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A critical review of evidence for preclinical differences between rasagiline and selegiline

A critical review of evidence for preclinical differences between rasagiline and selegiline
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Basal Ganglia Volume 2 Issue 4

December 2012
Gerlach M, Reichmann H, Riederer P


Monoamine oxidase M (MAO-B) inhibitors are used in the symptomatic treatment of Parkinson’s disease (PD) as they prolong the availability and activity of endogenous dopamine in the striatum by blocking its degradation. Two MAO-B inhibitors, rasagiline and selegiline, are currently licensed in Europe and North America. The differences between these agents at the clinical and preclinical level have been much debated. This review critically explores the evidence for preclinical differences between rasagiline and selegiline, and discusses the relevance of these differences for the treatment in PD.

Rasagiline is about 10 times more potent in the inhibition of MAO-B than selegiline in ex vivo studies. To achieve similar potency in the clinical setting the doses were adapted. At their selective MAO-B inhibitory dosages, rasagiline and selegiline do not produce the “cheese reaction” and do not cause a potentiation of the effects of L-DOPA combined with the decarboxylase inhibitor carbidopa on blood pressure or heart rate in conscious rats. However, in pithed rats, selegiline but not rasagiline increased noradrenaline and adrenaline release, and pulse rate, and potentiated dopamine pressor response at MAO-B selective dose. It is believed that this difference is the result of their different chemical structure that gives rise to different metabolites with distinct pharmacological properties. Whether this difference is relevant for the clinic in regard to the occurrence of cardiovascular adverse drug reactions is not known, because, it is not known at what concentrations l-amphetamine and l-methamphetamine exert a sympathomimetic effect in vivo, and whether such concentrations are achieved in the blood of PD patients.

Rasagiline is superior to selegiline in its potency to prevent spontaneous cell death seen in cell culture, and to reduce accelerated cell death following serum deprivation in vitro. In addition, rasagiline is more effective in regard to its ability to reverse changes in mitochondrial function that lead to apoptosis. Finally, in the lactacystin-treated mouse, rasagiline exerts a neurorestorative effect where selegiline has none. These effects were considered to be independent of the ability of both agents to inhibit MAO-B. It was concluded that these superior effects of rasagiline are attributable to additive effects of the parent active substance and its major metabolite, 1-R-aminoindan, and to possible neurotoxic effects of l-methamphetamine, one metabolite of selegiline. However, it is not known at what concentrations these compounds may exert any protective and neurotoxic effect, respectively, in vivo, and whether respective concentrations are achieved in the brain of PD patients.