"Looking for a cure for PSSD: are we focusing on the right way?"

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anacleta
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"Looking for a cure for PSSD: are we focusing on the right way?"

Unread post by anacleta »

A young Italian boy with PSSD contacted me to share with you a study done by himself about PSSD. He told me that he can not register for this forum because it is "closed."

his study:

Looking for a cure for PSSD: are we focusing on the right way?

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)[1] .
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[0]. 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[2][3][4][5][6][7][8][9][10]:
• 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[11] .


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[12]. 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[13][14][15][16][17][18][19][20][21][22]. 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 [19][23][24][25]. 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.

VALPROATE and SULPIRIDE Valproate is an anticonvulsive and a mood
stabilizer drug that act as a strong HDAC inhibitor and this may account of
its anticonvulsive and mood stabilizing effects. Sulpiride is a very
effective antidepressant (I want to recommend to everyone because is a
fantastic drug whit a rapid onset and persisting effect specially on
ruminative though, anxiety and bad feeling). It was found that a
combination of the two drugs in clinically relevant doses activate brain
demethylation. This effect was studied on GABA neurons but may occur also
in other type of neurons [26][27][28].

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)
-Quercitine 600 mg, 3 times a day (MegaQuercitin, Solaray)

-Genisteine 800mg, 4 times a day (Vital Nutrients - Genistein)

-Apigenine 30 mg, 3 times a day (Swanson Ultra, Apigenin)

-Luteoline 300 mg, 3 times a day(Swanson Ultra, Luteolin Complex)

-Sodium Butyrrate 600 mg, 3 times a day (BodyBio/E-Lyte - Sodium Butyrate)

-Sulpiride 100 mg, 2 times a day

-Valproate 200mg, 3 times a day




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

10- 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

16-http://link.springer.com/article/10.118 ... ltext.html

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

26- Clozapine and sulpiride but not haloperidol or olanzapine activate
brain DNA demethylation, Dong E

27- Selective DNA Methylation of BDNF Promoter in Bipolar Disorder:
Differences Among Patients with BDI and BDII, D'Addario C.

28- Valproate induces DNA demethylation in nuclear extracts from adult
mouse brain, Erbo Don
Recovery
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Re: "Looking for a cure for PSSD: are we focusing on the right way?"

Unread post by Recovery »

Any thoughts to this guys?
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Ghost
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Re: "Looking for a cure for PSSD: are we focusing on the right way?"

Unread post by Ghost »

I'd love to add him to the forum. What is his name? Is this "Recovery" who initially wrote this?

I totally see where he is coming from, and I think that there is something to it. I have a few questions on it where I'm confused a bit:

- Is the silencing of genes specific to the DRN, or is it all across the brain?

- Likewise, is the targeting of demethylation of genes specific to one area, or is it for the entire brain

- Have you tried this yourself? If yes, what happened?

I really like what you'd put together here. I would kill for endless time to read all of the papers and understand it fully. But I'm so busy with school.
- Medical Student & Friendly poltergeist - Lexapro Sept '14. [Hx] [PSSD Lab] [r/PSSD] [Treatment Plan] - Add "Ghost" in replies so I see it :)
Recovery
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Re: "Looking for a cure for PSSD: are we focusing on the right way?"

Unread post by Recovery »

Hi Ghost,

no, i am not the writer.
john099
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Re: "Looking for a cure for PSSD: are we focusing on the right way?"

Unread post by john099 »

what ever happened to this? Has anyone tried to follow this?
Benji19912
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Re: "Looking for a cure for PSSD: are we focusing on the right way?"

Unread post by Benji19912 »

john099 wrote: Mon Aug 17, 2020 9:50 am what ever happened to this? Has anyone tried to follow this?
If we imagine this could actually work I assume that means it would only be one piece of the puzzle rather than catalysing the brain to regain homeostasis?
Terabithia
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Re: "Looking for a cure for PSSD: are we focusing on the right way?"

Unread post by Terabithia »

Has anyone tried this regimen? It seems very plausible and in line with a lot of research i’ve done myself.
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