10 replies to this topic

[Flex]

I´ve read everywhere about Allosteric modulators or agonists but nearly nothing about influencing the gene expression, so therefore my request.

I´m open to any comments.

 

Heres what I´ve found:

 

Neuroprotective role of Bacopa monnieri extract in epilepsy and effect of glucose supplementation during hypoxia: glutamate receptor gene expression.

http://www.ncbi.nlm....pubmed/17940877

 

During epilepsy a significant down-regulation (P < 0.01) of mGluR8 gene expression was observed which was up-regulated (P < 0.05) near control level after B. monnieri treatment which is supported by Morris water maze experiment. In hypoxic neonates we observed up-regulation (P < 0.001) of the NMDAR1 gene expression whereas glucose and glucose + oxygen was able to significantly reverse (P < 0.001) the gene expression to near control level when compared to hypoxia and epinephrine treatment which was supported by open field test

 

 

[lostfalco]

ALCAR and HDAC inhibitors might be of interest. =)

 

ACLAR is an acetyl group donor and should synergize extremely well with HDACi's...in theory.

 

http://www.ncbi.nlm....pubmed/23670591

 

Neuropsychopharmacology. 2013 Oct;38(11):2220-30. doi: 10.1038/npp.2013.121. Epub 2013 May 14.

Upregulation of mGlu2 receptors via NF-κB p65 acetylation is involved in the Proneurogenic and antidepressant effects of acetyl-L-carnitine.

Cuccurazzu B1, Bortolotto V, Valente MM, Ubezio F, Koverech A, Canonico PL, Grilli M.

Author information

Abstract

Acetyl-L-carnitine (ALC) is a naturally occurring molecule with an important role in cellular bioenergetics and as donor of acetyl groups to proteins, including NF-κB p65. In humans, exogenously administered ALC has been shown to be effective in mood disturbances, with a good tolerability profile. No current information is available on the antidepressant effect of ALC in animal models of depression and on the putative mechanism involved in such effect. Here we report that ALC is a proneurogenic molecule, whose effect on neuronal differentiation of adult hippocampal neural progenitors is independent of its neuroprotective activity. The in vitro proneurogenic effects of ALC appear to be mediated by activation of the NF-κB pathway, and in particular by p65 acetylation, and subsequent NF-κB-mediated upregulation of metabotropic glutamate receptor 2 (mGlu2) expression. When tested in vivo, chronic ALC treatment could revert depressive-like behavior caused by unpredictable chronic mild stress, a rodent model of depression with high face validity and predictivity, and its behavioral effect correlated with upregulated expression of mGlu2 receptor in hippocampi of stressed mice. Moreover, chronic, but not acute or subchronic, drug treatment significantly increased adult born neurons in hippocampi of stressed and unstressed mice. We now propose that this mechanism could be potentially involved in the antidepressant effect of ALC in humans. These results are potentially relevant from a clinical perspective, as for its high tolerability profile ALC may be ideally employed in patient subpopulations who are sensitive to the side effects associated with classical antidepressants.

 

 

http://www.ncbi.nlm....pubmed/23382250

 

Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4804-9. doi: 10.1073/pnas.1216100110. Epub 2013 Feb 4.

L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors.

Nasca C1, Xenos D, Barone Y, Caruso A, Scaccianoce S, Matrisciano F, Battaglia G, Mathé AA, Pittaluga A, Lionetto L, Simmaco M, Nicoletti F.

Author information

Abstract

Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a well-tolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-ĸB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-ĸB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.

 

 

http://www.ncbi.nlm....pubmed/20064669

 

Trends Pharmacol Sci. 2010 Apr;31(4):153-60. doi: 10.1016/j.tips.2009.12.003. Epub 2010 Jan 11.

Transcriptional regulation of type-2 metabotropic glutamate receptors: an epigenetic path to novel treatments for chronic pain.

Chiechio S1, Copani A, Zammataro M, Battaglia G, Gereau RW 4th, Nicoletti F.

Author information

Abstract

Activation of metabotropic glutamate 2 (mGlu2) receptors inhibits pain transmission at the synapses between primary afferent fibers and neurons in the dorsal horn of the spinal cord. In addition, mGlu2 receptors are found in peripheral nociceptors, and in pain-regulatory centers of the brain stem and forebrain. mGlu2 receptor agonists produce analgesia in models of inflammatory and neuropathic pain, but their use is limited by the development of tolerance. A new therapeutic strategy could be based on the transcriptional regulation of mGlu2 receptors via the acetylation-promoted activation of the p65/RelA transcription factor. "Epigenetic" drugs that increase mGlu2 receptor expression, including l-acetylcarnitine and inhibitors of histone deacetylases, have a different analgesic profile with no tolerance to the therapeutic effect after repeated dosing.

 

 

 

Edited by lostfalco, 30 March 2015 - 07:30 PM.

[Mind_Paralysis]

Fascinating... Epigenetic drugs... I did not think such a thing was possible. But here it is... This might well be the future of ALL medicine!

 

This topic regards the metabotropic glutamate receptors in perticular, which is an area that Fasoracetam supposedly targets - so, would it be possible to have a look into the effects of fasoracetam on epigenetic expression? I believe Fasoracetam has been brought up by our friend Lostfalco in regards to the modulation of Kynurenic Acid in Schizophrenics before, so perhaps he might be interested in having a look?

 

I myself, am interested in the idea of epigenetically enhancing the Dopamine-receptors - would such a drug be possible? If one could externally enhance the DRD4 -receptors, for instance, perhaps increase their receptor-density, then that COULD be a super-effective, virtually side-effect treatment of some types of ADHD!

 

Such as my own. My 23andme.com genetic testing revealed that I carry the common DRD4 7r allele, which is one of the more implicated candidate genes in ADHD pathology.
 

A drug that enhances the CNS own DRD4's could be the ultimate trick - short of genetic therapy, that is.

 

 

EDIT:

HOOPLA! Yes, yes there is... But one of the only known agents I could find right off the bat, is our good old ENEMY Nicotine:

 

The epigenetic effect of nicotine on dopamine D1 receptor expression in rat prefrontal cortex.

http://www.ncbi.nlm....pubmed/23447334

 

But that's the wrong damn receptor... there's nothing wrong with my D1's - I don't have any of those polymorphisms - I'm an ADHD-er, not an addict.

 

There does seem to be some research going into this, but obviously mostly towards Schizophrenia:

http://news.uci.edu/...tric-disorders/

 

But there should be a possibility here... manipulation of Histones promoting the DRD4 -receptor... it should be possible.

Edited by Stinkorninjor, 12 April 2015 - 11:28 AM.

[Flex]

Its indeed interresting but allways consider how to reverse something when it turns out to be problematic.

the body´s own mechanism is able to do so after a given time (months to Years) but, depending on the mechanism, not allways !

Like in the case of longterm alterations from cocaine.

 

 

Found this:

Human genome guided identification of memory-modulating drugs

Table 2

Antidepressants (e.g., mirtazapine) = HTR2A

....

Fasoracetam = GRM1, GRM5

Memantine = GRIN2A

Antipsychotics = CHRM2, CHRM3, CHRM5, GRIN2A, HRH1, HTR2A

http://www.pnas.org/.../E4369.full.pdf

 

e.g. GRM5 = Metabotropic glutamate receptor 5

 

I cant tell whether those are up or downregulated.

Neither respectively or e.g. completely upregulated.

-------------------------------------------------------

 

Edit: Altough its a bit of topic its still interresting:

 

- (postsynaptic?) 5-ht1a seems to inhibits ampa and nmda currents:

 

..5-HT1A receptors are also involved in the modulation of excitatory glutamatergic neurotransmission, since their activation suppresses AMPA-mediated signaling through the inhibition of CAMKII (Cai et al., 2002a) and reduces NMDA-mediated currents in PFC neurons (Zhong et al., 2008

Serotonin modulation of cortical neurons and networks

http://www.ncbi.nlm....les/PMC3630391/

 

 

But also protect against Glutamte toxicity

 

A Review of the Neuroprotective Propertiesof the 5-HT1AReceptor Agonist Repinotan HCl (BAY x 3702) in Ischemic Stroke
WAY 100635 blocked these effects, indicating that the neuroprotective properties of repinotan are mediated through the 5-HT1A receptor.
The proposed neuroprotective mechanisms of repinotan are thought to be the result of
neuronal hyperpolarization via the activation of G protein-coupled inwardly rectifying K+ channels upon binding to both pre- and post-synaptic 5-HT1A receptors. Hyperpolarization results in inhibition of neuron firing and reduction of glutamate release

http://onlinelibrary...5.tb00055.x/pdf

 

more infos on 5-ht1a:

http://www.pssdforum. co m

An interesting article

http://www.pssdforum...?f=5&t=13#p2138

http://www.pssdforum...&start=10#p2164

 

 

 

 

Edited by Flex, 12 April 2015 - 12:23 PM.

[lostfalco]

"Moreover administration of uridine with DHA activates many brain genes, among them the gene for the m-1 metabotropic glutamate receptor"

 

http://www.ncbi.nlm....pubmed/19262950

 

J Nutr Health Aging. 2009 Mar;13(3):189-97.

Synapse formation is enhanced by oral administration of uridine and DHA, the circulating precursors of brain phosphatides.

Wurtman RJ1, Cansev M, Ulus IH.

Author information

Abstract

OBJECTIVE: 

The loss of cortical and hippocampal synapses is a universal hallmark of Alzheimer's disease, and probably underlies its effects on cognition. Synapses are formed from the interaction of neurites projecting from "presynaptic" neurons with dendritic spines projecting from "postsynaptic" neurons. Both of these structures are vulnerable to the toxic effects of nearby amyloid plaques, and their loss contributes to the decreased number of synapses that characterize the disease. A treatment that increased the formation of neurites and dendritic spines might reverse this loss, thereby increasing the number of synapses and slowing the decline in cognition.

DESIGN SETTING, PARTICIPANTS, INTERVENTION, MEASUREMENTS AND RESULTS: 

We observe that giving normal rodents uridine and the omega-3 fatty acid docosahexaenoic acid (DHA) orally can enhance dendritic spine levels (3), and cognitive functions (32). Moreover this treatment also increases levels of biochemical markers for neurites (i.e., neurofilament-M and neurofilament-70) (2) in vivo, and uridine alone increases both these markers and the outgrowth of visible neurites by cultured PC-12 cells (9). A phase 2 clinical trial, performed in Europe, is described briefly.

DISCUSSION AND CONCLUSION: 

Uridine and DHA are circulating precursors for the phosphatides in synaptic membranes, and act in part by increasing the substrate-saturation of enzymes that synthesize phosphatidylcholine from CTP (formed from the uridine, via UTP) and from diacylglycerol species that contain DHA: the enzymes have poor affinities for these substrates, and thus are unsaturated with them, and only partially active, under basal conditions. The enhancement by uridine of neurite outgrowth is also mediated in part by UTP serving as a ligand for neuronal P2Y receptors. Moreover administration of uridine with DHA activates many brain genes, among them the gene for the m-1 metabotropic glutamate receptor [Cansev, et al, submitted]. This activation, in turn, increases brain levels of that gene's protein product and of such other synaptic proteins as PSD-95, synapsin-1, syntaxin-3 and F-actin, but not levels of non-synaptic brain proteins like beta-tubulin. Hence it is possible that giving uridine plus DHA triggers a neuronal program that, by accelerating phosphatide and synaptic protein synthesis, controls synaptogenesis. If administering this mix of phosphatide precursors also increases synaptic elements in brains of patients with Alzheimer 's disease, as it does in normal rodents, then this treatment may ameliorate some of the manifestations of the disease.

 

 

Edited by lostfalco, 19 April 2015 - 06:43 PM.

[Flex]

@ lostfalco & others

Thanks

 

Willow bark ( which contains the natural form of Aspirine) and Imipramine decrease GrinA 2 and others, altough I dont get the needed ammount + dont know which brain area

See table 3:

 

Novel neurological and immunological targets for salicylate-based phytopharmaceuticals and for the anti-depressant imipramine

http://www.google.de....91071109,d.ZWU

 

 

[lostfalco]

No problem, Flex. =)

 

Thank Mr. Happy as well. I've gotta give props to him for bringing this to everyone's attention. http://www.longecity...ne-uridine-dha/

[Flex]

Damn I´ve mistaken ionotropic GriA2 with metabotropic mglur2..

So its down regulation by imipramine and Willow bark isnt maybe that good in terms of Cognition and Depression but perhaps for addiction. 

Edited by Flex, 20 April 2015 - 03:39 PM.

[DaveX]

This thread is the best.
I was looking at acetylation effect on receptor upregulation, and as part of it also came across ALCAR as having some role in it. I also occasionally had very good experiences with Sodium Butyrate (HDAC inhibitor), which however seem to get messed up easily if one takes anything like a methylation inhibitor like EGCG or any slightly different HDAC/HAT-inhibitor. Then I think one has to do deacetylation again (HAT-inhibitor, the most thorough I've found is Schisandra extract) until one can get back to the effects of Sodium Butyrate (in my case on PSSD and some psychological effects).
Still, that's just tentative and experimental.

And I've found that mglur2 and AMPA are complementary or close to interchangeable in some contexts, with a role in dopamine release in the nucelus accumbens, for example. (Various, google.)

Edit: Altough its a bit of topic its still interresting:

- (postsynaptic?) 5-ht1a seems to inhibits ampa and nmda currents:

..5-HT1A receptors are also involved in the modulation of excitatory glutamatergic neurotransmission, since their activation suppresses AMPA-mediated signaling through the inhibition of CAMKII (Cai et al., 2002a) and reduces NMDA-mediated currents in PFC neurons (Zhong et al., 2008
Serotonin modulation of cortical neurons and networks
http://www.ncbi.nlm....les/PMC3630391/

This is very useful and explains so much. So this might explain some (temporary!) pro-sexual effects of St. John's Wort and gives a decisive indicator for the role of postsynaptic 5ht1a receptors in sexual functioning (going by this, not so good).
Also find this in related articles:
https://www.ncbi.nlm...pubmed/16092936

"Moreover administration of uridine with DHA activates many brain genes, among them the gene for the m-1 metabotropic glutamate receptor"

http://www.ncbi.nlm....pubmed/19262950

This is also great, as I also found that taking Uridine greatly enhances the effects of some other things.

Edited by DaveX, 24 February 2020 - 01:50 AM.

[gamesguru]

Comments welcome on this one.  A study on fermented tea potently antagonizing a type I, mGluR5

Weird how they mention it is "pu-erh" tea specially.  Maybe it is something unique to the fermentation process, that brings out these benefits?  That would be interesting.

https://www.ncbi.nlm...pubmed/27578019

 

Lithium is also known to antagonize mGluR5, but it can have some weird effects too

https://www.ncbi.nlm...pubmed/28800512

[DaveX]

This is very useful and explains so much. So this might explain some (temporary!) pro-sexual effects of St. John's Wort and gives a decisive indicator for the role of postsynaptic 5ht1a receptors in sexual functioning (going by this, not so good).
Also find this in related articles:
https://www.ncbi.nlm...pubmed/16092936

I often regret saying anything on postsynaptic 5HT1a receptors. However part of that I think is that I also need to address my "HPA-axis", so they are not sufficient on their own. And the effects are often felt closer to taking antagonists, often within a few hours, although the half-life is much longer, and although one wants their upregulation, not their deactivation, from antagonism, rather than several days later. Upregulation seems to occur nearly parallely at some doses (I take Berberine or St. John's Wort, prefer the former). So that is pretty confusing. Nonetheless downregulating them, e.g. by Lithium excitation, is clearly worse (eventually) and one feels better upregulating them with antagonists...


Regarding ALCAR and mglur2. I am not sure it is such a big deal to upregulate mglur2, although I guess there is a dopaminergic effect, however when regularly taking (relatively high doses of) ALCAR one quickly notices exhaustion, because it seems to use up ATP. So one would at least have to add a donor of ATP production to it, like Creatine seems to be.

Edited by DaveX, 20 March 2020 - 02:46 PM.