Rasagiline and selegiline modulate mitochondrial homeostasis, intervene apoptosis system and mitigate α-synuclein cytotoxicity in disease-modifying therapy for Parkinson’s disease

Abstract

Parkinson's disease has been considered as a motor neuron disease with dopamine (DA) deficit caused by neuronal loss in the substantia nigra, but now proposed as a multi-system disorder associated with α-synuclein accumulation in neuronal and non-neuronal systems. Neuroprotection in Parkinson's disease has intended to halt or reverse cell death of nigro-striatal DA neurons and prevent the disease progression, but clinical studies have not presented enough beneficial results, except the trial of rasagiline by delayed start design at low dose of 1mg/day only. Now strategy of disease-modifying therapy should be reconsidered taking consideration of accumulation and toxicity of α-synuclein preceding the manifest of motor symptoms. Hitherto neuroprotective therapy has been aimed to mitigate non-specific risk factors; oxidative stress, mitochondrial dysfunction, apoptosis, deficits of neurotrophic factors (NTFs), inflammation and accumulation of pathogenic protein. Future disease-modify therapy should target more specified pathogenic factors, including deregulated mitochondrial homeostasis, deficit of NTFs and α-synuclein toxicity. Selegiline and rasagiline, inhibitors of type B monoamine oxidase, have been proved to exhibit potent neuroprotective function: regulation of mitochondrial apoptosis system, maintenance of mitochondrial function, increased expression of genes coding antioxidant enzymes, anti-apoptotic Bcl-2 and pro-survival NTFs, and suppression of oligomerization and aggregation of α-synuclein and the toxicity in cellular and animal experiments. However, the present available pharmacological therapy starts too late to reverse disease progression, and future disease-modifying therapy should include also non-pharmacological complementary therapy during the prodromal stage.