Posted by JohnX2 on March 24, 2002, at 21:55:38
In reply to Re: NMDA antagonist neurotoxicity » JohnX2, posted by christophrejmc on March 24, 2002, at 20:01:25
> > I've read some papers by Olney.
> > I get confused by the theories surrounding schizopherenia. He suggests that it is caused by hypofunctional NMDA receptors. Also, he believes that 5ht-2a antagonists will exacerbate hypofunctioning NMDA receptors. He suggests in one paper I read using a 5ht-2a agonist to protect against NMDA antagonist (hypofunctioning) neurotoxicity.
>
> > The neurotoxicity comes from regions of the brain where the NMDA receptors stimulate GABA neurons which in turn protect other neurons.
>
> Is this the PCP-based schizophrenia hypothesis? That's a bit interesting... I wonder if he goes through with it. Are there any (clean) 5HT-2a agonists on the market? I've also read that certain anticholinergics can protect against NMDA antagonist neurotoxicity... Some people say that the midazolam(?) given with ketamine can also prevent neurotoxicity... Would it be naive of me to think this would have something to do with GABA -- if so, that might explain why other drugs that antagonize NMDA while also affecting GABA in various ways, would not be a problem...
>Yes, this was the PCP theory. The Gaba safeguard holds true.
> > That medicine (memantine) has been in Germany for like 10 yrs+ and I don't think there has been case reports of Olney lesions from it.
>
> s/memantine/amantadine/g. I think it was amantadine that I heard causing neurotoxicity... but I'm not sure how factual that claim is. The biggest offenders, in order, seem to be phencyclidine, [some drug Olney was working on], dextromethorphan, and ketamine.
>I believe memantine is quite safe. It is fairly non-competitive and just caps toxic hyper- glutamate transmission. Seems the others may be toxic at high doses. DXM is a non-competetive antagonist and is generally fairly safe else they wouldn't put it in cough syrup. It will be interesting to see how the Neurodex product with DXM makes it through FDA approval given the potential for toxicity.
There are a few patents by Olney discussing his thoughts on safe gaurding nmda hypofunctioning at www.upsto.gov
Patent 5,902,815 (use of 5-ht2a agonist)
Patent 5,605,911 (use of alpha-2 agonist)The alpha-2 agonist works on an acetylcholine pathway.
It seems a lot of people aren't in harmony on this pcp based theory of schizophrenia.
I don't know of 5ht-2a agonists in the market do you?
BTW, how is the Selegiline trial going?
Regards,
John> I'm not sure how serious all of the cases are, and it's unlikely that they would perform an autopsy just for that...
>
> Hmm.. time to do some more reading.
>
> Thanks
> -chris
poster:JohnX2
thread:99188
URL: http://www.dr-bob.org/babble/20020322/msgs/99954.html