Pharmacological Aspects of (-)-Deprenyl

Abstract

Deprenyl, the selective irreversible inhibitor of monoamine oxidase-B (MAO-B), has been synthesised as a potential antidepressant, however, due to its dopamine potentiating capacity, became a registered drug in the treatment of Parkinson's disease. Deprenyl possesses a wide range of pharmacological activities; some of them are not related to its MAO-B inhibitory potency. Beside its dopamine potentiating effect, it renders protection against a number of dopaminergic, cholinergic and noradrenergic neurotoxins with a complex mechanism of action. By inducing antioxidant enzymes and decreasing the formation of reactive oxygen species, deprenyl is able to combat an oxidative challenge implicated as a common causative factor in neurodegenerative diseases. In a dose substantially lower than required for MAO-B inhibition (10(-9)-10(-13) M), deprenyl interferes with early apoptotic signalling events induced by various kinds of insults in cell cultures of neuroectodermal origin, thus protecting cells from apoptotic death. Deprenyl requires metabolic conversion to a hitherto unidentified metabolite to exert its antiapoptotic effect, which serves to protect the integrity of the mitochondrion by inducing transcriptional and translational changes. Pharmacokinetic and metabolism studies have revealed that deprenyl undergoes intensive first pass metabolism, and its major metabolites also possess pharmacological activities. The ratio of the parent compound and its metabolites reaching the systemic circulation and the brain are highly dependent on the routes of administration. Therefore, in the treatment of neurodegenerative diseases, reconsideration of the dosing schedule, by lowering the dose of deprenyl and choosing the most appropriate route of administration, would diminish undesired adverse effects, with unaltered neuroprotective potency.

A comparison of drug-seeking behavior maintained by d-amphetamine, l-deprenyl (selegiline), and d-deprenyl under a second-order schedule in squirrel monkeys

“…One possible factor is inhibition of dopamine uptake. d-Deprenyl has been shown to be a potent inhibitor of dopamine uptake in the rat striatum, while l-deprenyl only weakly inhibits dopamine uptake (Fang and Yu 1994;Magyar et al 2004). Thus, inhibition of dopamine uptake could also account for the observed differences in self-administration between d-deprenyl and l-deprenyl.…”

Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic

“…Deprenyl is also well tolerated (Robottom, 2011). Deprenyl protects human neurons from apoptosis induced by various kinds of insults by interfering with early apoptotic signaling events and may be applicable to delay the deterioration of neurons during advancing aging (Maruyama & Naoi, 1999; Magyar et al ., 2004). …”

Restorative role of Deprenyl on Mitochondrial function of aging rat cerebellum

“…Pharmacokinetic and metabolism studies have revealed that deprenyl undergoes intensive first pass metabolism, and its major metabolites also possess pharmacological activities [7].…”