Neuroprotective and neuro-survival properties of safinamide against methamphetamine-induced neurodegeneration: Hypothetic possible role of BDNF/TrkB/PGC-1α signaling pathway and mitochondrial uncoupling protein -2(UCP-2)

Abstract

Methamphetamine is a behavioral psychostimulant that has a high potential for misuse and induction of neurotoxicity. Safinamide is a novel inhibitor of monoamine oxidase B (MAOB) with neuroprotective properties. Methamphetamine abuse causes dysfunction in the respiratory chain of the mitochondria, but the specific signaling mechanism and role of the uncoupling protein-2(UCP-2) remain unclear. As we know, some indirect evidence indicates that neurodegeneration can be caused by inhibition of the brain-derived neurotrophic factor (BDNF) receptor, TrkB and its downstream signaling pathway, such as the PGC-1α protein. Neuroprotective strategies and approaches to the management, treatment or prevention of methamphetamine-induced neurodegeneration by modulating BDNF / TrkB / PGC-1α-UCP-2 can be considered as novel therapeutic approaches to these psychostimulant neurochemical and neurobehavioral approaches. Previous studies have shown that safinamide, a monoamine oxidase-B (MAOB) inhibitor, can function as a neuroprotective agent and inhibit the neurodegenerative process especially in Parkinson's disease but its impact on other neurodegenerative processes and drug-induced neurotoxicity remain unclear. Although there is some evidence that BDNF / TrkB / PGC-1α-UCP-2 signaling pathway and mitochondrial UCP-2 mediated safinamide induced neuroprotection but it's exact and precise mechanism of action and neuroprotective effects in neurodegenerative disorder and the protective properties against methamphetamine induced neurodegeneration and the role of BDNF / TrkB / PGC-1α signaling pathway and role of mitochondrial UCP-2 in this process have not yet been clarified. Therefore, in subjects addicted to methamphetamine, we hypothesized that safinamide will provide neuroprotection against methamphetamine-prompted neurodegeneration, and it appears that BDNF / TrkB / PGC-1α signaling pathway and mitochondrial UCP-2 are likely to play a critical role.

Keywords: BDNF/TrkB/PGC-1α; Methamphetamine; Neurodegeneration; Safinamide; UCP-2.