From: gts (gts_2000@yahoo.com)
Date: Mon Feb 17 2003 - 04:40:02 MST
As described in the abstract below, selegiline (deprenyl) also blocks
the neurotoxic effects of MDMA (ecstasy). The mechanism by which
selegiline protects the brain from ecstasy is relevant to any discussion
of neuroprotection by selegiline.
Hydrogen peroxide is a toxic by-product of the deamination of dopamine
by MAO-B, one which can cause cell death by lipid peroxidation of cell
membranes. Selegiline inhibits MAO-B, thus reducing lipid peroxidation.
This is however just one of the suggested mechanisms by which selegiline
is neuroprotective, and not the mechanism that I feel is most important.
In addition to reducing hydrogen peroxide levels, selegiline
up-regulates the production of SOD and catalase. Numerous experiments
show life-extension benefits associated with increased levels of these
two protective antioxidant enzymes.
ABSTRACT
The monoamine oxidase-B inhibitor L-deprenyl protects against
3,4-methylenedioxymethamphetamine-induced lipid peroxidation and
long-term serotonergic deficits
by
Sprague JE, Nichols DE
Department of Pharmacology and Toxicology,
School of Pharmacy and Pharmacal Sciences,
Purdue University, West Lafayette, Indiana, USA.
J Pharmacol Exp Ther 1995 May; 273(2): 667-73
ABSTRACT
3,4-Methylenedioxymethamphetamine (MDMA)-induced serotonergic
neurotoxicity was assessed in the striatum, hippocampus and frontal
cortex of rats by using [3H]paroxetine binding to label serotonin (5-HT)
uptake sites and 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels as
markers of serotonergic function. NMDA (40 mg/kg) induced a significant
decrease in both [3H]paroxetine binding Bmax and 5-HT and 5-HIAA levels
7 days after treatment. The monoamine oxidase-B inhibitor L-deprenyl (2
mg/kg) administered 30 min before MDMA blocked these decreases. MDMA (40
mg/kg) also maximally increased the formation of thiobarbituric acid
reactive substances (an indicator of lipid peroxidation) 12 hr after
treatment in all three brain regions studied. This increase in
malondialdehyde formation was also blocked by pretreatment with
L-deprenyl. Tryptophan hydroxylase (TPH) activity was also significantly
reduced 18 hr after MDMA. L-Deprenyl reversed this decrease in TPH
activity. Another experiment confirmed that a significant fraction of
[3H]dopamine uptake into hippocampal synaptosomes was blocked by 500 nM
fluoxetine, a selective 5-HT uptake inhibitor. These data suggest that
the deamination by monoamine oxidase-B of excessive dopamine within the
5-HT terminal generates hydrogen peroxide that may lead to membrane
lipid peroxidation, and perhaps other oxidative insults, resulting in
selective 5-HT terminal degeneration subsequent to MDMA treatment.
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