Neuroprotective effects of some monoamine oxidase-B inhibitors against DSP-4-induced noradrenaline depletion in the mouse hippocampus.
DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], a selective noradrenaline (NA) uptake blocker, is capable of inducing long-lasting depletion of NA in some noradrenergic axon terminals and of subsequently causing cell death to NA neuronal cell bodies in rodents. R(-)-Deprenyl, a selective monoamine oxidase (MAO)-B inhibitor, has been shown to be capable of protecting animals against this DSP-4-induced neuronal degeneration. Its action, however, has been claimed to be unrelated to the inhibition of MAO-B activity but rather due to competition for the NA uptake sites. The effects of several types of MAO inhibitors against DSP-4 toxicity, MAO-B activity both in vivo and in vitro, and NA uptake into the hippocampus have been assessed. N-(2-Hexyl)-N-methylpropargylamine (2-HxMP), a potent MAO-B inhibitor, for example, exerts no appreciable effect on NA uptake but is quite potent in counteracting the NA-depleting effect of DSP-4. Such results rule out the possibility that the neuroprotective effect of the MAO-B inhibitors is due mainly to their effect on NA uptake. The in vitro inhibition of MAO-B activity seems to correlate positively with their neuroprotective effects against DSP-4. In comparison to the MAO-B inhibitors, NA uptake blockers, such as desipramine and S(+)-deprenyl, exhibit relatively low efficacy in protecting the NA axon terminals from the effects of DSP-4-induced damage. The restoration of hippocampal NA levels is significantly enhanced with repeated treatments of R(-)-deprenyl or 2-HxMP even at very low doses following the DSP-4 insult.(ABSTRACT TRUNCATED AT 250 WORDS)
Yu
P H
PH
Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada.
Davis
B A
BA
Fang
J
J
Boulton
A A
AA
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism* / Q000502:physiology; D010293:Pargyline / Q000031:analogs & derivatives / Q000494:pharmacology; D010624:Phenelzine / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D012642:Selegiline / Q000494:pharmacology; D013997:Time Factors
D001596:Benzylamines; D008996:Monoamine Oxidase Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D011437:Propylamines; C009054:propargylamine; D012642:Selegiline; D010293:Pargyline; D010624:Phenelzine; C012102:DSP 4; D003891:Desipramine; D009638:Norepinephrine