Neuroprotective Strategies in Neurodegenerative Disorders

Neurodegeneration is the progressive loss of the structure or the function of the neurons. Indeed, the dopaminergic function in Parkinson’s disease (PD) is strongly damaged. Currently, L-DOPA is the most effective treatment for PD. However, the wearing off and on-off phenomena represent a limit of this therapy. Moreover, events like a stroke can cause severe impairments and neural death. In this context, the sirtuin family has shown to have a significant influence on the extent of neuronal death. In this work, firstly, we highlighted the ability of sulforaphane, an isothiocyanate, in counteracting and preventing the neurotoxicity induced by L-DOPA. This effect is mediated by the NRF2 pathway through the increase of cellular antioxidant defenses. Secondly, in C. elegans, we found that knock-out of mitochondrial sirtuin sir-2.3, homologous to mammalian SIRT4, is protective in both chemical ischemia and hyperactive channel induced necrosis. Furthermore, the block of glycolysis enhances the protective effect of sir-2.3 knock-out both in vivo and in culture, suggesting that this occurs independently of the insulin/IGF pathway. Analysis of ROS in sir-2.3 knock-out reveals that ROS become elevated in this mutant under dietary deprivation (DD) and early on in dietary deprived animals under ischemic conditions, suggesting that mitohormetic elevation of ROS is operative in this mutant. In conclusion, this work suggests novel pathways that can be targeted for the design of therapies aimed at protecting neurons from age linked damages.