![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 32. This is the beginning of the thread.
Posted by JayDee on January 9, 2005, at 22:32:37
Can someome help me interprate these abstracts?
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Effect of antioxidant N-acetyl-l-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine.Fukami G, Hashimoto K, Koike K, Okamura N, Shimizu E, Iyo M.
Department of Psychiatry, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo, Chiba 260-8670, Japan.
Several lines of evidence suggest that oxidative stress may play a role in the behavioral changes and neurotoxicity in rats after administration of methamphetamine (MAP). N-acetyl-l-cysteine (NAC) is a precursor of glutathione, and it also exerts as an antioxidant. In this study, we investigated the effects of NAC on the behavioral changes (hyperlocomotion and development of sensitization) and neurotoxicity in male Wistar rats after administration of MAP. Pretreatment with NAC (30, 100 or 300 mg/kg, i.p.) attenuated significantly hyperlocomotion in rats induced by a single administration of MAP (2 mg/kg, i.p.), in a dose-dependent manner. Furthermore, pretreatment with NAC (100 mg/kg, i.p., 15 min before MAP injection, once daily for 5 consecutive days) blocked significantly the development of behavioral sensitization in rats after repeated administration of MAP (2 mg/kg, once daily for 5 consecutive days), whereas the behaviors in rats after repeated administration of NAC plus saline groups were not different from those of control (vehicle plus saline) groups. One week after administration of MAP (7.5 mg/kgx4, 2-h intervals), levels of dopamine (DA) in rat striatum were significantly decreased as compared with control groups. Pretreatment with NAC (1, 3, 10 or 30 mg/kg, i.p., 30 min before each MAP injection) attenuated significantly the MAP-induced reduction of DA in rat striatum, in a dose-dependent manner. These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse.
PMID: 15234256
Neuropsychopharmacology. 2004 Jun 16 [Epub ahead of print]Protective Effects of N-acetyl-L-cysteine on the Reduction of Dopamine Transporters in the Striatum of Monkeys Treated with Methamphetamine.
Hashimoto K, Tsukada H, Nishiyama S, Fukumoto D, Kakiuchi T, Shimizu E, Iyo M.
1Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.
Several lines of evidence suggest that oxidative stress might contribute to neurotoxicity in the dopaminergic nerve terminals after administration of methamphetamine (MAP). We undertook the present study to determine whether intravenous administration of N-acetyl-L-cysteine (NAC), a potent antioxidant drug, could attenuate the reduction of dopamine transporter (DAT) in the striatum of monkey brain after administration of MAP. Positron emission tomography studies demonstrated that repeated administration of MAP (2 mg/kg as a salt, four times at 2-h intervals) significantly decreased the accumulation of radioactivity in the striatum after intravenous administration of [(11)C]beta-CFT. In contrast, the binding of [(11)C]SCH 23390 to dopamine D(1) receptors in the monkey striatum was not altered after the administration of MAP. A bolus injection of NAC (150 mg/kg, i.v.) 30 min before MAP administration and a subsequent continuous infusion of NAC (12 mg/kg/h, i.v.) over 8.5 h significantly attenuated the reduction of DAT in the monkey striatum 3 weeks after the administration of MAP. These results suggest that NAC could attenuate the reduction of DAT in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity in dopaminergic nerve terminals related to chronic use of MAP in humans.Neuropsychopharmacology advance online publication, 16 June 2004; doi:10.1038/sj.npp.1300512
My interpretation:1.)N-acetyl-l-cysteine prevents sensitization and neurotoxicity by blocking the effects of Methamphetamine rather then just reducting oxidative stress.
Why does N-acetyl-l-cysteine do this?
anyone with personal experience with this?What is the duration of a N-acetyl-l-cysteine dose?
Posted by JayDee on January 10, 2005, at 12:17:04
In reply to Methamphetamine vs N-acetyl-l-cysteine, posted by JayDee on January 9, 2005, at 22:32:37
Does anyone have these full studies?
Posted by CareBear04 on January 10, 2005, at 22:56:12
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine, posted by JayDee on January 10, 2005, at 12:17:04
sorry, i don't have the brainpower right now to make it through the abstracts, but all i can say is AVOID n-acetylcysteine! if i remember right, it's aka "mucomyst," which is the most disgusting thing that has ever gone through my body. it was administered as an antidote to too much tylenol, and it is the most foul stuff ever! sorry i couldn't read the article, but all i can say is that i would take meth, crack, or anything else over the n-acetylcysteine!
Posted by Iansf on January 11, 2005, at 0:26:23
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine » JayDee, posted by CareBear04 on January 10, 2005, at 22:56:12
> sorry, i don't have the brainpower right now to make it through the abstracts, but all i can say is AVOID n-acetylcysteine! if i remember right, it's aka "mucomyst," which is the most disgusting thing that has ever gone through my body. it was administered as an antidote to too much tylenol, and it is the most foul stuff ever! sorry i couldn't read the article, but all i can say is that i would take meth, crack, or anything else over the n-acetylcysteine!<
I've tried NAC and found virtually no noticeable effect at all. Were you perhaps given an extreme dose of it, or was it given in a nonstandard form (e.g., injected or as a powder or liquid rather than a pill)? And what, by the way, does it do to counteract the effect of the Tylenol? I'm not even sure what the effect of too much Tylenol is, though I do understand it can cause liver failure in some people. Thanks.
Posted by CareBear04 on January 11, 2005, at 10:41:58
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine » CareBear04, posted by Iansf on January 11, 2005, at 0:26:23
hi-- i didn't even know that n-acetylcysteine comes in a pill. i guess i did have an "Extreme' form of it-- it was this horrid, urine-colored liquid that smelled like rotten eggs and made me really sick to my stomach. they gave me dose after dose because it's supposed to protect against liver failure, and they gave me extra doses by mistake when the attending dr. said i didn't need any more. this was in the middle of the night, and when i refused to take anymore, they threatened to put in an NG tube to get it down... so i pretended to drink it and throw it up when i really just slowly poured it out into the emesis basin. after two or three rounds of this, they gave up, and the next day, the attending confirmed that i wasn't supposed to be given any more.
so... that's my experience with n-acetylcysteine. i didn't know it had another purposes or that it came in a pill. i guess that would make it more... palatable? i have a hard time thinking about it without feeling queasy. anyway, if you figure the article out, i'd be interested in hearing about it!
Posted by Larry Hoover on January 11, 2005, at 11:04:18
In reply to Methamphetamine vs N-acetyl-l-cysteine, posted by JayDee on January 9, 2005, at 22:32:37
> Can someome help me interprate these abstracts?
> My interpretation:
>
> 1.)N-acetyl-l-cysteine prevents sensitization and neurotoxicity by blocking the effects of Methamphetamine rather then just reducting oxidative stress.Methamphetamine causes massive release of dopamine from storage sites in presynaptic neurons. The flood of dopamine overwhelms the capacity of enzymes which normally detoxify dopamine that escapes the reuptake pumps. Dopamine is readily oxidizable to quinone and semiquinone derivatives, which are toxic. Oxidation is inhibited by glutathione, so NAC boosts the protective ability of natural antioxidant capacity, reducing oxidative damage via dopamine derivatives.
> Why does N-acetyl-l-cysteine do this?
By directly increasing formation of glutathione. If you increase substrate concentration, you increase products. It's that simple.
> anyone with personal experience with this?
>
> What is the duration of a N-acetyl-l-cysteine dose?That I don't know. But, in any case, having lots of glutathione available is a good thing.
Lar
Posted by Larry Hoover on January 11, 2005, at 11:12:43
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine » JayDee, posted by CareBear04 on January 10, 2005, at 22:56:12
> sorry, i don't have the brainpower right now to make it through the abstracts, but all i can say is AVOID n-acetylcysteine! if i remember right, it's aka "mucomyst," which is the most disgusting thing that has ever gone through my body. it was administered as an antidote to too much tylenol, and it is the most foul stuff ever! sorry i couldn't read the article, but all i can say is that i would take meth, crack, or anything else over the n-acetylcysteine!
They were saving your life. Liver failure is an absolutely horrible way to go. You can't imagine it. It is far far worse than swallowing oral NAC.
Tylenol (acetominophen/paracetamol) destruction in the liver requires one molecule of glutathione for every molecule of tylenol. If you use up all the glutathione, the liver cells are programmed to self-destruct, via a process called apoptosis. It is the rupturing liver cells that kill you. Not only does your liver fail to work, but all those enzymes that weren't destroyed are loose in the body. It's not pretty. NAC directly stimulates glutathione formation, in a dose-dependent manner.
Taking a tylenol overdose induces a situation something like firefighters responding to a fire with a pumper full of water. When they run out of that water, they can no longer fight the fire. The doctors were giving you massive amounts of oral NAC, analogous to the firefighters hooking up to a hydrant. By having an unlimited supply of water/NAC, the firefighters/liver cells can do their job.
Lar
Posted by CareBear04 on January 11, 2005, at 11:30:07
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine » CareBear04, posted by Larry Hoover on January 11, 2005, at 11:12:43
hey larry,
the details are beyond me, but thanks for the explanation. this happened two years ago in a drug-induced psychotic state. i don't doubt that they were saving my life, and i'm glad they did because, as you said, liver failure is a horrible way to die. but the fact remains-- and this was my only real point-- that oral liquid mucomyst is some pretty foul stuff, even though it's sometimes lifesaving and important. thanks again!
Posted by JayDee on January 11, 2005, at 16:10:33
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine » JayDee, posted by Larry Hoover on January 11, 2005, at 11:04:18
Larry, thanks for the reply.
But that doesn't explain why NAC reduceses the effects of MAP (in this case, acute hyperlocomotion)
Hyperlocomotion couldn't possibly be a result of oxidative stress could it??The abstract also doesnt explain behaverial sensitzation other then that NAC attenuates MAP induced dopmaine deficits.
Posted by Larry Hoover on January 11, 2005, at 18:30:36
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine, posted by JayDee on January 11, 2005, at 16:10:33
> Larry, thanks for the reply.
>
> But that doesn't explain why NAC reduceses the effects of MAP (in this case, acute hyperlocomotion)
> Hyperlocomotion couldn't possibly be a result of oxidative stress could it??
>
> The abstract also doesnt explain behaverial sensitzation other then that NAC attenuates MAP induced dopmaine deficits.I'll take a look at this again, but I can't right now. I'll also check related research. I attributed the adverse effects of the methamphetamine to oxidized dopamine, which destroys any dopamine-binding element (receptor, reuptake transporter, etc.). I could certainly be wrong about that. More, anon.
Lar
Posted by chemist on January 13, 2005, at 0:21:49
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine » JayDee, posted by Larry Hoover on January 11, 2005, at 18:30:36
> > Larry, thanks for the reply.
> >
> > But that doesn't explain why NAC reduceses the effects of MAP (in this case, acute hyperlocomotion)
> > Hyperlocomotion couldn't possibly be a result of oxidative stress could it??
> >
> > The abstract also doesnt explain behaverial sensitzation other then that NAC attenuates MAP induced dopmaine deficits.
>
> I'll take a look at this again, but I can't right now. I'll also check related research. I attributed the adverse effects of the methamphetamine to oxidized dopamine, which destroys any dopamine-binding element (receptor, reuptake transporter, etc.). I could certainly be wrong about that. More, anon.
>
> Lar
>
hello all, chemist here...might i join? the pubs i have on hand - from 1982 through 2004 - indicate that the neurotoxicity (this word is to be used with care, especially in re: the work of ricaurte and mccann, to name the most obvious contenders) of MA in re: both DA and 5-HT receptors appears to be axonal in nature...also, a bit of a chicken-and-egg problem, as the oxidation of DA is likely (specifically) a result of decreased (endplate locus) expression of tyrosine hydroxylase...on the radar recently (1995-current) is the role of monoamine vesicular transporter (type II), which sequesters DA from oxidative mechanisms...i have one pub (Ann. N.Y. Acad. Sci., 1025:146-150, 2004) on hand wherein this mechanism is addressed in re: MA specifically; and there is a freebie (JPET, 311:1-7, 2004) wherein microglia activation is fingered as the cause of DA receptor damage. i will state that mccann and ricaurte's review (Neuro. Bio. Rev., 27:821-826, 2004) is rather unbiased and the refs therein are a broad sampling from the literature. i was impressed with the MPTP challenge for rats dosed with MA, either with prior methylphenidate administration or with subsequent treatment...the methylphenidate staves off MPTP DA trouble if used prophylactically, and is somewhat of a restorative agent if used later....hope this sheds some light..all the best, chemist
Posted by Larry Hoover on January 13, 2005, at 10:26:03
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine, posted by JayDee on January 11, 2005, at 16:10:33
> Larry, thanks for the reply.
>
> But that doesn't explain why NAC reduceses the effects of MAP (in this case, acute hyperlocomotion)
> Hyperlocomotion couldn't possibly be a result of oxidative stress could it??
>
> The abstract also doesnt explain behaverial sensitzation other then that NAC attenuates MAP induced dopmaine deficits.I'm going to have to emphasize the opening sentence in each of the quoted abstracts. The researchers were trying to discover the role of oxidative stress in the development of persistent behavioural changes following acute exposure to methamphetamine. Earlier work by this same team had shown that blockade of excitatory NMDA receptors would also abolish this effect.
There are three redox-sensitive cysteine residues (sulfhydryl functional group) on this NMDA-receptor complex. Glutathione is basically a sulfhydryl sacrificial molecule. It takes the oxidative heat, and quenches it, before the receptor sulfhydryls can be affected. At least, that's the way it's supposed to work.
One of the mechanisms by which methamphetamine does its damage is by inhibiting MAO. When combined with dopamine efflux induced by this drug, the inhibition of MAO leaves dopamine open to a multitude of auto-oxidative and enzyme catalyzed oxidative transformations. The products of these reactions can still have dopamine-like affinities for receptors and transporters, but their chemistry has changed. They can undergo reactions with the receptor sites, taking them out of action. So, I think the persistent effects are mediated by a host of factors, but all of them can be attenuated by antioxidants. The fact that N-acetyl-cysteine works in this role (and selenium, in other references) points to glutathione as a key molecule. The seleno form of glutathione is even more effective than is the sulfur version.
Now, as to the conclusion that NAC might be a post-exposure treatment for methamphetamine toxicity, I respectfully have to disagree. It may encourage a faster rate of recovery, by preventing new avenues of oxidative stress from exerting additive damage in these synapses, but I can't see that it will directly reverse these adverse effects. You need the enhanced NAC concentration to be present with the methamphetamine exposure.
That's how I read it, anyway.
Lar
Posted by Larry Hoover on January 13, 2005, at 10:29:09
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine, posted by chemist on January 13, 2005, at 0:21:49
Thanks for stepping up.
> ...also, a bit of a chicken-and-egg problem, as the oxidation of DA is likely (specifically) a result of decreased (endplate locus) expression of tyrosine hydroxylase...
Another DA oxidative effect, decreased dopamine synthesis. But wouldn't that attenuate some of the other effects?
> on the radar recently (1995-current) is the role of monoamine vesicular transporter (type II), which sequesters DA from oxidative mechanisms...i have one pub (Ann. N.Y. Acad. Sci., 1025:146-150, 2004) on hand wherein this mechanism is addressed in re: MA specifically; and there is a freebie (JPET, 311:1-7, 2004) wherein microglia activation is fingered as the cause of DA receptor damage.
Do you have a link?
> i will state that mccann and ricaurte's review (Neuro. Bio. Rev., 27:821-826, 2004) is rather unbiased and the refs therein are a broad sampling from the literature. i was impressed with the MPTP challenge for rats dosed with MA, either with prior methylphenidate administration or with subsequent treatment...the methylphenidate staves off MPTP DA trouble if used prophylactically, and is somewhat of a restorative agent if used later....hope this sheds some light..all the best, chemist
>Only one thing left out. How does NAC/glutathione fit into this all?
Lar
Posted by ed_uk on January 13, 2005, at 10:51:17
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine » JayDee, posted by Larry Hoover on January 13, 2005, at 10:26:03
Hi Larry,
If a person was taking amphetamines daily, which supplements do you think would be most effective in reducing the risk of neurotoxicity?
Would you suggest NAC + Selenium?
Best Regards,
Ed.
Posted by Larry Hoover on January 13, 2005, at 12:15:18
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine » Larry Hoover, posted by ed_uk on January 13, 2005, at 10:51:17
> Hi Larry,
>
> If a person was taking amphetamines daily, which supplements do you think would be most effective in reducing the risk of neurotoxicity?
>
> Would you suggest NAC + Selenium?
>
> Best Regards,
> Ed.I think that would be a good idea, but I would also add alpha-lipoic acid and vitamin C. These antioxidants work as a team, not in isolation.
Lar
Posted by chemist on January 13, 2005, at 12:24:36
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine » chemist, posted by Larry Hoover on January 13, 2005, at 10:29:09
hi larry et al...comments below....all the best, chemist
> Thanks for stepping up.
>
> > ...also, a bit of a chicken-and-egg problem, as the oxidation of DA is likely (specifically) a result of decreased (endplate locus) expression of tyrosine hydroxylase...
>
> Another DA oxidative effect, decreased dopamine synthesis. But wouldn't that attenuate some of the other effects?*** from what i read (and surmise in general about these things) the answer is yes. the interesting ``problem'' that is lurking pertains to the anatomical as well as pharmacological specificity and effects of MA. this is a borrowed observation, by the way, and perhaps is only a ``problem'' in that i do not understand it. the studies (commencing in 1982, to the best of my knowledge) where high doses of amphetamine and derivatives were administered in rodent models (later primate) with the goal being to find out where in the brain these drug were responsible for what effect have largely nailed the areas in, well, rodent and (non-human) primate models....the subtlety in the causality remains troubling (again, to me): the dose-dependence relation with neuronal loss (temporary is the best word i can use to describe it) has been established to the point of there being little room for question, while the 5-HT end of things seems to be related to the drug(s) used.***
>
> > on the radar recently (1995-current) is the role of monoamine vesicular transporter (type II), which sequesters DA from oxidative mechanisms...i have one pub (Ann. N.Y. Acad. Sci., 1025:146-150, 2004) on hand wherein this mechanism is addressed in re: MA specifically; and there is a freebie (JPET, 311:1-7, 2004) wherein microglia activation is fingered as the cause of DA receptor damage.
>
> Do you have a link?**** yes, and i just checked: not a freebie (neither) unless you have a subscription (personal or institutional). i apologize for the misinformation.****
>
> > i will state that mccann and ricaurte's review (Neuro. Bio. Rev., 27:821-826, 2004) is rather unbiased and the refs therein are a broad sampling from the literature. i was impressed with the MPTP challenge for rats dosed with MA, either with prior methylphenidate administration or with subsequent treatment...the methylphenidate staves off MPTP DA trouble if used prophylactically, and is somewhat of a restorative agent if used later....hope this sheds some light..all the best, chemist
> >
>
> Only one thing left out. How does NAC/glutathione fit into this all?**** the involvement of NAC - good, bad, or none - is not addressed in any publications i have on hand, not even alluded to: my gut reaction is that NAC is a good thing to take for the reasons you outline - i think many of us are on the same page about antioxidants in general - yet the connection with DA is circumstantial and/or anecdotal at best. however, just because yours truly has not read an article or many does not mean the science is not being investigated. thus, off to the stacks i go....all the best, chemist ****
>
> Lar
Posted by CareBear04 on January 13, 2005, at 14:11:44
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine » Larry Hoover, posted by chemist on January 13, 2005, at 12:24:36
hi chemist and larry and everyone-- the technical details of these drugs are beyond me, but i'm interested in what i think i read somewhere in the posts about NAC protecting against neurotoxicity, specifically amphetamine or meth? at a daily dose of adderall of about 40-50mg, is there a risk of brain damage? how about in the long-term?
also, since my only exposure to NAC has been in concentrated liquid mucomyst form, may i ask what other forms it comes in? i assume there must a pill that is less unpleasant... is it less potent than the liquid and is it obtainable without a prescription?
thanks for all the info. i wish my mind were up to deciphering the jargon, but i'm very impressed by how knowledgable people on this board are!
Posted by chemist on January 13, 2005, at 14:42:58
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine, posted by CareBear04 on January 13, 2005, at 14:11:44
hello there, chemist here....i am certain larry and/or others can fill in the blanks better than i, but here are some leads: the NAC neuroprotection vis a vis stimulants is not the open and shut case as i indicated, there are a few data that suggest that NAC is a putative ``winner'' in this regard.
as for brain damage and long term use, what exactly do you mean? i do pose the question in all seriousness, as ``brain damage'' and ``long term'' are subject to individual interpretation: i do not, for instance, consider ``brain zaps'' resulting from use of SSRI/SNRI medication to be brain damage nor do i consider 5 years to be a long term treatment with, say, lithium.
that said: there are more concrete and well-documented data from the use of hormone replacement therapy (WHI vs. harvard nurse study) than for amphetamine use over a 20 year period. the point? i do not know, the medical community does not know, and indications are that if one does not abuse the drug, life goes on.
NAC is ingested by myself in tablet form, and i am not certain if capsules are available but would not be surprised. no prescription necessary, not a controlled substance nor any reason to think it ought to be one.
more answers from more informed sources than i, certainly....all the best, chemist
> hi chemist and larry and everyone-- the technical details of these drugs are beyond me, but i'm interested in what i think i read somewhere in the posts about NAC protecting against neurotoxicity, specifically amphetamine or meth? at a daily dose of adderall of about 40-50mg, is there a risk of brain damage? how about in the long-term?
>
> also, since my only exposure to NAC has been in concentrated liquid mucomyst form, may i ask what other forms it comes in? i assume there must a pill that is less unpleasant... is it less potent than the liquid and is it obtainable without a prescription?
>
> thanks for all the info. i wish my mind were up to deciphering the jargon, but i'm very impressed by how knowledgable people on this board are!
Posted by lars1 on January 14, 2005, at 7:44:43
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine, posted by CareBear04 on January 13, 2005, at 14:11:44
> at a daily dose of adderall of about 40-50mg, is there a risk of brain damage? how about in the long-term?
I've said what little I know about this in another thread (http://www.dr-bob.org/babble/20041228/msgs/436668.html). I'm hoping that others who know more may jump in here.
Posted by lars1 on January 14, 2005, at 8:20:38
In reply to Methamphetamine vs N-acetyl-l-cysteine, posted by JayDee on January 9, 2005, at 22:32:37
Reports cited earlier in this thread suggest that N-acetyl-l-cysteine may be protective against amphetamine neurotoxicity. Other reports (see below) indicate that L-cysteine is itself neurotoxic. Are N-acetyl-l-cysteine and L-cysteine completely different substances with respect to their neurological effects? Or is this another case where the dose makes the poison?
Lars
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Science. 1990 May 4;248(4955):596-9.
L-cysteine, a bicarbonate-sensitive endogenous excitotoxin.
Olney JW, Zorumski C, Price MT, Labruyere J.
Washington University School of Medicine, Department of Psychiatry, St. Louis, MO 63110.After systemic administration to immature rodents, L-cysteine destroys neurons in the cerebral cortex, hippocampus, thalamus, and striatum, but the underlying mechanism has never been clarified. This neurotoxicity of L-cysteine, in vitro or in vivo, has now been shown to be mediated primarily through the N-methyl-D-aspartate subtype of glutamate receptor (with quisqualate receptor participation at higher concentrations). In addition, the excitotoxic potency of L-cysteine was substantially increased in the presence of physiological concentrations of bicarbonate ion. L-Cysteine is naturally present in the human brain and in the environment, and is much more powerful than beta-N-methylamino-L-alanine, a bicarbonate-dependent excitotoxin, which has been implicated in an adult neurodegenerative disorder endemic to Guam. Thus, the potential involvement of this common sulfur-containing amino acid in neurodegenerative processes affecting the central nervous system warrants consideration.
*******************************************
Neurochem Res. 1996 Mar;21(3):293-8.
Contributing mechanisms for cysteine excitotoxicity in cultured cerebellar granule cells.
Mathisen GA, Fonnum F, Paulsen RE.
Norwegian Defence Research Establishment, Division for Environmental Toxicology, Kjeller, Norway.Several possible mechanisms for cysteine toxicity on rat cerebellar granule cells were studied and compared with the excitotoxic effect of glutamate. It was shown that the excitotoxic potency of both cysteine and glutamate increased in the presence of elevated concentrations of bicarbonate or increased pH. Pharmacological studies showed that the cysteine toxicity was specifically coupled to the NMDA receptor, whereas the glutamate toxicity was mediated to a smaller extent also by non-NMDA receptors. Treatment of cerebellar granule cells with cysteine led to an increased extracellular level of glutamate. In addition, cysteine sensitized NMDA receptors by reducing disulfide bonds in the receptor to sulfhydryl groups. A mechanism for cysteine excitotoxicity may therefore be formation of cysteine-sensitized NMDA receptors that are stimulated either by cysteine and/or by endogenous glutamate. This mechanism may also be important for the effects observed during regulated physiological release of cysteine.
Posted by lars1 on January 14, 2005, at 13:23:54
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine » JayDee, posted by Larry Hoover on January 13, 2005, at 10:26:03
> One of the mechanisms by which methamphetamine does its damage is by inhibiting MAO. When combined with dopamine efflux induced by this drug, the inhibition of MAO leaves dopamine open to a multitude of auto-oxidative and enzyme catalyzed oxidative transformations.
Would it be safe to assume that since conventional MAO inhibitors like Nardil and Parnate don't cause dopamine efflux, they don't cause any of the dopaminergic damage that amphetamines do?
Posted by djmmm on January 14, 2005, at 14:42:50
In reply to Re: MAO inhibition » Larry Hoover, posted by lars1 on January 14, 2005, at 13:23:54
> > One of the mechanisms by which methamphetamine does its damage is by inhibiting MAO. When combined with dopamine efflux induced by this drug, the inhibition of MAO leaves dopamine open to a multitude of auto-oxidative and enzyme catalyzed oxidative transformations.
>
> Would it be safe to assume that since conventional MAO inhibitors like Nardil and Parnate don't cause dopamine efflux, they don't cause any of the dopaminergic damage that amphetamines do?
No...MAOIs lack the potent catecholamine stimulation that occurs with Methamphetamine. It is the massive release of catecholamines (and serotonin at higher doeses) and their effect on post-synaptic receptors, that contribute to neurotoxicity. The resulting increase in blood pressure, and core body temperature also play a significant role.MAOI's prevent the oxidation of dopamine into 6-hydroxydopa and 6-hydroxydopamine (both neurotoxins)...6-hydroxydopamine is further oxidized into superoxide, hydroxyl free radicals and hydrogen peroxide. If anything, Nardil and Parnate are neuroprotective.
Posted by ed_uk on January 14, 2005, at 14:49:41
In reply to Re: MAO inhibition, posted by djmmm on January 14, 2005, at 14:42:50
Hi djmmm,
How likely do you think that it is that SSRIs might be neurotoxic?
Ed.
Posted by JayDee on January 15, 2005, at 21:33:33
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine » JayDee, posted by Larry Hoover on January 13, 2005, at 10:26:03
Thanks again for the reply Larry,
Did I say anything about NAC post treatment to supress neurotoxicity? (I dont remember)
I do know that you would most need the presence of NAC at peak dopamine levels or just afterwards, which would require and pre or concurrent dose of NAC with METH.Let me clarify the question i was trying to ask in the original post.
Would/Does NAC supress or reduce the Postitive effects of methamphetamine? In the case of this abstract; I was referring to 'hyperlocomotion' as a postive effect. I could be wrong.
Posted by Larry Hoover on January 24, 2005, at 6:39:52
In reply to Re: Methamphetamine vs N-acetyl-l-cysteine, posted by CareBear04 on January 13, 2005, at 14:11:44
> hi chemist and larry and everyone-- the technical details of these drugs are beyond me, but i'm interested in what i think i read somewhere in the posts about NAC protecting against neurotoxicity, specifically amphetamine or meth? at a daily dose of adderall of about 40-50mg, is there a risk of brain damage? how about in the long-term?
The neurotoxicity issue is not one of long-term exposure, exactly. It's about exceeding a threshold of dopamine stimulation/detoxification. I can't give you an absolute assurance that the dose you mention is safe (science doesn't do black and white), but it is well within the realm of doses which are considered to be safe. You have abundant natural processes to detoxify your synapses, the little gaps between neurons where all the neurotransmitters do their jobs, and where all those multitude of receptors lie. It's like pouring liquid into a funnel. So long as you don't overflow it, it doesn't matter how fast your pour the liquid into it. There is a threshold, though, beyond which you make a mess. It's the same thing in your brain. Stay within the natural capacity of your brain's "funnel", and you'll be fine.
> also, since my only exposure to NAC has been in concentrated liquid mucomyst form, may i ask what other forms it comes in? i assume there must a pill that is less unpleasant... is it less potent than the liquid and is it obtainable without a prescription?
For some strange and obtuse reason, Canadians cannot import NAC from the States, where it is over-the-counter. Yes, pills and capsules are readily available. Bulk powder, too. See: http://www.easycart.net/BeyondACenturyInc./Amino_Acids_single.html
> thanks for all the info. i wish my mind were up to deciphering the jargon, but i'm very impressed by how knowledgable people on this board are!
If you can't decipher the jargon, how do you know we're knowledgable?
Jargon is a something you can learn. It'll seep into your pores, via osmosis.
Lar
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