sjv is a new member. I don't know anything about his project, whether the science he quotes is accurate, or if the supplements are helpful for PSSD.
Everyone knows the main theory about the pathogenesis of PSSD: the excessive release of serotonin (which has a mixed but essentially inhibitory role on sexual functions) by the serotonergic neurons due to the "desensitized" 5-HT1A autoreceptors (that act as sentinels that regulate the release of a substance according on how much there is already in circulation, this mechanism is also called negative feedback) .
The "down regulation" of the 5-HT1A autoreceptors is instead caused by chronic and excessive activation by its natural "agonist" (serotonin) that is made available in abnormal quantities by the use of SSRIs. It is therefore natural to think to the autoreceptors as something that is "damaged" by excessive competition and that can be cured using an antagonist that lead him to be again "sensitive."
At this point that we have to reflect: the autoreceptor is a sentinel, a switch that if "on" sends a chemical signal. What the cell (neuron) have to do when it receives this chemical signal is written in the genes, that is in the sequence of the DNA; how much it should do (that is, how much to increase or decrease the release of serotonin) it depends on the genes expression.
Essentially two mechanism regulate gene expression:
• Binding of chemical groups directly to DNA (covalently) that function as silencers or activators. The main inhibitor is the methyl group that, binding at particular points of the promoter sequences, silences gene expression. The protein that bind methyl groups to DNA is the DNMT.
• The other is the tangling of the DNA around proteins (called histones): if the DNA is wrapped on itself, the molecular machines that should read the instruction contained in the DNA, cannot bind the DNA because there isn’t sufficient space. The ability of a histone to compact a DNA molecules (and thus repress gene expression) depends on the presence of particular molecules bound to the histone. The main one is the acetate group: if it binds to histone, forces him to expand and so molecular machines can come in and gene expression is activated. The acetyl groups are linked to histone by HAT and detached from it by HDAC. Also histones can be methylated in some particular positions, and this has mixed effects on gene expression.
SSRIs activate gene silencing
It’s well known that SSRIs activate the gene-silencing mechanisms. During the assumption has been seen:
• Increase in the expression of certain proteins that carry methyl groups (called MeCP2 and MBD1)
• Increase the mRNA synthesis of HDAC2 gene (the HDAC of a particular subtype of histone)
• There’s a decreased acetylation in the histone "H3" in three areas of serotonin projection: the caudate-putamen (striatum), the frontal cortex and the dentate gyrus (5-HT neurons are extensively arborized, and their axons reach all brain areas).
All this suggests the induction of gene silencing.
Now we can rethink to the neuron such a stubborn person who does something of wrong: we told him to correct his behavior (the autoreceptor send his message to the cell) but it will not change his behavior (excessive release of serotonin) because it is a person who does not listen what we told him (reduced gene expression). So we cannot think to reactivate the negative feedback mechanism only binding them an antagonist because who is stuck in a situation of "off" is not the autoreceptor but the DNA expression is. The right strategy therefore have to be the reactivation of gene plasticity which can then be guided in the right direction by the use of a 5-HT1A autoreceptors antagonist.
A possible partial theoretical confirmation of this hypothesis is the results of a study in which rats whit an animal model of tardive dyskinesia (a disorder in some ways similar to the PSSD) had a partial remission of the disease using a HDAC inhibitor .
How to induce gene expression plasticity
Firstly, we recall the main objectives:
• To promote the demethylation of DNA by inhibiting DNMT: the new synthesized DNA is less methylated and then whit an increased gene expression.
• Inhibit the deacetylation of histones, in particular inhibiting HDAC
• Encourage the acetylation of histones, in particular by increasing the activity of HAT
It has also been seen that the increase of histone acetylation is accompanied by a demethylation of DNA, that is, the two events have a synergistic effect. It 's important to note first of all that these effects are time and dose dependent, ie the effects are proportional to the dose taken and manifests itself after some time.
Several compounds can do this. Most of them are natural occuring compounds and found in green tea but this does not mean that they are little effective: some are very promising for the treatment of other diseases in which the gene expression change is crucial. Other are drugs are already used for other purposes. Unlucky, often they have a low biodisponibility and a short half-life, than high and multiple doses should be necessary. Most promising are listed for first.
EPIGALLOCATECHINE GALLATE (EPCG) One of most studied, well caracterized and most effective natural compound that influence gene expression. Is one of major component of green tea extract. It can easily cross blood-brain barrier and is demonstrated that directly bind DNA . It is DNMT1, DNMT3, HDAC1 inhibitor and a MeCP2 inhibitor using Mg2+ as cofactor. Increase amount of glutathione and indirectly the acetilation of histone H3 and H4. Unlucky it is also a weak inhibitor of HAT, has a very low biodisponibility and may be hepatotoxic. Has been demonstrated that minimum effective dose in order to induce genetic effect is 800 mg 2 times a day. The ingestion of high grade, dried green extract, which contains a lot of different catechine, gallate and flavonoid, is more effective then the ingestion of pure EPGC: all the “gallate” and “chatechin” compounds are generally HDAC and DNMT inhibitor and they have a synergistic effect. They’re generally recognized as safe.
QUERCITINE A flavonoid, is a strong enhancer of H3 and H4 histone acetylation, thus activates SIRT1 and SIRT6 mediated deacetylation; Inhibit DNMT and LSD1 (histone demethylating protein). It is also a weak MAOI. Was found to be active at a concentration of 75-100 um. GENISTEINA (and less DAIDZEINE and BIOCIANINE A) They are phytoestrogens and belongs to the category of isoflavones. They are strong inhibitor of HDAC (mostly HDAC1) and DNMT (mostly DNMT1 and DNMT3); less strong inhibitor of MeCP2. Was proved to demethylate ipermethylated genomes without lead to ipomethylation. It has a strong and synergic effect whit other DNMT and HDAC inhibitor. It is an estrogen receptor agonist and then may produce non-hormonal effects.
SODIUM BUTIRRATE It is a strong and natural occurring HDAC inhibitor and one of most studied. It has a lot of other positive effects and has been demonstred to be neuroprotective.
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CURCUMINE Strong inhibitor of HDAC, HAT, DNMT, MeCP2. Has been shown to be able to induce demetilation of hypermethylated zone of DNA, in a stronger way than genisteine. Because its potent HAT inhibitor activity it may be a second line treatment or can be used to prevent ssri’s induced modification of genetic expression.
LUTEOLINE Luteolin is a flavone, a type of flavonoid. Increase histone acetylation, particularly H3 e H4, inhibiting their HDAC and activating SIRT6-mediated deacetylation; Inhibit DNMT and LSD1 (histone demetylating protein). Thus, weak diminish phosporylation on H3 and H4 and is a weak indirect antagonist of DNMT.
APIGENINE A flavone, is a HDAT inhibitor (soprattuto H1 and H3) and weak activator of SIRT6 mediated deacetylation. Apigenin may also stimulate adult neurogenesis. Concentration over 5-10 um are not recommended because gaba agonism and other central effects. It is a weak MAOI.
DIALLIL SULFIDE, ANACARDIC ACID and GARLIC A lot of compounds in garlic and broccoli are HDAC and DNMT inhibitor, then high grade dried garlic extract and to eat broccoli may be strongly recommended.
SAM, vitamins B and ZINC S-Adenosil-Methionine is the natural transporter of methyl groups and work in a synergic way whit DNMT, than induce methylation. Its natural counterpart is S-Adenosil-Omocisteine, a strong demethylating agent which expression increase during the use of HDAC inhibitor: this mean that there’s a synergistic effect between increase of acetylation and the activation of demethylation. For this reason, the supplement of SAMe is not recommended. The vitamins of group B are used to carrier and bind methyl group, then supplementation of high amount of B vitamins is not recommended if the increase of demethylation is wanted. The Zn2+ ion is he natural cofactor of HDAC, then the uses of Zn2+ supplements may increase their activities.
I hope that a combination of the induction of gene’s plasticity and the antagonism to serotonin receptors may help to recover from the disease.
Here the right dosage for each components, obtained form the ones used in the studies:
-EPGC 600 mg, 3 times a day (Piping Rock Health Products - EGCG Green Tea 600 mg Standardized Extract, standardized in 30% in EGCG, then 3 caps. 3 times a day of this supplement)
-Quercitine 600 mg, 3 times a day (MegaQuercitin, Solaray)
-Genisteine 800mg, 4 times a day (Vital Nutrients - Genistein)
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Among the others, that are not necessary for the treatments but may have coadiuvant effects:
-Sodium Butyrrate 600 mg, 3 times a day (BodyBio/E-Lyte - Sodium Butyrate)
-Sulpiride 100 mg, 2 times a day
-Apigenine 30 mg, 3 times a day (Swanson Ultra, Apigenin)
-Luteoline 300 mg, 3 times a day(Swanson Ultra, Luteolin Complex)
List of citations
0- Effects of selective serotonin and serotonin/noradrenaline reuptake inhibitors on extracellular serotonin in rat diencephalon and frontal cortex, Tracy M. Felton et al.
1- Mechanisms of control of 5-HT neurons are: • self-inhibition through 5-HT1A autoreceptors (activation of these receptors by 5-HT diminish neuronal firing and produce a negative feedback regulation of transmitter release) • 5-HT1B/1D receptors, located on nerve terminals, respond to 5-HT released locally in the terminal fields inhibiting further transmitter release. These 2 mechanisms ensure tight feedback control of the activity of serotonergic neurons and of terminal 5-HT release. Thus, a prolonged treatment whit ssri may lead to a reduction of binding site for serotonin on SERT, then its ability to reuptake serotonin is chronically diminished. Chronic administration of selective serotonin reuptake inhibitors (but not amitriptyline) results in the desensitization of 5-HT1A somatodendritic autoreceptor function in the dorsal raphe but not in hippocampus, and also results in the desensitization of physiological responses mediated by postsynaptic 5-HT1A receptors. In general, changes in 5-HT1A receptor number have not been observed following chronic administration of antidepressants. A study (Julie G Hensler, 2002) ipotizes that the desensitization of somatodendritic 5-HT1A autoreceptors in the dorsal and median raphe following chronic SSRI treatment do not appear to be mediated by changes in 5-HT1A receptor binding but may be due to a reduced capacity of the 5-HT1A receptor to activate G protein. By contrast, no significant change in postsynaptic 5-HT1A binding following chronic antidepressant treatment.
2- Newton SS, Duman RS (August 2006). “Chromatin remodeling: a novel mechanism of psychotropic drug action”. Mol. Pharmacol. 70 (2)
3- Safarinejad MR, Sperm DNA Damage and Semen Quality Impairment After Treatment With Selective Serotonin Reuptake Inhibitors Detected Using Semen Analysis and Sperm Chromatin Structure Assay
4- The genetics of selective serotonin reuptake inhibitors, Kroeze
5- Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology, Csoka
6- Faure C, Mnie-Filali O, Haddjeri N (February 2006). “Long-term adaptive changes induced by serotonergic antidepressant drugs”. Expert Rev Neurother
7- Palotás M, Palotás A, Puskás LG, et al. (December 2004). “Gene expression profile analysis of the rat cortex following treatment with imipramine and citalopram”. Int. J. Neuropsychopharmacol
8- Kálmán J, Palotás A, Juhász A, et al. (November 2005). “Impact of venlafaxine on gene expression profile in lymphocytes of the elderly with major depression–evolution of antidepressants and the role of the “neuro-immune” system”.
9- Yamada M, Yamada M, Higuchi T (July 2005). “Antidepressant-elicited changes in gene expression: remodeling of neuronal circuits as a new hypothesis for drug efficacy”. Prog. Neuropsychopharmacol. Biol. Psychiatry
101- Boehm C, Newrzella D, Herberger S, Schramm N, Eisenhardt G, Schenk V, Sonntag-Buck V, Sorgenfrei O (2006). “Effects of antidepressant treatment on gene expression profile in mouse brain: cell type-specific transcription profiling using laser microdissection and microarray analysis”.
11- RGFP109, a histone deacetylase inhibitor attenuates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset: a proof-of-concept study, Johnston TH
12- Histone deacetylase inhibitors reverse CpG methylation by regulating DNMT1 through ERK signaling, Sarkar S
13- Green tea polyphenols for prostate cancer chemoprevention: A translational perspective J.J. Johnson
14- Flavonoids Influence Epigenetic-Modifying Enzyme Activity: Structure-Function Relationships and the Therapeutic Potential for Cancer Gilbert, E.R.; Liu, D.
15- Epigenetic activities of flavonoids in the prevention and treatment of cancer, Christian Busch
17- Epigenome, Cancer Prevention and Flavonoids and Curcumin, Višnja Stepanić
18- Dietary Polyphenols May Affect DNA Methylation, Mingzhu Fang
19- Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain disease, Ronald Ross Watson,Victor R. Preedy
20- Mechanisms for the Inhibition of DNA Methyltransferases by Tea Catechins and Bioflavonoids, Won Jun Lee
21- The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells, Zhu WG
22- Epigenetic changes induced by curcumin and other natural compounds, Simone Reuter
23- Green Tea Polyphenols in drug discovery - a success or failure?, Thomas J. Smith
24- Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E, Chow HH
25- Molecular targets of (-)-epigallocatechin-3-gallate (EGCG): specificity and interaction with membrane lipid rafts, Patra SK
Edited by scallywag, 28 November 2016 - 07:26 AM.
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