A2: PROJ 3: MECHANISMS OF ACIDOSIS ENHANCED ISCHEMIC BRAIN DAMAGE: DRUG

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetes exaggerates brain damage induced by cerebral ischemia. The underlying mechanisms for this important, clinically relevant phenomenon are poorly understood. The objective of this project is to identify the role of mitochondria and mitochondrial-initiated cell death pathways in hyperglycemic ischemia. The results obtained from past 5 years showed that that 1) both acidosis and high glucose contribute to the detrimental effects of hyperglycemia/diabetes on ischemic neurons; 2) cerebral ischemia in diabetics results in alteration of mitochondrial morphology. This includes severe mitochondrial swelling and release of mitochondrial matrix proteins at the early reperfusion phase after stroke; 3) diabetes induces expression of neuro-inflammatory molecules such as the pro-inflammatory cytokine interleukin-1 (IL-1) and intercellular adhesive molecule-1 (ICAM-1); 4) diabetic ischemia enhances production of free radicals, and activates the mitochondrion-mediated cell death pathway, resulting in nuclear fragmentation and cell death; 5) the detrimental effects of hyperglycemia on ischemic brain are not only to neurons but to astrocytes as well; 6) pharmacological agents that preserve mitochondria, scavenge free radicals or suppress neuro-inflammation protect the brain from ischemic injury in normoglycemic and/or hyperglycemic subjects.