RUOLO DELLA MITOCONDRIOGENESI NELLA NEUROPROTEZIONE:NUOVI APPROCCI ALLA TERAPIA SPERIMENTALE DELL'ISCHEMIA CEREBRALE

Mitochondrial bioenergetic failure, with severe ATP depletion and reactive oxygen species (ROS) overgeneration occurs during cerebral ischemia. We hypothesized that stimulation of mitochondrial biogenesis could help reduce cerebral ischemic damage. We observed that levels of proliferator-activated receptor γ coactivator 1α and nuclear respiratory factor-1 were reduced in primary mouse cortical neurons under oxygen-glucose deprivation (OGD). OGD also reduced neuronal mitochondrial mass and function, as assessed by mtDNA measurement and citrate synthase activity. The glycogen synthase kinase-3 (GSK-3) inhibitor SB216763 activated an efficient mitochondrial biogenesis program in control cortical neurons and counteracted the OGD-mediated mitochondrial biogenesis impairment. Further, SB induced an antioxidant response that reduced mitochondrial reactive oxygen species generation and ischemic neuronal damage. Two other structurally unrelated GSK-3 inhibitors mimicked SB216763 effects. In presence of diverse mitochondrial inhibitors the protective effects of SB216763 were abolished. When systemically administered in vivo, SB216763 reduced the infarct size and recovered the loss of mitochondrial DNA in mice subjected to permanent middle cerebral artery occlusion. Finally, we observed that levels of mitochondrial biogenesis markers were induced by metformin or SRT2183 (a Sirtris molecule that activates SIRT1) treatments. Moreover, metformin and SRT2183 reduced OGD-mediated ischemic neuronal damage. We conclude that strategies to restore mitochondrial biogenesis impairment during cerebral ischemia and to reduce reactive oxygen species might pave the way of novel promising therapies for future treatment of cerebral ischemia.