Gap junctions and ion channels role in sexual dysfunction caused by antidepressants

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kpavel
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Gap junctions and ion channels role in sexual dysfunction caused by antidepressants

Unread post by kpavel »

What's up guys. Since July I've been developing an interesting topic. I decided to understand how Tribulus works and explored a recovery case reported in the discord channel. Based on my pubmed findings and talking with several guys (about mine and their fight with pssd) and reading what I had time for I began experimenting October-December (together with parts of mitochondrial supplementation described here before). I had some notable success but even without it I think the following remedies (herbals, a drug, and food amines), have some potential, maybe decisive, in sexual field. In fact I was looking for something to effectively fix cardiac and cognitive dysfunction.

First of all, for experienced guys, I wanna say that links to scientific studies I put here are in [n] form, where 'n' is the study number. I've created a page with studies at https://kpavel.dreamwidth.org/621.html

A) Diosgenin/CAMPEDEX-5. Diosgenin belongs to ecdysteroids and is contained in Dioscorea family of plants and fenugreek. Similar compounds like dioscin/protodioscin are in Tribulus terrestris, Pedalium Murex, Corchorus Depressus, Smilax China, Rhizoma polgonati. It is often present in different prosexual Chinese formulas for example Qilin pills and several others [85]. The most known Dioscorea plant is Wild Yam, a female supplement but is suitable for males. A Mexican variety of diosgenin containing plant was used to synthesize human steroid hormones (see the story https://medherb.com/Materia_Medica/Dios ... thesis.htm).

But my reason of using wild yam was not it being a steroid-like thing. I found several interesting actions of diosgenin.
- Diosgenin possibly increases DHEA and DHT production [78].
- Dioscin (which can convert to diosgenin in the body) strongly upregulates Connexin 43 gap junction protein and induces M1 immune phenotype transition [58].
- In diabetic heart disease model dioscin remarkably attenuates profibrotic and inflammatory cytokines TGF-β1, TNF-α and IL-1β. It also decreased PDE5 levels in that study [77].
- Diosgenin is useful in the prevention and treatment of neurological diseases including cognitive impairment [263].
- Diosgenin enhances BK(Ca) ion channels. These channels are necessary for erections [198] both in men and in women. Viagra won't work without them [116][251]. Gene therapy for restoring these channels was successfully trialed in the previous decade.
- Dioscin can inhibit pkc alpha and betaII (https://pubmed.ncbi.nlm.nih.gov/27649624/). Since 5-ht2 receptors are pkc activating ones, this may be relevant. Not mentioning that pkc betaII can be a reason of desensitizing 5ht1a receptors (https://www.ncbi.nlm.nih.gov/pubmed/1860872/).

Dioscorea is a part of a novel European prosexual formula CAMPEDEX-5 (allicin + nuciferine + diosgenin) [255]. This supplement may help erection and premature ejaculation. Interestingly Allicin improves cx43 expression [117]. Nuciferine has interesting Flibanserin/atypical antipsychotic-like pharmacological profile [118].

Now, what is gap junction? 'Gap junctions allow the exchange of ions, second messengers, and small metabolites between adjacent cells and are formed by two unrelated protein families, the pannexins and connexins.'[110]
- Direct role of Connexin43 hemichannels in erectile function [61][75][89][128][213].
- Antidepressants seem to block gap junctions [26][32][113][199], MDMA too [216].
- Finasteride decreases CX43 [57].
- Gap junctions are differentially regulated by hormones including retinoids [143].
- Blocked by anandamide, an endocannabinoid [108].
- Anesthetics like propofol (MJ story) or lidocaine regulate GJ [112][202].
- CX43 are necessary for proper GnRH pulses [12].
- Memory and reward functions [64][104][138].
- CX43 is important in cardiac disease and protective for mitochondria [56][129][153].
- Gap junctions play a role in wakefulness [59, 111] and nociception [28].
Although potentially important, gap junctions topic is almost non-existent in pssd and pfs research sphere except for last year hypothesis [197] and trace mentioning of CX43 downregulation by finasteride.
- Multiple sclerosis studies include gap junctions discussion [60][84].
- Bladder function [242].
- Circadian clockwork [106].
- Neurological manifestations like ataxia or spasticity are possible with cx43 mutations [156].

B) Clavulanic acid. This is an interesting bacteria-produced agent which is commonly used with penicillin-group antibiotics to prevent resistance. There are 3 reasons I was interested in the stuff. First, there were several improvement reports from PFS sufferers who used antibiotics. Second, pssdforum had one such report recently (viewtopic.php?f=22&t=3980). Some mentions of CA happened in our community at least since 2009.
Third and most important, CA was planned to be trialed since 2009 but experiments were suddenly stopped [21][146]. Clavulanic acid was shown inrease erections and libido for humans, monkeys and rats [55] for some reason.
Possible mechanisms:
- increase in dopamine in synapse via Munc18-1 and Rab4 [53].
- apomorphine-like action involving oxytocin release [54], possibly ht2c receptor plays a role.
- Rab4 may be a way to increase intercellular gap junctions [205].
- Rab4a is a factor to increase BKCa channels.

C) Spermidine. It is a polyamine and a derivative of ornithine via ornithine decarboxylase (ODC).
Polyamines are absolutely necessary in life. 'The content of spermidine and spermine in mammalian cells has important roles in protein and nucleic acid synthesis and structure, protection from oxidative damage, activity of ion channels, cell proliferation, differentiation, and apoptosis.'[107][190]

- Polyamines exert lifespan extension, possibly via epigenetic mechanisms [233].
- Spermine preserves gap junctions, and specifically CX43 [131, 132, 194, 195, 235].
- Polyamines modulate NMDA receptors [17][185][249].
- Spermidine preserves mitochondrial function [228] via autophagy [227][231] and multiple genes [226], blocks cell apoptosis [256], and provides metabolic switching between OXPHOS and glycolysis [186].
- Spermidine is necessary for myelin restoration [121].
- Polyamines play a great role in learning and working memory [147][167][170][243].
- Ketogenic diet is high in spermine (meat) and spermine is necessary to prevent epilepsy pharmacoresistance [184].
- Muscles depend on spermidine to grow [119][196][224] and physical exercise stimulates polyamine production [124].
- Spermidine upregulates CB1 cannabinoid receptors [229].
- Spermidine potentially counteracts autoimmunity [230].
- Spermidine notably increased testosterone and decreased cortisol in one study [253].
- Important for fertility [164].
- Essential for hair growth [18].
- Helpful in glaucoma [6].
- Androgens and other steroids modulate polyamine synthesis [23].
- Polyamines regulate circadian clock [51, 150].
- Polyamines supplementation accelerates production of gut microbiota [122].
- Polyamines definitely play a role in antibiotic resistance and in resistance to infections [13][193].
- Polyamines are sodium channels blockers [247]. (But how this works is unclear to me.)
- Spermine may increase 5a-reductase https://pubmed.ncbi.nlm.nih.gov/24800957/

Notable spermidine and spermine sources: foods (wheat germ, mushrooms, legumes (peas, soy, beans, lentils, peanuts), beef liver, meat, cauliflower, broccoli, rice bran) [114], brewer's yeast (Saccharomyces cerevisiae), intestinal microbiota [187] & probiotics (e.g. Bifidobacterium animalis ssp. lactis LKM512 (Bifal) [201]), fermentation products, spermidine supplement.

https://www.youtube.com/watch?v=iEL8CGj6svM

Initially I tried Tribulus itself. And first week it was good, better libido, better short-term memory and I was less compulsive. Then 'a surprise' happened, I got post-orgasmic headaches, one of which lasted about 10 minutes. So I was frightened for a few weeks but luckily this never happened for after I stopped the herb. Don't know why but this stuff is really not risk free though very popular.

And now good things that heppened with diosgenin/high spermidine diet.
1) Stronger emotions of all kinds. Also voice sound got stable deep even in the evening. Also I think caffeine is now more exciting.
2) Better body coordination and return of proper reaction. Doing an upper kick is better, catching of a falling thing is possible again. Faster walking speed. Stronger hand grip. No cardiac issues. Also breathing easy. On waking up mouth isn't much dry. Running capacity is good now. My left hand thumb still had increased tonus and sometimes I couldn't tap smartphone with it. Now it's almost gone.
3) Greatly improved skin in the sense of under-eye sagging and skin on hands and feet look improved much to a younger type of elasticity, subcutaneous fat. I had big problems there so it's my personal achievement.
4) Sensitivity is better in the sense that unpleasurable period can sometimes happen, but often can orgasm in 2-5 minutes. And I had worsening on Tribulus guys.
5) My tinnitus that was shortened to minimum but happened every day wtth my mitochondrial plan disappered.
6) I suspect that I have much better cold tolerance now. No shivering like it was when going outside from a cold room.
7) Touch to the skin doesn't have a slight burning component. Now removing itching is only a pleasure.

I planned to get pure clavulanic acid somewhere but it is always sold with amoxicillin. I was told that I had bad reaction to penicillin in childhood. So I won't touch antibiotics. Pure form is sold only on a pair sites for researches and at Alibaba but have no experience buying stuff like that, is it safe, pure and so on. So next year I guess.
User avatar
kpavel
Posts: 324
Joined: Thu Aug 15, 2019 7:50 am
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Re: Gap junctions and ion channels role in sexual dysfunction caused by antidepressants

Unread post by kpavel »

One of guys who worked with Dr. David Healy writes in his transplantology study:
To validate this result with a molecular reagent, we employed the dominant negative gap junction H7 construct. Injection of this mRNA into embryos results in the formation of nonfunctional connexin chimeras, reducing or abolishing native gap junction communication [60, 98, 99]. Embryos were injected with H7 mRNA at the 1-cell stage, resulting in ubiquitous expression, and cultured in ivermectin following transplantation of eye primordium. When donor tissue was visualized, hyperinnervation was strongly inhibited and levels were indistinguishable from those of untreated controls (3 of 38; P =0.41) (Fig. 5b, bi). These results confirm those of chemical gap junction inhibition, and show that gap junction communication is essential for ectopic eyes to hyperinnervate hosts in response to membrane depolarization.

Finally, we sought to determine whether 5-HT signaling was acting upstream or downstream of gap junction communication. Embryos receiving grafts were cultured in a combination of the gap junction inhibitor lindane and 50 μM 5-HT. Animals raised in these conditions and exposed to ivermectin after eye transplant demonstrated hyperinnervation in 23 % of the animals examined, a rate that was statistically indistinguishable from animals treated with 5-HT alone (n =31; P =0.38 (Fig. 5c, ci). The finding that 5-HT can reverse the inhibitory effect of the lindane suggests that 5-HT signaling occurs downstream of gap junction communication.
Janie
Posts: 120
Joined: Sat Feb 11, 2017 4:59 pm
Contact:

Re: Gap junctions and ion channels role in sexual dysfunction caused by antidepressants

Unread post by Janie »

kpavel wrote: Sun Dec 27, 2020 6:10 pm What's up guys. Since July I've been developing an interesting topic. I decided to understand how Tribulus works and explored a recovery case reported in the discord channel. Based on my pubmed findings and talking with several guys (about mine and their fight with pssd) and reading what I had time for I began experimenting October-December (together with parts of mitochondrial supplementation described here before). I had some notable success but even without it I think the following remedies (herbals, a drug, and food amines), have some potential, maybe decisive, in sexual field. In fact I was looking for something to effectively fix cardiac and cognitive dysfunction.

First of all, for experienced guys, I wanna say that links to scientific studies I put here are in [n] form, where 'n' is the study number. I've created a page with studies at https://kpavel.dreamwidth.org/621.html

A) Diosgenin/CAMPEDEX-5. Diosgenin belongs to ecdysteroids and is contained in Dioscorea family of plants and fenugreek. Similar compounds like dioscin/protodioscin are in Tribulus terrestris, Pedalium Murex, Corchorus Depressus, Smilax China, Rhizoma polgonati. It is often present in different prosexual Chinese formulas for example Qilin pills and several others [85]. The most known Dioscorea plant is Wild Yam, a female supplement but is suitable for males. A Mexican variety of diosgenin containing plant was used to synthesize human steroid hormones (see the story https://medherb.com/Materia_Medica/Dios ... thesis.htm).

But my reason of using wild yam was not it being a steroid-like thing. I found several interesting actions of diosgenin.
- Diosgenin possibly increases DHEA and DHT production [78].
- Dioscin (which can convert to diosgenin in the body) strongly upregulates Connexin 43 gap junction protein and induces M1 immune phenotype transition [58].
- In diabetic heart disease model dioscin remarkably attenuates profibrotic and inflammatory cytokines TGF-β1, TNF-α and IL-1β. It also decreased PDE5 levels in that study [77].
- Diosgenin is useful in the prevention and treatment of neurological diseases including cognitive impairment [263].
- Diosgenin enhances BK(Ca) ion channels. These channels are necessary for erections [198] both in men and in women. Viagra won't work without them [116][251]. Gene therapy for restoring these channels was successfully trialed in the previous decade.
- Dioscin can inhibit pkc alpha and betaII (https://pubmed.ncbi.nlm.nih.gov/27649624/). Since 5-ht2 receptors are pkc activating ones, this may be relevant. Not mentioning that pkc betaII can be a reason of desensitizing 5ht1a receptors (https://www.ncbi.nlm.nih.gov/pubmed/1860872/).

Dioscorea is a part of a novel European prosexual formula CAMPEDEX-5 (allicin + nuciferine + diosgenin) [255]. This supplement may help erection and premature ejaculation. Interestingly Allicin improves cx43 expression [117]. Nuciferine has interesting Flibanserin/atypical antipsychotic-like pharmacological profile [118].

Now, what is gap junction? 'Gap junctions allow the exchange of ions, second messengers, and small metabolites between adjacent cells and are formed by two unrelated protein families, the pannexins and connexins.'[110]
- Direct role of Connexin43 hemichannels in erectile function [61][75][89][128][213].
- Antidepressants seem to block gap junctions [26][32][113][199], MDMA too [216].
- Finasteride decreases CX43 [57].
- Gap junctions are differentially regulated by hormones including retinoids [143].
- Blocked by anandamide, an endocannabinoid [108].
- Anesthetics like propofol (MJ story) or lidocaine regulate GJ [112][202].
- CX43 are necessary for proper GnRH pulses [12].
- Memory and reward functions [64][104][138].
- CX43 is important in cardiac disease and protective for mitochondria [56][129][153].
- Gap junctions play a role in wakefulness [59, 111] and nociception [28].
Although potentially important, gap junctions topic is almost non-existent in pssd and pfs research sphere except for last year hypothesis [197] and trace mentioning of CX43 downregulation by finasteride.
- Multiple sclerosis studies include gap junctions discussion [60][84].
- Bladder function [242].
- Circadian clockwork [106].
- Neurological manifestations like ataxia or spasticity are possible with cx43 mutations [156].

B) Clavulanic acid. This is an interesting bacteria-produced agent which is commonly used with penicillin-group antibiotics to prevent resistance. There are 3 reasons I was interested in the stuff. First, there were several improvement reports from PFS sufferers who used antibiotics. Second, pssdforum had one such report recently (viewtopic.php?f=22&t=3980). Some mentions of CA happened in our community at least since 2009.
Third and most important, CA was planned to be trialed since 2009 but experiments were suddenly stopped [21][146]. Clavulanic acid was shown inrease erections and libido for humans, monkeys and rats [55] for some reason.
Possible mechanisms:
- increase in dopamine in synapse via Munc18-1 and Rab4 [53].
- apomorphine-like action involving oxytocin release [54], possibly ht2c receptor plays a role.
- Rab4 may be a way to increase intercellular gap junctions [205].
- Rab4a is a factor to increase BKCa channels.

C) Spermidine. It is a polyamine and a derivative of ornithine via ornithine decarboxylase (ODC).
Polyamines are absolutely necessary in life. 'The content of spermidine and spermine in mammalian cells has important roles in protein and nucleic acid synthesis and structure, protection from oxidative damage, activity of ion channels, cell proliferation, differentiation, and apoptosis.'[107][190]

- Polyamines exert lifespan extension, possibly via epigenetic mechanisms [233].
- Spermine preserves gap junctions, and specifically CX43 [131, 132, 194, 195, 235].
- Polyamines modulate NMDA receptors [17][185][249].
- Spermidine preserves mitochondrial function [228] via autophagy [227][231] and multiple genes [226], blocks cell apoptosis [256], and provides metabolic switching between OXPHOS and glycolysis [186].
- Spermidine is necessary for myelin restoration [121].
- Polyamines play a great role in learning and working memory [147][167][170][243].
- Ketogenic diet is high in spermine (meat) and spermine is necessary to prevent epilepsy pharmacoresistance [184].
- Muscles depend on spermidine to grow [119][196][224] and physical exercise stimulates polyamine production [124].
- Spermidine upregulates CB1 cannabinoid receptors [229].
- Spermidine potentially counteracts autoimmunity [230].
- Spermidine notably increased testosterone and decreased cortisol in one study [253].
- Important for fertility [164].
- Essential for hair growth [18].
- Helpful in glaucoma [6].
- Androgens and other steroids modulate polyamine synthesis [23].
- Polyamines regulate circadian clock [51, 150].
- Polyamines supplementation accelerates production of gut microbiota [122].
- Polyamines definitely play a role in antibiotic resistance and in resistance to infections [13][193].
- Polyamines are sodium channels blockers [247]. (But how this works is unclear to me.)
- Spermine may increase 5a-reductase https://pubmed.ncbi.nlm.nih.gov/24800957/

Notable spermidine and spermine sources: foods (wheat germ, mushrooms, legumes (peas, soy, beans, lentils, peanuts), beef liver, meat, cauliflower, broccoli, rice bran) [114], brewer's yeast (Saccharomyces cerevisiae), intestinal microbiota [187] & probiotics (e.g. Bifidobacterium animalis ssp. lactis LKM512 (Bifal) [201]), fermentation products, spermidine supplement.

https://www.youtube.com/watch?v=iEL8CGj6svM

Initially I tried Tribulus itself. And first week it was good, better libido, better short-term memory and I was less compulsive. Then 'a surprise' happened, I got post-orgasmic headaches, one of which lasted about 10 minutes. So I was frightened for a few weeks but luckily this never happened for after I stopped the herb. Don't know why but this stuff is really not risk free though very popular.

And now good things that heppened with diosgenin/high spermidine diet.
1) Stronger emotions of all kinds. Also voice sound got stable deep even in the evening. Also I think caffeine is now more exciting.
2) Better body coordination and return of proper reaction. Doing an upper kick is better, catching of a falling thing is possible again. Faster walking speed. Stronger hand grip. No cardiac issues. Also breathing easy. On waking up mouth isn't much dry. Running capacity is good now. My left hand thumb still had increased tonus and sometimes I couldn't tap smartphone with it. Now it's almost gone.
3) Greatly improved skin in the sense of under-eye sagging and skin on hands and feet look improved much to a younger type of elasticity, subcutaneous fat. I had big problems there so it's my personal achievement.
4) Sensitivity is better in the sense that unpleasurable period can sometimes happen, but often can orgasm in 2-5 minutes. And I had worsening on Tribulus guys.
5) My tinnitus that was shortened to minimum but happened every day wtth my mitochondrial plan disappered.
6) I suspect that I have much better cold tolerance now. No shivering like it was when going outside from a cold room.
7) Touch to the skin doesn't have a slight burning component. Now removing itching is only a pleasure.

I planned to get pure clavulanic acid somewhere but it is always sold with amoxicillin. I was told that I had bad reaction to penicillin in childhood. So I won't touch antibiotics. Pure form is sold only on a pair sites for researches and at Alibaba but have no experience buying stuff like that, is it safe, pure and so on. So next year I guess.
May I ask what diosgenin source did you take?
Was that the campedex-5? I'm interested in improving skin sagging too.
User avatar
kpavel
Posts: 324
Joined: Thu Aug 15, 2019 7:50 am
Contact:

Re: Gap junctions and ion channels role in sexual dysfunction caused by antidepressants

Unread post by kpavel »

Janie wrote: Wed Aug 18, 2021 6:21 am May I ask what diosgenin source did you take?
Was that the campedex-5? I'm interested in improving skin sagging too.
Solaray Wild Yam root extract 10% diosgenin. I didn't buy campedex-5. Spermidine from food and nicotinamide supplements will help as well, and I've seen studies like higher spermidine and nicotinamide levels in naked mole-rat who are in shape whole their life, and a study where internal organs were saved better into aging with high spermidine diet or mice experiment where restoring mitochondrial DNA favorably changed appearance.
https://www.ncbi.nlm.nih.gov/pmc/articl ... gure/Fig4/
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