Neuroprotective Effects of Some Monoamine Oxidase-B Inhibitors Against DSP-4-Induced Noradrenaline Depletion in the Mouse Hippocampus |
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Authors: | P H Yu B A Davis J Fang A A Boulton |
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Institution: | Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada |
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Abstract: | Abstract: 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. This suggests that in addition to neuroprotection, these MAO-B inhibitors may rescue some of the noradrenergic axon terminals damaged by DSP-4. |
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Keywords: | Monoamine oxidase Neurotoxicity DSP-4 Noradrenaline Hippocampus Uptake |
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