Disclosing Carbon Monoxide Protection in Cerebral Ischemia: Insights into the cellular mechanisms

Dissertation presented to obtain the PhD degree in Biochemistry, NeurosciencesThe present work demonstrates the ability of carbon monoxide (CO) to prevent apoptosis in primary culture of astrocytes. For the first time, the anti-apoptotic behaviour can be clearly attributed to the inhibition of mitochondrial membrane permeabilisation (MMP), a key event in the intrinsic apoptotic pathway. In isolated non-synaptic mitochondria CO partially inhibits (i) loss of membrane potential, (ii) the opening of a non specific pore through the inner membrane, (iii) swelling and (iv) cytochrome c release, which are induced by calcium, diamide or atractyloside (a ligand of adenine nucleotide translocase, ANT). CO directly modulates ANT function by enhancing ADP/ATP exchange and prevents its pore-forming activity.(...