Aspirin Binds To PPARα To Stimulate Hippocampal Plasticity And Protect Memory

[rei]

Interesting study on aspirin from july of last year Aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory

 

[Hugh Johnson]

Peat did mention that he noticed that many people had maintained their sharp minds by taking aspirin. Anecdotal of course, but still a valuable data points. He also made the recommendation of 500mg twice a day.

 

[ecstatichamster]

Peat did mention that he noticed that many people had maintained their sharp minds by taking aspirin. Anecdotal of course, but still a valuable data points. He also made the recommendation of 500mg twice a day.

that seems a high dose. Can you tell me where you heard or read Peat recommending this. Thanks.

 

[Hugh Johnson]

that seems a high dose. Can you tell me where you heard or read Peat recommending this. Thanks.

Sorry, it was an interview I heard years ago.

 

[Arnold Grape]

that seems a high dose. Can you tell me where you heard or read Peat recommending this. Thanks.

Agreed — I’ve read that Peat takes aspirin in 5-700 mg doses, when he feels like it. 1 gram daily would be a hefty dose, although not drastically different than I’ve heard mentioned here.

 

[ecstatichamster]

Thanks @Arnold Grape

 

[Sativa]

The many OTC ways of accessing PPAR-alpha, which directly stimulates Allopregnanolone:

• agmatine
• palmitoylethanolamide
• salicylic acid (aspirin = acetylsalicylic acid)
• caffeine

Anything that increases cAMP will also activate PPAR-alpha which directly stimulates Allopregnanolone.
PDE4 inhibitors, like caffeine, have this property.

PDE4 hydrolyzes cyclic adenosine monophosphate (cAMP) to inactive adenosine monophosphate (AMP). Inhibition of PDE4 blocks hydrolysis of cAMP, thereby increasing levels of cAMP within cells.

Agmatine increases cAMP levels, which activates PPAR-alpha & PGC1-alpha, thus directly stimulating Allopregnanolone.
-
PPAR-alpha mediates the anti-inflammatory actions of palmitoylethanolamide.
Palmitoylethanolamide (PEA), an endocannabinoid-like molecule, reduces pain and inflammation through PPAR-alpha - the molecular target responsible for the anti-inflammatory properties of PEA.
-

Aside:

Incidentally, Palmitoylethanolamide potentially induces 5α-reductase.
A potential anti-finasteride 'remedy solution'?
This could potentially occur via Allopregnanolone, or... an indirect effect of PEA's numerous effects on the Cannabinoid system...​

...interestingly, the effect of PEAmide was partially inhibited by finasteride, a 5α-reductase inhibitor.

The most potent selective inhibitors of 5α-R are:

• polyunsaturated fatty acids (especially linolenic acid)
• zinc
• green tea
• Riboflavin was also identified as a 5α-reductase inhibitor .[14]
• Potentially the Ganoderic acids in lingzhi mushroom
• Potentially Saw Palmetto.

The following reactions are known to be catalyzed by 5α-reductase:[9]

• Cholestenone → 5α-Cholestanone
• Progesterone → 5α-Dihydroprogesterone
• 3α-Dihydroprogesterone → Allopregnanolone
• 3β-Dihydroprogesterone → Isopregnanolone
• Deoxycorticosterone → 5α-Dihydrodeoxycorticosterone
• Corticosterone → 5α-Dihydrocorticosterone
• Cortisol → 5α-Dihydrocortisol
• Aldosterone → 5α-Dihydroaldosterone
• Androstenedione → 5α-Androstanedione
• Testosterone → 5α-Dihydrotestosterone
• Nandrolone → 5α-Dihydronandrolone

@Lokzo @LeeLemonoil @Blossom @Rafael Lao Wai @Inaut

 

[Sativa]

@haidut
if you are still around... feel free to express any thoughts on the induction of 5α-reductase...
re:
...Palmitoylethanolamide (PEA) potentially induces 5α-reductase - a potential anti-finasteride 'remedy solution'?

...interestingly, the effect of PEA was partially inhibited by finasteride, a 5α-reductase inhibitor.

This could potentially occur via PEA's PPAR-α mediated Allopregnanolone release?

Source:
J Neuroendocrinol. 2011 Jul;23(7):591-600. doi: 10.1111/j.1365-2826.2011.02152.x.
Palmitoylethanolamide stimulation induces allopregnanolone synthesis in C6 Cells and primary astrocytes: involvement of peroxisome-proliferator activated receptor-α.
~Link: Palmitoylethanolamide stimulation induces allopregnanolone synthesis in C6 Cells and primary astrocytes: involvement of peroxisome-proliferator act... - PubMed - NCBI

 

[Sativa]

Note that the following also stimulate BDNF production...

• agmatine
• palmitoylethanolamide

Incidentally, OTC Agmatine mimic's quite well the pro-neurogenesis profile of the potent prescription drug Ketamine...(ref below)

Palmitoylethanolamide Enhances BDNF Production & Neurogenesis in the Hippocampus Following Ischemic Brain Injury
...PEA has the ability to induce BDNF production in astrocytes and enhance neurogenesis after brain ischemia, which may be mediated by activation of ERK1/2 and CREB.
-
Acute agmatine administration, similar to ketamine, reverses depressive-like behavior induced by chronic unpredictable stress in mice
Agmatine is an endogenous neuromodulator that has been shown to have antidepressant-like properties.
We have previously demonstrated that it can induce a rapid increase in BDNF levels after acute administration, suggesting that agmatine may be a fast-acting antidepressant.
...
The ability of agmatine to reverse chronic unpredictable stress induced behavioral and biochemical alterations was evaluated and compared with those elicited by the fast-acting antidepressant (ketamine) and the conventional antidepressant (fluoxetine).
...
...similarly to ketamine, agmatine is able to reverse chronic unpredictable stress induced depressive-like behavior in the TST.

Incidentally, here's an ilustrative graphic from the above study lol

 

[nwo2012]

But doesn't Agmatine also increase NO?

 

[Sativa]

But doesn't Agmatine also increase NO?

a bit of a simplistic superficial analysis lol
There are nuances involved here.
It seems both agmatine & progesterone (GASP) raise eNOS; lower nNOS & iNOS.

Agmatine
(raises eNOS • lowers nNOS, iNOS)
Progesterone
(raises eNOS • lowers iNOS, nNOS)
Aspirin
(lowers ALL - eNOS, iNOS, nNOS ~ conflicting - possibly raises eNOS)
Caffeine
(lowers eNOSi • NOS? nNOS?)
Methylene Blue
(lowers eNOS, iNOS, nNOS)

Here's my main thread on Agmatine Agmatine - A 'Peaty' Substance With Potential?

 

[nwo2012]

Nice reply, many thanks.

 

[Hans]

The most potent selective inhibitors of 5α-R are:

• polyunsaturated fatty acids (especially linolenic acid)
• zinc
• green tea
• Riboflavin was also identified as a 5α-reductase inhibitor .[14]
• Potentially the Ganoderic acids in lingzhi mushroom
• Potentially Saw Palmetto.

I'm not so sure about the zinc. I've seen studies where people take large doses and experienced an increase in T and DHT.

 

[Kingpinguin]

I'm not so sure about the zinc. I've seen studies where people take large doses and experienced an increase in T and DHT.

cant remember where I saw that but read somewhere that zinc inhibits shbg to bind to estrogen. But it not testosterone so more shbg to bind to testosterone and more free estrogen. But it likely has other mechanisms tho to increase T.

 

[Hans]

cant remember where I saw that but read somewhere that zinc inhibits shbg to bind to estrogen. But it not testosterone so more shbg to bind to testosterone and more free estrogen. But it likely has other mechanisms tho to increase T.

Zinc supplementation (120mg twice daily) significantly increased DHT (19%), and also slightly increased testosterone (8%) in eugonadal men (490 to 750ng/dl), showing an upregulation of 5 alpha reductase even at a very high dose zinc. (30)
Zinc is also an aromatase inhibitor.
I should add that supplemental zinc does not increase T on a zinc sufficient diet.

 

[Sativa]

I'm not so sure about the zinc. I've seen studies where people take large doses and experienced an increase in T and DHT.

it's quoted straight from the research paper. take your queries up with the authors lol
aside: just because something inhibits 5α-R doesn't automatically imply a certain effect on T/DHT etc. things are more nuanced than this.

 

[SQu]

a bit of a simplistic superficial analysis lol
There are nuances involved here.
It seems both agmatine & progesterone (GASP) raise eNOS; lower nNOS & iNOS.


Here's my main thread on Agmatine Agmatine - A 'Peaty' Substance With Potential?

I've looked through all your posts on that thread in search of agmatine dosage, perhaps I missed it? I'm currently giving my husband agmatine at approximately 750mg a day for glaucoma (roughly the examine.com suggested dosage, haven't checked again recently though). Now that I read it has anti-depressive effects I'd like to know if there's a larger dosage for that. He's recently developed gall stones, depression and bad anxiety, linked I think.

 

[Sativa]

I've looked through all your posts on that thread in search of agmatine dosage, perhaps I missed it?
...
Now that I read it has anti-depressive effects I'd like to know if there's a larger dosage for that.
He's recently developed gall stones, depression and bad anxiety, linked I think.

From what i gather, there is no set agmatine dosage...
I have used it in doses ranging from 200mg to 1g.

Note that agmatine has notable/potent psychoactive effects. Agmatine, like ketamine, is a very useful brain reset/refresh aid, which translates to resetting drug tolerances & aiding in withdrawal symptoms.
It is used by people - as evidenced by their reddit contributions - in doses ranging from 1.5g to 5+g... (a higher dose will result in more notable psychedelic effects)

Have you considered using Palmitoylethanolamide? It's a safe & perhaps somewhat more holsitic approach compared to Agmatine; it also induces Allopregnanolone synthesis.
Agmatine has many modes of action which might over-complicate matters.
Palmitoylethanolamide, on the other hand, is more like a sleek slender tool with elegant potential, also the body naturally degrades it. PEA is a natural potent anti-histamine too...
Agmatine is perhaps more of a sprawl, but both have their merits.

Agmatine pharmacological insight:

Agmatine was found to exert modulatory actions directly & indirectly at multiple key molecular targets underlying cellular control mechanisms of cardinal importance in health and disease.

• Neurotransmitter receptors: Nicotinic, imidazoline I1 and I2, α2-adrenergic, glutamate NMDAr, and serotonin 5-HT2A and 5HT-3 receptors.
• Ion channels. Including: ATP-sensitive K+ channels, voltage-gated Ca2+channels, and acid-sensing ion channels (ASICs).

 

[SQu]

Thank you so much @Sativa. I think I'll try 1g and see how that goes. I don't think psychedelic is a wise goal in this case but brain reset sounds promising. I wonder about potential for helping PTSD then. Will read more closely.

 

[Sativa]

Thank you so much @Sativa. I think I'll try 1g and see how that goes. I don't think psychedelic is a wise goal in this case but brain reset sounds promising. I wonder about potential for helping PTSD then. Will read more closely.

Well, the psychedelic effects are part and parcel of Agmatine's pharmacological actions! Notably Agmatine's BDNF, HT2A, AMPA, cannabinoid-modulating (via imidazoline) & HT3 blocking...

PTSD, from what i recall & gather, is centered around cortisol. Just use any anti-cortisol tool... Salicylic acid & Palmitoylethanolamide are some top solutions for PTSD, as both these substances do everything you want.