Psycho-Babble Medication Thread 16450

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Nardil and GABA

Posted by Elizabeth on December 8, 1999, at 19:19:28

Hey everybody.

Nardil, or one of its metabolites rather, is known to increase brain GABA concentrations by inhibiting GABA transaminase. This is believed to be related to its hydrazine structure, but I can't find any information on whether Marplan (also a hydrazine derivative) does this as well. I'm wondering if anybody knows the exact mechanism. For some reason I'm thinking it has to do with pyridoxal phosphate (i.e., vitamin B6) depletion (like, the metabolite forms a complex with p5p that inhibits GABA-T) but I have no idea where I might have read that (can't find anything about it anywhere). Anybody know more?

 

Re: Nardil and GABA

Posted by JohnB on December 8, 1999, at 21:01:58

In reply to Nardil and GABA, posted by Elizabeth on December 8, 1999, at 19:19:28

Hi, Elizabeth. I've copied and pasted an article, below, regarding Phenelzine's GABA elevating effects. There are, of course, many additional articles on MedLine, available through a no-cost PubMed search. My take on this article is that PLZ exerts its GABA elevating effects through inhibition of the anabolic enzyme glutamic acid decarboxylase (GAD) and, to a greater extent, the catabolic enzyme GABA transaminase (GABA-T)." Unfortunately, I wasn't able to find anything regarding the GABA elevating properties of Marplan, except an article suggesting complete GABA receptor blockage when Marplan is used in conjunction with Clozapine (an anti-psychotic.)

Sorry,

JohnB


-----------------
Chronic administration of the antidepressant phenelzine and its N-acetyl analogue: effects on GABAergic function.

McKenna KF, McManus DJ, Baker GB, Coutts RT
Department of Psychiatry, University of Alberta, Edmonton, Canada.

The MAO inhibitor phenelzine (2-phenylethylhydrazine; PLZ) is used widely in psychiatry for the treatment of depression and panic disorder. Its N-acetyl metabolite, N2-acetylphenelzine (N2AcPLZ) is a reasonably potent nonselective inhibitor of monoamine oxidase (MAO) that causes elevation in brain levels of the biogenic amines. In the studies reported here, PLZ (0.05 mmol/kg/day), N2AcPLZ (0.10 mmol/kg/day) or vehicle were administered to male rats for 28 days s.c. with Alzet minipumps, and their effects on GABAergic function were examined. Whole brain concentrations of gamma-aminobutyric acid (GABA) were significantly elevated in the PLZ but not in the N2AcPLZ-treated group. PLZ was found to inhibit the anabolic enzyme glutamic acid decarboxylase (GAD) and, to a greater extent, the catabolic enzyme GABA transaminase (GABA-T). The results of these investigations suggest that the free hydrazine moiety in PLZ is crucial to producing the elevated levels of GABA, probably through inhibition of GABA-T. Despite the considerable increase in whole brain GABA levels in the PLZ-treated rats, there were no significant differences in GABAA or benzodiazepine receptor binding parameters (KD or Bmax) between the groups as measured using 3H-muscimol and 3H-flunitrazepam in radioligand binding assays.

PMID: 7931216, UI: 95016587

 

Re: Nardil and GABA

Posted by Adam on December 8, 1999, at 22:35:08

In reply to Nardil and GABA, posted by Elizabeth on December 8, 1999, at 19:19:28

> Hey everybody.
>
> Nardil, or one of its metabolites rather, is known to increase brain GABA concentrations by inhibiting GABA transaminase. This is believed to be related to its hydrazine structure, but I can't find any information on whether Marplan (also a hydrazine derivative) does this as well. I'm wondering if anybody knows the exact mechanism. For some reason I'm thinking it has to do with pyridoxal phosphate (i.e., vitamin B6) depletion (like, the metabolite forms a complex with p5p that inhibits GABA-T) but I have no idea where I might have read that (can't find anything about it anywhere). Anybody know more?


The metabolite(s) of phelzine that inhibit GABA transaminase is unkown, but is dependant on MAO-B metabolism for
production (read about this a while ago). I found something once that suggested clozapine and isocarboxazid increase
GABA by dysregulation of GABA release via GABA(A) receptor binding. I think something like that was suggested for
phenelzine also in the reference where they determined MAO-B was most important. I can't remember why.

As for the mechanisms of hydrazine analog action on GABA transaminase, check out the following:

http://pubs.acs.org/isubscribe/journals/jmcmar/39/i03/pdf/jm950437v.pdf

Binding and reactivation kinetics suggests hydrazine action is not due to depletion of a cofactor, but rather the
dissociation of the cofactor from the enzyme.

Hope this is helpful.

 

Re: Nardil and GABA

Posted by Adam on December 8, 1999, at 22:36:31

In reply to Re: Nardil and GABA, posted by Adam on December 8, 1999, at 22:35:08

JohnB slipped in.

 

Re: Nardil and GABA, sorry...

Posted by Adam on December 12, 1999, at 22:23:40

In reply to Nardil and GABA, posted by Elizabeth on December 8, 1999, at 19:19:28

When I posted the link above, I did so from work. I wanted to look at the paper
again myself, and used the link here to try to get the pdf at home. I was unable
to log on, as it appears you need a subscription. We must have some sort of
authorization at work that I was unaware of.

The reference the link pointed to is below. When I found that reference a while ago,
through Medline, I just clicked on the link to the publishers site and got the pdf
no problem. The process was so transparent it did not occur to me that someone might
get stopped and asked for a password if they tried it. I'm terribly sorry if that
was the case.

J Med Chem 1996 Feb 2;39(3):686-94

Slow-binding inhibition of gamma-aminobutyric acid aminotransferase by hydrazine
analogues.

Lightcap ES, Silverman RB

Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113, USA.



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