38 replies to this topic

[NDM]

Please pay attention to these brief quotes from a 2007 paper on pyroglutamic acid (aka 5-OP). 5-OP is an ingredient of AOR Ortho-Mind and, from what I've read from Michael, is the mother-molecule from which all the various racetams are derived. Michael seems to endorse the safety of 5-OP, on grounds that it is an orthomolecule. On his webpage I've seen that he's taking more 5-OP than piracetam, for example.

However, the quotes below clearly indicate that the toxicity of 5-OP was known from 1973 onwards, with studies cited from 1973, 1984, 1985, 1989, 1990, 1993, 2001. I don't understand Michael's claims and AOR's claims about the safety of 5-OP, given all these references about 5-OP neurotoxicity.

I hope that my lack of background in biochemistry & pharmacology led me to misinterpret the quotes below, and I beg the members qualified in pharmacology to clarify them for me. Also, what are the implications for the racetams users (I personally take only 5-OP because it's easier to get and because I've bought Michael's arguments).


"5-OP was already shown to be neurotoxic (Rieke et al., 1984; Rieke et al., 1989). This organic acid was shown to promote excitotoxicity (Bennet Jr et al., 1973; Dusticier et al., 1985; Barone and Spignoli, 1990) and inhibit brain energy metabolism (Escobedo and Cravioto, 1973; Silva et al., 2001). In addition, chronic intrastriatal infusion of 5-OP produced selective neuron sparing lesions in the rat striatum (Rieke et al., 1984), which has been assumed to be due to glutamate-induced excitotoxic damage (Rothstein et al., 1993)."

"5-OP was shown to be excitotoxic (Bennet Jr et al., 1973; Rieke et al., 1989; Barone and Spignoli,
1990) as well as to compromise brain energy metabolism by inhibiting Na+,K+-ATPase (Escobedo and Cravioto, 1973; Rieke et al., 1984), reducing CO2 production, ATP and lipid syntheses, and also respiratory chain enzyme activities (Silva et al., 2001)."

"Taken together, our present results clearly indicate that 5-OP decreases the non-enzymatic
antioxidant defenses in rat brain, as shown by the significant reduction observed in TRAP
and TAR measurements, and provokes oxidative damage to proteins, probable by enhancing
RS production in cerebral cortex and cerebellum."

And here is the full abstract & bibliographic details of the paper:

Metab Brain Dis (2007) 22:51–65
DOI 10.1007/s11011-006-9041-2
ORIGINAL PAPER
5-Oxoproline Reduces Non-Enzymatic Antioxidant Defenses in vitro in Rat Brain
Carolina D. Pederzolli · ˆ Angela M. Sgaravatti · C´esar A. Braum · Cristina C. Prestes · Giovanni K. Zorzi · Mirian B. Sgarbi · Angela T. S. Wyse · Cl´ovis M. D. Wannmacher · MoacirWajner · Carlos S. Dutra-Filho

5-Oxoproline (pyroglutamic acid) accumulates in glutathione synthetase deficiency, an inborn metabolic defect of the γ -glutamyl cycle. This disorder is clinically characterized by hemolytic anemia, metabolic acidosis and severe neurological disorders. Considering that the mechanisms of brain damage in this disease are poorly known, in the present study we investigated whether oxidative stress is elicited by 5-oxoproline. The in vitro effect of (0.5–3.0 mM) 5-oxoproline was studied on various parameters of oxidative stress, such as total radical-trapping antioxidant potential, total antioxidant reactivity, chemiluminescence, thiobarbituric acid-reactive substances, sulfhydryl content, carbonyl content, and 2,7-dichlorofluorescein fluorescence, as well as on the activities of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase in cerebral cortex and cerebellum
of 14-day-old rats. Total radical-trapping antioxidant potential and total antioxidant reactivity were significantly reduced in both cerebral structures. Carbonyl content and 2,7-dichlorofluorescein fluorescence were significantly enhanced, while sulfhydryl content was significantly diminished. In contrast, chemiluminescence and thiobarbituric acid-reactive substances were not affected by 5-oxoproline. The activities of catalase, superoxide dismutase and glutathione peroxidase were also not altered by 5-oxoproline. These results indicate that 5-oxoproline causes protein oxidation and reactive species production and decrease the non-enzymatic antioxidant defenses in rat brain, but does not cause lipid peroxidation. Taken together, it may be presumed that 5-oxoproline elicits oxidative stress that may represent a pathophysiological mechanism in the disorder in which this metabolite accumulates.

Edited by chrono, 12 November 2011 - 03:30 AM.

[Galantamine]

L-pyroglutamic acid has some therapuetic appeal in the rhelm of traumatic brain injury, but its efficacy as a nootropic is lacking.

Attached Files

•  _L_pyroglutamic_acid_inhibits_energy_production_and_lipid_synthesis_in_cerebral_cortex_of_young_.pdf   203.91KB   34 downloads

[medicineman]

L-pyroglutamic acid has some therapuetic appeal in the rhelm of traumatic brain injury, but its efficacy as a nootropic is lacking.

http://www.sciencedi...16c9b189ed8ea46

I think if you are going to supplement with ANYTHING which you don't know the mechanism to, you should definitely supplement with some potent anti-oxidants. In the above study, the damage done to cells is due to reduction in reduced glutatione. Glutatione is the bodys defense to any oxidative insult.

The studies you mention do show that glutamate is the culprit, but glutamate as shown by the study I mention, induces its damage via reactive oxygen species. N-Acetyl Cysteine is a wonderful supplement to add to your regimen if your taking shit your not sure about... It is in my opinion the ultimate scavenger of reactive species... I take 500mg a day.... Studies show that it increases glutatione levels dramatically in cells. Too much has shown be unhealthy, so sticking to a small and effective dose, while taking other anti-oxidants, might compensate for any damage about to take place due to reactive oxygen species..

The best offense is a good defense... I think testing supplements is fine, but always make sure you have a reserve of protection in case things don't work out like you wish. In this case, NAC (n-acetylcysteine) for the win....

[NDM]

Thanks for the replies so far - I really hope that this thread will develop into a substantive discussion, because the topic seems to have many ramifications for the whole area of nootropics.


All the terms below are, as far as I was able to detect, synonyms. Different studies on the same item (5-OP) use different synonyms in their title, an unfortunate practice which undermines potentially useful connecting of the dots:

5-Oxo-L-Proline
L-Pyrrolidone Carboxylate
L-5-oxo-pyrrolidine-2-carboxylic acid
L-2-pyrrolidone-5-carboxylic acid
L-pyroglutamic acid
Pyroglutamate

[NDM]

I begin to explore some of the ramifications...


First, users of AOR - Ortho Liv - a liver detox combo - should be aware that one of the ingredients - METADOXINE - is a hybrid of pyroglutamate and vit B6. Below is a very useful quote from


Subst Abuse Treat Prev Policy. 2006; 1: 35. doi: 10.1186/1747-597X-1-35.PMCID: PMC1764726

A follow up study on the efficacy of metadoxine in the treatment of alcohol dependence

Irene Guerrini


"Several studies have proposed the use of metadoxine in the treatment of acute and chronic alcohol misusers [17-21]. Metadoxine is an ion-pair between pyrrolidon carboxilate (PCA) and pyridoxine (vit. B6) with the two compounds linked in a single product by salification. This process synergistically increases its pharmacological activity [17]. In animal studies metadoxine increases the plasma and urinary excretion of ethanol, inhibits the increased production of fatty acid esters in the liver during chronic alcohol intake, reduces oxidative stress and prevents glutathione depletion in the hepatic tissues [17]. In the brain metadoxine increases the level of GABA and acetylcholine in the frontoparietal cortex of guinea pigs [22]. In mice it increases the level of dopamine in the striatum[23,24].In human studies, it has also been postulated that metadoxine is effective in maintaining abstinence, in decreasing the craving for alcohol and in improving the cognitive function mainly short-term memory [17,19,20]. The improvement of the short-term memory can be related to the effect of this compound on the cholinergic and gabaergic system reported by Antonelli and coworkers in guinea pigs [22].

Clinical trials showed that in acutely intoxicated patients metadoxine reduces the ethanol blood levels and increases the urinary clearance of ethanol and its metabolites [21]. Metadoxine seems to be effective in the recovery of fatty liver and in improving the laboratory blood tests [18] and, as shown by Shpilenya and coworkers (2002), it seems to ameliorate the clinical and behavioural symptoms during alcohol intoxication [21]. Caballeria and co-workers (1998) reported in a double-blind randomized multicentre study that metadoxine significantly improves the liver enzymes and reduces the rate of steatosis after just a month of treatment [18]."

Here's the last quote, from the conclusion [remember PCA = 5-OP]:

"An anti-craving effect has been suggested to explain the ability of this compound to induce alcohol abstinence and to improve clinical symptoms [17].

Both the pyrrolidon carboxilate (PCA) and the pyridoxol are also important molecules involved in the energy metabolism and in maintaining the homeostasis of the brain. Wei et coworkers (1999) showed that serious cognitive deficit occurs in vitamin B(6)-deficient animals [25]. Nutritional deficiency is an important element in the pathogenesis of cognitive impairment and consequently affects the patients' compliance to the treatment. Furthermore PCA has been shown to have antioxidant effects and seems to reduce the aging process in the brain [26]." [however, the abstract of reference 26 speaks only of metadoxine, not of PCA as such]



So what the heck is going on:


1. 5-OP is said (in the paper quoted in my 1st post) to increase oxidative stress in the brain (protein oxidation), but metadoxine reduces oxidative stress and glutathione depletion in the liver! How come?


2. 5-OP is said to reduce brain energy production, but metadoxine boosts brain performance! How come?


In the quote above they use the phrase "synergistically increase" which seems to suggest that the beneficial effects # 1 and # 2 above are to be expected independently, albeit at lower intensities, in both 5-OP and B6. Metadoxine seems to have been created to amplify these beneficial effects. But the implication seems to be that even on its own 5-OP would have those effects...

Is it possible for a substance to increase brain performance by decreasing brain energy production???? This seems to be a contradiction in terms, unless 5-OP allows an increased efficiency of brain energy utilization.


Again, if metadoxine is so wonderful, shall we all supplement with it [I drink 3 beers * 3 times a week...]?
How come all the negatives of 5-OP seem to disappear by simply pairing it with B6?

By mixing vodka with cranberry juice one does not nullify vodka's negative effects...

[NDM]

another odd ramification - topical pyroglutamic acid is a great moisturizer!!!



L'acide pyrrolidone carboxylique (PCA) et la peau

E.J. CLAR*A. FOURTANIER*
Copyright 1981 International Journal of Cosmetic Science

KEYWORDS

Pyrrolidonecarboxylic acid • moisturization • cosmetics • skin tests • biophysics

SummaryThe medical and biological literature was reviewed with stress laid on the role of pyrrolidone carboxylic acid (PCA) and its sodium salt (NaPCA) in skin, its metabolism, its functions.

The paper also includes a summary of 8 years of evaluation work carried out in our Laboratory on creams and lotions containing PCA-NaPCA which were assessed by biophysical (impedance measurement, α relaxation) and clinical methods.

It is now definitely demonstrated that PCA is an hydrating agent and that all the cosmetic preparations containing at least 2% of the PCA-NaPCA salt system improve the condition of dry skin at short or long term provided an adequate vehicle is used (e.g. aqueous solutions are ineffective).

The mecanism of action is discussed with reference to metabolism and physiological role of PCA in stratum corneum.

Received 11 January 1980

DIGITAL OBJECT IDENTIFIER (DOI)10.1111/j.1467-2494.1981.tb00275.x About DOI

[NDM]

I found on amazon.com this account of the effects of pyroglutamic acid...the guy is taking it at night...which would make sense given that it lowers brain energy metabolism. He claims that the next day he's very sharp and crystal clear...Maybe pyroglutamic acid works along the same lines as DMAE, melatonin, or theanine? Maybe it works by rebooting the brain at night?

How the heck to reconcile the earlier abstract about the neurotoxicity of pyroglutamic acid, with accounts such as this one? Is the path to mental clarity and performance paved with neurotoxicity? Or is pyroglutamic acid acting as a mild neurotoxine that stimulates brain's hormesis? The negative abstract I cited in the opening of this thread says that it is neurotoxic, but it doesn't say just how much...Maybe it's only marginally neurotoxic and the cost/benefit balance is overall OK.



"Be Smarter. Think Clearer. Improve Memory. Be More Present., August 3, 2008

By Mark Alan Effinger "eAgent" (Portland, Oregon) - See all my reviews

Pyroglutamic Acid is, in some ways, a miracle amino acid.
As the founder and CEO of a brainstorming software firm, I am expected to have something "oin the ball, when it comes to how to optimize the brain.
L-Pyroglutamic Acid is one of the key ingredients.
I work sometimes 20 hour days, back-to-back. The stress this puts on your choline stores in the brain is significant.
L-Pyroglutamic Acid is one of the major amino acids to restore that critical neurochemical, and put you back on track.
I take 2000-3000 mgs immediately before bed. Wake up feeling great, and VERY sharp and crystal-clear.
I've tried 5 different brands, and Source Naturals L-Pyroglutamic Acid 1000mg - 120 - Tablet seems to provide the greatest overall benefit.

Mark Alan Effinger
RichContent.com
ThoughtOffice.com"

[Zoroaster]

This is kind of unsettling news. We should do some research on the mechanism by which pyroglutamic acid is doing its damage and make sure the racetams don't have the potential to have the same effect.

[NDM]

@Zoroaster: unsettling indeed...I got a stock of 240 tablets * 1g...and don' t know what to do...take it or throw it away. One of my concerns is whether pyroglutamate works acutely or only long-term.

If, let's say, I have a difficult cognitive task on Tuesday, is it enough to take pyroglutamate Monday night? If yes, than I would limit my intake only to those days when I have to be in peak cognitive shape.
But since the racetams are pyroglutamate derivatives, and since I've read that they work chronically, with effects kicking in after a while, I fear that the same might be the case with pyroglutamate...


Here's another ramification:

"Pyroglutamate plus TMG is a great combination for BBB uptake of glycine and enhancement of the cholinergic system needed for verbal memory."

statement by a pharmacist, lifted from
http://overcomingcan..._and_autism.htm

[medicineman]

this is like comparing ecstasy to amphetamine. they both are very similar in structure, yet anyone who has taken both, knows that they are completely different. and the up to date scientists know how much more harmful amphetamine is compared to x.

[NDM]

this is like comparing ecstasy to amphetamine. they both are very similar in structure, yet anyone who has taken both, knows that they are completely different. and the up to date scientists know how much more harmful amphetamine is compared to x.

the fact that sometimes small differences of structure may lead to large differences of function does not allow us to assume that the small differences of structure between pyroglutamate and racetams exempt the latter from the neurotoxicity of the former. It remains an empirical question. Actually Michael from AOR trusts pyroglutamate more than the racetams because the former is an orthomolecule, hence likelier, on theoretical grounds, to be safer than synthetic/artificial derivatives.

[gerhard]

I had thought that there were a substantial number of trials showing piracetam free of toxicity?

[kilgoretrout]

I don't believe it.

Does anyone have the time to back-calculate from that paper what the equivalent human doses would be?

I would place a wager that it translates in something immense.

I would not necessarily trust the exactitude of something just because it is published in a journal.. HOW MANY DIFFERENT STUDIES, HOW MANY DIFFERENT LABS GOT RESULTS LIKE THIS?

I bet just the one, eh?

My experience was that it is a phenomenal substance. In modest doses, 1g once perhaps twice a day, very effective and really clarifying everything. More than that and I got a "too much coffee" feeling.

It is a naturally occuring amino acid, right? And all these -racetams that were derived from it have supposedly been given in massive doses with zero "toxicity", right?

I have a problem with:
- vague terms like "toxicity", "exitotoxicity" (that one's a real doozy)
- extrapolating the effects of substances given in epic doses IVed into the bloodstream of tiny little frightened caged rodents up to us.

[kilgoretrout]

I am going to have to see more than one research report by a couple bored Japanese med-tech geeks who were infusing gigantic doses of this ACID direclty into a couple unfortunate rodents, no doubt "just to see what happened".

Yes I am making up that scene, but I find it hard to believe anything so neurotoxic could do this to a bunch of frail over 65 year olds:

"...The two-month study involved 40 patients aged 65 and above, who were all
suffering from memory problems. Half of these patients received pyroglutamic
acid every day for two months, while the other half, who made up the control
group, received a placebo. At the end of the study the researchers found that
the group taking pyroglutamic acid demonstrated significant improvements in
memory function, compared to the control group"

FROM THE "Your Favorite Noots" topic (posted by me):

One thing I used to love taking I have not seen metioned here, perhaps it would be good to remind people about (it has been mentioned at Imminst before):

L-PYROGLUTAMIC ACID (aka PYROGUTAMATE)

More than DMAE, more than standard amino precursors, more even then Aniracetam, I always found that when on this I got a really remarkable sense of well-being alterness & focus. I like the way the emailer to Sahelian below puts it: "a keen feeling of concentration" way better than any -racetam or caffeine etc. Almost like a smooth non-jittery amphetamine high. From an amino? I was quite suprised. (But watch out... it needs to be taken on an empty stomach, but more than 1g can cause pretty strong stomach upset... it tastes like battery acid in the mouth, one of the sourest things in existence I think). [NOTE: one author below says the opposte (must take with a lot of food to avid diahrea, but I disagree... other than a small amount of buffering starch or whatever, food will impair absorption.

I was using the 1g tabs from Source Naturals. Too bad I could not find it in capsules... which ought to help quell the stomach issues, keeping it high and dry till it is a little closer to the intestines.

After seeing the following, I am going to have to try adding this to the regimen above:

Pyroglutamate supplement by Ray Sahelian, M.D.
http://www.raysahelian.com/pyroglutamate.html
"...Pyroglutamate Emails
I'm taking smart pills pyroglutamate with piracetam, and I'm feeling very energized with a keen feeling of concentration. Piracetam at 200 mg only gave a feeling of confusion, but as soon as I combine it with this pyroglutamate, the effects were remarkable. My short term memory has also increased...."


As it turns out:

http://www.smart-drugs.com/JamesSouth-Nootropics.htm
"The four main commercially available "racetam" nootropics all share a pyrrolidine nucleus, while Piracetam, Oxiracetam, and Pramiracetam, also share an acetyl group. The racetams (especially Piracetam and Oxiracetam) are closely related in structure to the amino acid Pyroglutamic Acid. Pyroglutamic Acid has been shown in some studies to have weak nootropic activity (Gouliaev and Senning 1994). Pyroglutamic Acid is naturally present in many human foods, as well as the mammalian brain."


http://keywen.com/en/OXIRACETAM

PYROGLUTAMIC ACIDUpDw('PYROGLUTAMIC_ACID','-Abz-');

• The racetams (especially Piracetam and Oxiracetam) are closely related in structure to the amino acid Pyroglutamic Acid. (Web site)UpDw('PYROGLUTAMIC_ACID','6e3aca1');
• Oxiracetam, aniracetam and pyroglutamic acid prevent brain acetylcholine decrease and amnesia induced by scopolamine.UpDw('PYROGLUTAMIC_ACID','ff40754');

Pyroglutamic Acid: The Natural Brain-boosting Nutrient That Can Improve Mental Fatigue And A Poor Memory

http://www.thehealthierlife.co.uk/natural-health-articles/mental-health/pyroglutamic-acid-improve-mental-fatigue-00926.html

EXCERPTS FROM THIS ARTICLE:

"...Researchers have found that it possesses brain-boosting properties without causing harmful side effects..."

...The brain-stimulating benefits of pyroglutamic acid have been known about for several years. As early as 1984, Italian researchers reported that pyroglutamic acid encouraged the release of the memory chemical acetylcholine in the brain.1

...research carried out by Italian researchers, showed that pyroglutamic acid helps preserve acetylcholine levels in the brain, as well as protecting it from chemicals that can worsen memory.2, 3

..."An animal study carried out by Russian researchers found that pyroglutamic acid was just as effective in improving memory and learning as prescription-only medications, such as Piracetam.4

...In fact, Dr Ward Dean, a founding member of the Board of the American Academy of Anti-Aging Medicine, believes that: 'Pyroglutamic acid is the nutritional equivalent to the most popular pharmaceutical-grade prescription-only smart drugs.'

...The memory-boosting abilities of pyroglutamic acid have also been proved in human studies. Scientists at the department of Neurological Pathology at the University of Catania, in Italy, compared pyroglutamic acid against a placebo (dummy) treatment.

...The two-month study involved 40 patients aged 65 and above, who were all suffering from memory problems. Half of these patients received pyroglutamic acid every day for two months, while the other half, who made up the control group, received a placebo. At the end of the study the researchers found that the group taking pyroglutamic acid demonstrated significant improvements in memory function, compared to the control group.5"

In a recent study conducted by scientists at the Laboratory of Pharmacology at the Russian Academy of Medical Sciences, in Moscow, pyroglutamic acid was found to improve blood circulation in the small arteries of the brain without any side effects.6


An adequate flow of blood to your brain is necessary for essential metabolic
processes to take place in your brain cells. It increases the brain's ability to
use glucose, meaning your brain cells have more energy available for their
everyday needs, and feelings of tiredness and low mood are also improved.7


1. Antonelli T et al. Pharmacol Res Commun 1984;16(2):189-197

2. Spignioli G et al. Pharmacol Res Commun 1987;19(12):910-912

3. Pepeu G, Spignoli G. Prog Neuropsychopharmacol Bio Psychiatry 1989;13:S77-S88

4. Romanova GA et al. Eksp Klin Farmakol 1992;55(5):6-8

5. Grioli S et al. Fundam Clin Pharmacol 1990;4(2):169-173

6. Lunshina EV et al. Eksp Klin Farmakol 2002;65(3):3-5

7. Mirzoian SA et al. Eksp Klin Farmakol 1994;57(1):22-24

Edited by kilgoretrout, 04 August 2009 - 03:29 AM.

[Galantamine]

Individuals 65 years and up are generally categorized as being a population with risk of excitotoxicity-induced brain pathologies. Pyroglutamic acid may be a good supplement for this age-range. Refer to post #2.

[acantelopepope]

With the continuing question of piracetam's neurotoxicity, I want to revive this thread for further discussion.

I found it interesting that one user reported L-PGA (Pyroglutamic acid) actually worked synergistically with piracetam.

Another thought I had: if someone is experiencing neurotoxicity, what would be the most prevalent symptoms? More importantly, what would be the strongest agents to alleviate the symptoms?

I haven't done much looking into these questions yet, but I won't leave them unanswered. If someone can point me in the right direction it would help.

Edited by acantelopepope, 18 January 2010 - 12:05 AM.

[outsider]

Well from my point of view, and I won't please anyone here, any synthetic man-made molecule has some form of toxicity attached to it. It can be small or great (Viox).

But for some people they are just not bothered with a particular toxicity but for others they might be very sensitive. It depends on your particular body.

[medicineman]

Well from my point of view, and I won't please anyone here, any synthetic man-made molecule has some form of toxicity attached to it. It can be small or great (Viox).

But for some people they are just not bothered with a particular toxicity but for others they might be very sensitive. It depends on your particular body.

nature is the most potent and most lethal laboratory..... man made or not, one end of the therapeutic window compared to the other end, is only a matter of dosage..... digoxin being the ultimate example (obtained from the foxglove plant, yet is an essential cardio drug. healthcare workers shiver at the name of it though)

[tarakosha]

I just purchased Piracetam and Pyroglutamic acid after doing a lot of research online. I am new to noots but have been taking DMAE for about 3 months from 250 to 400mg/day mostly to induce night dreaming and I wouldn't mind extra cognitive and life span benefits reported on DMAE. Back to Pyroglutamic acid: it tastes worse than vitamin C, 10 times stronger -buy caps or your teeth enamel will wear off. I just started taking it about 6 days ago, about 1/2 teaspoon/per day, divided into 3 doses all during the day. I haven't noticed anything significant yet from taking yet. I am also in college -- I will know for sure after some time if I start retaining more information and remembering/recalling easier. When it comes to toxicity: Pyroglutamic acid is NOT the same as Glutamate, and Glutamate is not the same as GLutamine! These are 3 different things. Glutamine - is amino acid, helps to support immune system and keep positive nitrogen balance -good for burn victims and it helps to assimilate nutritives from GI tract. Glutamate -is MSG -gives 'umami' taste and is a proven excitotoxin -excites your nerves until they die. I put MSG ( 1 tablespoon) into my pot of soup one time, to have 'umami' taste and developed eye twitch for a week that twitched constantly. I did a search online for Glutamate (MSG) and found it to be the cause and a great excitotoxin. Pyroglutamic Acid on the other hand PROTECTS from glutamate toxicity: -

PGA protects cortical neurons against Glu-induced neurotoxity

.

Zhongguo Yao Li Xue Bao. 1999 Aug;20(8):733-6.
L-pyroglutamic acid protects rat cortical neurons against sodium glutamate-induced injury.
Xiao XQ, Liu GQ.
Department of Pharmacology, China Pharmaceutical University, Nanjing.
AIM: To evaluate the effects of L-pyroglutamic acid (L-PGA, L-5-oxo-2-pyrrolidinecaroxylic acid) on sodium glutamate-induced neurotoxicity in rat cortical neurons. METHODS: In primary cortical cultures from 16-d-old fetal rat, neuronal viability and contents of nitrite in the bathing medium after transient exposure to sodium glutamate (Glu) were measured; with Fura 2-AM as an intracellular calcium indicator, AR-CM-MIC cation measurement system was used to examine cytosolic free calcium ([Ca2+]i). RESULTS: L-PGA 10-80 mumol.L-1, inhibited Glu (500 mumol.L-1)-induced neuronal loss in a concentration-dependent manner with IC50 value of (41 +/- 9) mumol.L-1 (95% confidence limits: 30.3-54.7 mumol.L-1). L-PGA also attenuated Glu-induced NO release. L-PGA 1, 3, 10, 30, and 100 mumol.L-1 depressed Glu-caused [Ca2+]i elevation by 20.5%, 34.4%, 47.7%, 70.6%, and 80.4%, respectively. CONCLUSION: L-PGA protects cortical neurons against Glu-induced neurotoxity which may be related to inhibition of NO formation or suppression of the rise in [Ca2+]i.
PMID: 10678108 [PubMed - indexed for MEDLINE]

Also see this research: A new endogenous anxiolytic agent: L-pyroglutamic acid. : http://www.ncbi.nlm..../pubmed/2455680
It will take me about 6 months to finish Pyroglutamic Acid, then I will start Piracetam and see the difference. Right now I am taking DMAE 200mg/ x2 day, Acetyl-L-Carnitine 250mg / x2 day with DMAE, and Pyroglutamic Acid at 1/2 teaspoons/day. I don't want to mix Piracetam as I would like to experience each individually, and only then will I mix and match.I will increase my dose of Pyroglutamic acid to 1-1.5 grams a day after 2 weeks when I get my caps from amazon.

Also see: http://www.sciencedi...2b2c6d63261a4c5
and: http://www.biomedexp...roglutamic_acid

Edited by tarakosha, 11 April 2010 - 05:37 PM.

[tarakosha]

I am also confused by the following researches on Pyroglutamic Acid:
http://www.ncbi.nlm....Pubmed_RVDocSum
and:
http://www.ncbi.nlm....Pubmed_RVDocSum

But then again, if it is exhibiting neurotoxic effects why Source Naturals would sell Pyroglutamic as a Supplement, they would know better than that?!
Many other websites claim Pyroglutamic acid as a safe natural nootrope, howver the research in this post and the post above I posted with links, they contradict each other. Can anyone make sense from all of this?

Edited by tarakosha, 11 April 2010 - 06:37 PM.

[chrono]

The papers cited in the original post are 6238648 and 2565247, both by the same head researcher. The material was injected directly into the rats' brains, so I don't think it's possible to predict what dose is required to produce this effect when orally administered to humans.

A more recent study (8789605) was unable to find any lesions by the same method of administration, as was this older one posted by tarakosha. However, I would regard the possibility, taken with the excitotoxic and metabolic data, as a very good reason not to take 5-OP. Especially if the benefits are as negligible as reported.

Piracetam is a different story entirely. A chemical derivative does not necessarily share any of the pharmacological properties of a precursor compound. I couldn't find a synthesis for piracetam, but I'd hazard that it's MANY synthetic steps away, based on the difference between the molecules.

And also based on how different they are, I would find it pretty surprising if they shared the same mechanism of action. Combined with the substantial body of safety data, I'd say there's not much of a case for piracetam toxicity here.

Attached Files

•  274px_Piracetam.svg.png   8.72KB   1 downloads
•  800px__S__Pyroglutamic_acid_Structural_Formulae.png   12.79KB   1 downloads

Edited by chrono, 13 April 2010 - 09:56 AM.

[noos]

Hi, I purchased magnesium pidolate supplement and I am liking it. It can be placebo or other thing I am takin but it seems to give a calm energy.

Anyone still using pidolate? tarakosha?

[dreth7]

So what was ever decided on Pyroglutamic Acid?

[chrono]

So what was ever decided on Pyroglutamic Acid?

Well, unfortunately, it's really not possible to 'decide' on even the most well-studied pharmaceuticals in a final way...let alone ones like these, where we're making guesses based on how it behaves when injected directly into the brains of rats.

I think the comments I made above are pretty reasonable: it's a potential (yet unknown) risk, for what seems to be a fairly paltry benefit (if any). I think there are much better options all over this board.

[QuantumTubule]

Metab Brain Dis (2007) 22:51–65
DOI 10.1007/s11011-006-9041-2
ORIGINAL PAPER
5-Oxoproline Reduces Non-Enzymatic Antioxidant Defenses in vitro in Rat Brain
Carolina D. Pederzolli · ˆ Angela M. Sgaravatti · C´esar A. Braum · Cristina C. Prestes · Giovanni K. Zorzi · Mirian B. Sgarbi · Angela T. S. Wyse · Cl´ovis M. D. Wannmacher · MoacirWajner · Carlos S. Dutra-Filho

5-Oxoproline (pyroglutamic acid) accumulates in glutathione synthetase deficiency, an inborn metabolic defect of the γ -glutamyl cycle. This disorder is clinically characterized by hemolytic anemia, metabolic acidosis and severe neurological disorders. Considering that the mechanisms of brain damage in this disease are poorly known, in the present study we investigated whether oxidative stress is elicited by 5-oxoproline. The in vitro effect of (0.5–3.0 mM) 5-oxoproline was studied on various parameters of oxidative stress, such as total radical-trapping antioxidant potential, total antioxidant reactivity, chemiluminescence, thiobarbituric acid-reactive substances, sulfhydryl content, carbonyl content, and 2,7-dichlorofluorescein fluorescence, as well as on the activities of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase in cerebral cortex and cerebellum
of 14-day-old rats. Total radical-trapping antioxidant potential and total antioxidant reactivity were significantly reduced in both cerebral structures. Carbonyl content and 2,7-dichlorofluorescein fluorescence were significantly enhanced, while sulfhydryl content was significantly diminished. In contrast, chemiluminescence and thiobarbituric acid-reactive substances were not affected by 5-oxoproline. The activities of catalase, superoxide dismutase and glutathione peroxidase were also not altered by 5-oxoproline. These results indicate that 5-oxoproline causes protein oxidation and reactive species production and decrease the non-enzymatic antioxidant defenses in rat brain, but does not cause lipid peroxidation. Taken together, it may be presumed that 5-oxoproline elicits oxidative stress that may represent a pathophysiological mechanism in the disorder in which this metabolite accumulates.

This abstract is demonstrating a compound that is profoundly neurotoxic, there is just the question of the potency of this neurotoxicity.
The same studies need to be performed for Piracetam as this is capable of clevage into glutamic acid aswell

Researchers have found that it possesses brain-boosting properties without causing harmful side effects..."

Statements like this have almost no scientific value, yet group concenious seems swayed but such, often all it means that there was no significant increase in mortality, often over a short peroid aswell. one must ask what made them draw these conclusions

[chrono]

The same studies need to be performed for Piracetam as this is capable of clevage into glutamic acid aswell

That's a lot of cleaving. Is this likely, or even possible, under physiological conditions? What chemical reactions are necessary for this to occur?

Also, piracetam and levetiracetam are excreted mostly unchanged (with some "inactive" metabolites) [1] [2] [3] [4] [5]. A search for piracetam + L-PGA produced no results, probably indicating that no study has found evidence of such metabolism. And some of the cited research found brain lesions in L-PGA concentrations as low as 20 nmol. It seems pretty likely that in the long history of piracetam study (including huge dosages), evidence of a metabolite which is obviously neurotoxic at such low dosages would have come up, if it was possible.

Edited by chrono, 12 November 2011 - 06:45 AM.

[QuantumTubule]

Cleaving Nitrogen-Carbon bonds happens often in biological systems. Piracetam doesnt Cleave to Glutamic acid, but to something rather similar, it lacks the carboxylic acid group but one position over there is a "ethyl carboxylic" off the nitrogen. One would assume that both of these substances interact with the same class if substrates, what ever this is(I dont know-may just be receptor), however the action maybe be agonist or antagonist etc. As 5-OP is demonstrating toxicity at 20nmol/L it is likely that this is the toxin not Glutamic acid which requires far higher concentrations. My guess is that 5-OP is acting as a high affinity glycine agonist of NMDA channels, which piracetam may do aswell. This is a bit over my head.
Just saying I would like to see the same proticol as "5-Oxoproline Reduces Non-Enzymatic Antioxidant Defenses in vitro in Rat Brain" performed for Piracetam

[sam7777]

This is a great topic for addressing the assumed safety/toxicity of these highly marketed amino acids that are neutraceuticals.

What I would like to see is a good break down like this over Taurine.