SUPRA-ADDITIVE IMPACT OF MITOCHONDRIAL DYSFUNCTION AND SUBSEQUENT OXIDATIVE STRESS IN CENTRAL NERVOUS SYSTEM PATHOLOGY

Abstract

Mitochondrial dysfunction, oxidative stress and their interplay are core pathological features of neurodegenerative diseases. In Parkinson's disease (PD), mitochondrial dysfunction and oxidative stress have a supra-additive impact on the pathological, cytoplasmic accumulation of dopamine and its subsequent release. Moreover, dopamine and their metabolites provide an additional source of reactive oxygen species (ROS) during their breakdown by monoamine oxidase or auto-oxidation. Therefore those drugs which simultaneously target mitochondrial dysfunction, oxidative stress and subsequent pathological dopamine release may have disease- modifying potential in addition to symptomatic improvement by the blockade of self-amplifying circuits leading to ROS generation. To fulfill this aim we have developed a novel series of potent and selective MAO-B inhibitory (hetero)arylalkenylpropargylamine compounds having also protective properties against the supra-additive effect of mitochondrial dysfunction and oxidative stress. The compounds were tested in a wide range of in vitro and in vivo toxin-induced animal models of PD. The compounds exhibited consistent protective effects against i) in vitro oxidative stress induced pathological dopamine release and the formation of toxic dopamine quinone in the rat striatum and rescued dopaminergic neurons; ii) in vivo MPTP-induced striatal dopamine depletion and motor dysfunction in mice using acute, subchronic, and chronic protocols. In conclusion the above strategy seems a plausible approach to halt the progressive loss of nigrostriatal dopaminergic neurons and to combat PD.