Anti-apoptotic actions of (-)Deprenyl in the CNS : pharmacological, histological and behavioural evidence
Gelowitz, Douglas Leonard
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($-$)Deprenyl is an irreversible inhibitor of monoamine oxidase B (MAO-B) frequently used as an adjuvant therapy in the treatments of Parkinson's and Alzheimer's Disease (PD and AD). Recent evidence, however, has found that certain deprenyl metabolites are associated with an anti-apoptotic action within some neuronal populations. Interestingly, deprenyl's anti-apoptotic actions do not depend upon the inhibition of MAO-B. Due to a paucity of information surrounding ($-$)deprenyl's ability to spare neurons in vivo, a series of studies were conducted to further investigate this phenomenon in two diverse models of apoptotic neuronal death: hypoxia/ischemia and kainic acid induced excitotoxicity. Results indicated that ($-$)deprenyl reduced delayed neuronal death in a model of unilateral global ischemia/hypoxia within the CA1 CA3 and CA4 subfields of the hippocampus as compared to saline-treated subjects, and that the observed parameters were consistent with an anti-apoptotic action of ($-$)deprenyl, but inconsistent with MAO-B inhibition. Similarly, within the kainic acid model of apoptotic neuronal death, data revealed that ($-$)deprenyl increased hippocampal neuronal numbers compared to saline-matched controls. Furthermore, it was discovered that ($-$)deprenyl treatment could be stopped 14 days following CNS insult by kainate, with evidence of neuronal sparing still present by day 28, and that ($-$)deprenyl treatment can produce functional recovery of normal exploratory behaviour within an open-field paradigm following kainate administration. Given deprenyl's anti-apoptotic actions, it is proposed that ($-$)deprenyl may be beneficial in the treatment of a variety of neurodegenerative diseases where evidence of apoptosis exists, such as PD and AD, by slowing the disease process itself.
DegreeDoctor of Philosophy (Ph.D.)
Copyright DateJanuary 1997