with some pretty clever paradigms.
 
Thanks for that. just came across a YouTube video that claimed the drug losartan, A blood pressure medication has neuroprotective affects and prevents amphetamine induced chronic brain changes. unfortunately, it apparently also reduces/Blocks amphetamine reward, again, reinforcing what I said earlier about protective strategies dampening reward. The thing is, researchers see this as a positive thing, as did the guy on the video as it might have potential in treating dependency. although I’m no neuroscientist, I believe the link between potentially harmful protein Signaling networks and drug reward can be uncoupled. if we consider the topic of this thread, GSK3 Beta, it apparently has well over 40 substrates in Neurons, and a handful of them are involved in synaptic function. One comprehensive review I remember reading, explained that in Many experiments, GSK3 mutated to make it constantly active and resistant to inhibition by other cellular enzymes, did not result in any cell death. in contrast, over expression of the actual GSK3 protein did enhance neuronal apoptosis even when the main active site (the kinase domain) was knocked out. note that the kinase Domain is necessary for GSK3 to regulate synaptic function and generate amphetamine related behaviours. here is an interesting study which talks about its role in synaptic function.

 
since GSK3 is believed to be the main target of the mood stabiliser lithium I wonder if anyone here can share their experience using it. I want to know more about how exactly lithium affects both drug and natural rewards. I do think some negative reports about lithium come from people experiencing severe physical side-effects, which then leads to aversion to the compound. I would also be interested to know how lithium and perhaps other mood stabilisers affects other aspects of behaviour such as motivation, risk-taking, behaviour, cognition and resilience and if possible, their effects on more complex emotions like hope/positivity.
The reason I’m interested in this is because heightened GSK3 activity reportedly generates manic like behaviour, including dramatically enhanced behavioural responses to amphetamine, but at the same time, increased expression and severity of depressive symptoms when subjected to chronic stress. on the other hand, lithium and other more selective GSK3 inhibitors produced both antimanic and antidepressant effects. in one of the very few online anecdotes about lithium I could find, A user of the medication with bipolar described it as putting a protective cover on their lives. they stated that they greatly appreciated the lithium induced suppression of their severe mood swings which were described as alternating “ between states of exuberant joy and deep depression“. however, they later decided to use lithium on an as needed basis since they began to miss their normal emotions. I don’t say this to discredit mood stabilisers, they’ve saved countless lives and dramatically improved The quality of countless more. I just hope future research on neuronal substrates of mood regulation Will lead to Discovery of new mood modulating agents that lack nasty side-effects and enhance general well-being of the user. in my opinion, any drug that, either as a side-effect, or as the intended overall effect blocks reward is destined for failure. this is especially the case for addiction. that’s why naltrexone and disulfiram performed so poorly in treating opioid and ethanol dependence respectively.
 
Supplementing lithium in low doses or infrequently is better than supplementing, let’s say selenium. 7-up with Li or lithium waters that used to be popular, there’s a reason why people liked them. Almost everyone would benefit from a bit of lithium now and then imho.
 
SpiralusSancti said:
Supplementing lithium in low doses or infrequently is better than supplementing, let’s say selenium. 7-up with Li or lithium waters that used to be popular, there’s a reason why people liked them. Almost everyone would benefit from a bit of lithium now and then imho.
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Yes, I’ve heard about that. it also apparently has some significant anti-suicidal properties which is very interesting. strangely, I read a study of therapeutic doses of lithium in healthy humans and I think it produced significant dysphoric symptoms in most test subjects. this is in line with the anti-dopaminergic effects of lithium, most of which probably stem from its inhibition of GSK3 Beta. on the other hand, I read an article stating that long-term lithium administration has anti-anhadonic effects, via modulation of AMPA receptor function. whilst I have come to believe more selective GSK3 inhibitors will come with many neurological/mood related side-effects, they should actually be quite safe in that their effects should be rapidly reversible upon stopping the inhibitor. GSK3 is a constitutionally active enzyme And there’s lots of it around in the CNS. thankfully, all known Cellular signalling pathways or Chemical inhibitors that block its activity only do so reversibly and temporarily without damaging the enzyme.
 
not sure if anyone’s looked at the article links I posted, I do apologise if they are presented as a terrible mass of unknown links, this is because of my visual impairment. however, one of my posts contains a single link about GSK3 in the cellular and behavioural effects of psychostimulants and I would encourage people to read that to better understand my interest in this enzyme.
 
Neuroprotection said:
not sure if anyone’s looked at the article links I posted, I do apologise if they are presented as a terrible mass of unknown links, this is because of my visual impairment. however, one of my posts contains a single link about GSK3 in the cellular and behavioural effects of psychostimulants and I would encourage people to read that to better understand my interest in this enzyme.
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Interesting read so far, this discussion. Thanks for sharing the links as well. FTFY:
✌️
 
Neuroprotection said:
Yes, I’ve heard about that. it also apparently has some significant anti-suicidal properties which is very interesting. strangely, I read a study of therapeutic doses of lithium in healthy humans and I think it produced significant dysphoric symptoms in most test subjects.
Click to expand...
I noticed anti-suicidal properties (I’m not really suicidal, I guess, but at a time I tried it like that it did lessen such and other negative thoughts and put me in a positive mindset). I didn’t use therapeutic doses just tried it in mini-doses and once or twice in a quite big dose. Big dose produced some sort of positive mania. Such self experimenting is probably better avoided just in case. But I love that we have a metal with such a great properties.
 
glad to know you enjoyed it and found it interesting. Also, I really appreciate you reposting the links in a better format for myself and others to identify and read.
Thanks again for this.
 
SpiralusSancti said:
I noticed anti-suicidal properties (I’m not really suicidal, I guess, but at a time I tried it like that it did lessen such and other negative thoughts and put me in a positive mindset). I didn’t use therapeutic doses just tried it in mini-doses and once or twice in a quite big dose. Big dose produced some sort of positive mania. Such self experimenting is probably better avoided just in case. But I love that we have a metal with such a great properties.
Click to expand...

Very interesting. it should be noted that lithium’s mechanism of action is not fully understood however, a study I came across stated that despite being a rather weak inhibitor of GSK3 in vitro or when administered acutely, long-term administration in vivo at therapeutic doses, alters brain enzymes/Signalling proteins to produce dramatic and powerful inhibition of GSK3. this is perhaps why lithium takes time to produce antimanic affects. at lower doses or when acutely administered, positive effects of lithium on suicidal ideation or depression probably still relies on significant GSK3 as a major mechanism, but other mechanisms related to ion channel inhibition are probably also involved. I used to be really interested in trying lithium supplementation, but after suffering a strange bout of anhedonia/Numbness, Including sudden loss of my Normally extremely high libido and thrill/reward seeking behaviour i’ve changed my mind. not going to go any more into my personal story as I’ve already made a thread about that entitled “helpful substances in the fight against anhedonia“ posted on the dark side. nevertheless, I have recovered from that and don’t want anything that could risk returning me to that state. my impulsivity/thrillseeking and reward seeking behaviour has always been part of me and whilst it does cause me many issues, it also gives me something to Drive me and look forward to each day. The thing is, during that period of depression I went through, I had no desire for self harm/suicide or anything related to that and thankfully, I never have. basically, I’ve heard that lithium does exactly what I don’t want, lowering pleasure/thrillseeking, negatively affecting libido amongst other effects. I think a far better supplement for me would be bioavailable chelated magnesium. this is because magnesium, whilst producing calming/antistress effects can also produce activating/energising effects as well. interestingly, it shares with lithium, though to a much lesser extent The ability to reduce cocaine self administration in animals but the mechanism/effects are markedly different. For example, whilst lithium decreases/Blocks the rewarding value and dopaminergic activating effects of cocaine, magnesium more likely reduces the negative symptoms that drive cocaine consumption, such as stress/Anxiety. furthermore, magnesium is thought to have potent antidepressant effects of its own. finally, and most interestingly, i’ve read that high-dose magnesium can actually produce a significant conditioned place preference in rats. i’ve also read it can increase some types of aggressive behaviour, don’t think it was violence as such, I think it was more likely that animals with higher magnesium were more confident and able to stand up to an aggressor. this is in stark contrast to lithium, which completely blocks drug reward at least of the psychostimulants, produces conditioned place avoidance in animals and generally counters/suppresses behavioural activation.
Actually, in line with what I’ve just said, the study on magnesium and cocaine seem to suggest that magnesium was acting somehow as a substitute for cocaine, as it was able to trigger cocaine and other Psychostimulant appropriate responding in drug experienced as well as naive rats, if I remember correctly.
I know anecdotal reports are not the most reliable, especially with the placebo effect involved, but there might be some scientific merit to those who claim they get dramatically enhanced energy and euphoria from magnesium supplements. this is probably a combination of magnesium’s importance in metabolic regulation of the entire body, but it also likely has dopaminergic affects that involve presynaptic, postsynaptic and downstream dopamine receptor mechanisms.
 
Neuroprotection said:
Very interesting. it should be noted that lithium’s mechanism of action is not fully understood however, a study I came across stated that despite being a rather weak inhibitor of GSK3 in vitro or when administered acutely, long-term administration in vivo at therapeutic doses, alters brain enzymes/Signalling proteins to produce dramatic and powerful inhibition of GSK3. this is perhaps why lithium takes time to produce antimanic affects. at lower doses or when acutely administered, positive effects of lithium on suicidal ideation or depression probably still relies on significant GSK3 as a major mechanism, but other mechanisms related to ion channel inhibition are probably also involved. I used to be really interested in trying lithium supplementation, but after suffering a strange bout of anhedonia/Numbness, Including sudden loss of my Normally extremely high libido and thrill/reward seeking behaviour i’ve changed my mind. not going to go any more into my personal story as I’ve already made a thread about that entitled “helpful substances in the fight against anhedonia“ posted on the dark side. nevertheless, I have recovered from that and don’t want anything that could risk returning me to that state. my impulsivity/thrillseeking and reward seeking behaviour has always been part of me and whilst it does cause me many issues, it also gives me something to Drive me and look forward to each day. The thing is, during that period of depression I went through, I had no desire for self harm/suicide or anything related to that and thankfully, I never have. basically, I’ve heard that lithium does exactly what I don’t want, lowering pleasure/thrillseeking, negatively affecting libido amongst other effects. I think a far better supplement for me would be bioavailable chelated magnesium. this is because magnesium, whilst producing calming/antistress effects can also produce activating/energising effects as well. interestingly, it shares with lithium, though to a much lesser extent The ability to reduce cocaine self administration in animals but the mechanism/effects are markedly different. For example, whilst lithium decreases/Blocks the rewarding value and dopaminergic activating effects of cocaine, magnesium more likely reduces the negative symptoms that drive cocaine consumption, such as stress/Anxiety. furthermore, magnesium is thought to have potent antidepressant effects of its own. finally, and most interestingly, i’ve read that high-dose magnesium can actually produce a significant conditioned place preference in rats. i’ve also read it can increase some types of aggressive behaviour, don’t think it was violence as such, I think it was more likely that animals with higher magnesium were more confident and able to stand up to an aggressor. this is in stark contrast to lithium, which completely blocks drug reward at least of the psychostimulants, produces conditioned place avoidance in animals and generally counters/suppresses behavioural activation.
Actually, in line with what I’ve just said, the study on magnesium and cocaine seem to suggest that magnesium was acting somehow as a substitute for cocaine, as it was able to trigger cocaine and other Psychostimulant appropriate responding in drug experienced as well as naive rats, if I remember correctly.
I know anecdotal reports are not the most reliable, especially with the placebo effect involved, but there might be some scientific merit to those who claim they get dramatically enhanced energy and euphoria from magnesium supplements. this is probably a combination of magnesium’s importance in metabolic regulation of the entire body, but it also likely has dopaminergic affects that involve presynaptic, postsynaptic and downstream dopamine receptor mechanisms.
Click to expand...
Do you have a link for that magnesium cpp study? Sounds interesting.
 
Skorpio said:
Do you have a link for that magnesium cpp study? Sounds interesting.
Click to expand...


pubmed.ncbi.nlm.nih.gov

Magnesium-induced conditioned place preference in mice - PubMed

A conditioned place preference procedure was used in mice to test the hypothesis that magnesium possesses reinforcing properties. Mice were conditioned to the nonpreferred end of a three-compartment straight shuttle box with MgCl2 injections alternating with saline injections on the preferred...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
 
another interesting link about GSK3 I found, can’t believe I forgot to post it earlier. just want to say, only a few months ago when I hated GSK3 based on the false belief that it was innately neurotoxic and pro apoptotic, Reading the following article really Hurt me. this is because I did not want it to be a proapoptotic/Toxic enzyme that contributes to the beneficial/fun/recreational part of amphetamine effects. However, when I discovered I was wrong about GSK3, I actually re-read this article in celebration. I don’t blame anyone who thinks I’m a bit weird, I think that about myself but I’m happy with it. Here’s the link:

www.ncbi.nlm.nih.gov

Inhibition of GSK3 attenuates amphetamine-induced hyperactivity and sensitization in the mouse

Glycogen synthase kinase 3 (GSK3) is implicated in mediating dopamine-dependent behaviors. Previous studies have demonstrated the ability of amphetamine, which increases extracellular dopamine levels and influences behavior, to regulate the activity of ...
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
 
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