Ischemic and Hypoglycemic Brain Damage, Involvement of the Mitochondrial Permeability Transition Pore

Sammanfattning: Brain damage from ischemia-reperfusion and hypoglycemia are major causes of morbidity and mortality. Therapeutic strategies include hypothermia, glutamate-receptor blockade, immunosuppression and lately treatment aiming at preserving mitochondrial integrity and function. Mitochondria are the main producers of cellular energy but mitochondria also participate in cell signaling and take an active part in the life/death decision of a cell. Oxidative stress and high mitochondrial calcium loads can trigger the formation of a large pore in the mitochondrial inner membrane, the mitochondrial permeability transition pore. The consequent disruption of the mitochondrial membrane potential, osmotic swelling and loss of metabolites and mitochondrial proteins through a ruptured outer membrane may lead to immediate or delayed cell death. In this study we demonstrate that isolated mitochondria from different brain regions have different sensitivity to calcium-induced permeability transition and furthermore that this correlates with the selective vulnerability of these regions to ischemia-reperfusion injury. Also, important modulators of the pore such as Bcl-2 and free radical production are altered after ischemia. Thus, Bcl-2 levels decrease at 4h and at 24h after forebrain ischemia in parallel with a 50% increase of free radical production in mitochondria isolated from the vulnerable hippocampus. These alterations are not seen in isolated mitochondria from the more resistant cortex region. We also show that cyclosporin A and MeValCsA, potent blockers of the mitochondrial permeability transition pore, protect neurons from oxygen/glucose deprivation in vitro and from ischemia-reperfusion injury in vivo. Moreover, cyclosporin A protects mitochondria and neurons from hypoglycemic brain damage. We conclude that calcium-induced mitochondrial permeability transition differs between brain regions and that mitochondria from different regions respond differentially to ischemic stress. The results of the present thesis support the view that the mitochondrial permeability transition pore is of importance in the development of brain injury after ischemia-reperfusion and hypoglycemia.