The effect of stroke and other cerebral insults on the release of free fatty acids

Pathologic processes including: ischemia, traumatic brain injury (TBI), and subarachnoid hemorrhage (SAH) result in increases in FFAs in animal studies. This dissertation examines mechanisms of FFA efflux from ischemic rat cerebral cortex using a four-vessel occlusion model in conjunction with the cortical window technique and assesses FFA concentrations in human CSF in patients with various neurological diseases. Under non-ischemic conditions, topically applied phospholipase C (PLC) and phospholipase A₂ (PLA₂) result in increased FFA concentrations. During ischemia-reperfusion injury, Ca++-dependent PLA₂ resulted in significant attenuation of FFA efflux while inhibition of Ca++-independent PLA ₂, secretory PLA₂, and PLC did not. Under ischemic conditions, the Ca++-dependent PLA₂ appears to be activated by increases in intracellular Ca++ by influx of Ca+ -through membrane Na+/Ca++ exchanger (NCX), of mitochondrial NCX, and/or opening of the mitochondrial permeability transition pore, as evidenced by the ability of inhibitors of these processes to result in significant attenuation of ischemia-reperfusion evoked efflux. Maintenance of alkalotic pH via inhibition of the Na+/H + exchanger-1 isoform may also limit PLA₂ activation as evidenced by SM20220's ability to decrease ischemia-reperfusion evoked FFA efflux.; SAH, TBI, and ischemia result in significant increases in all FFAs during the first 48 hours following insult. CSF from patients with SAH demonstrates a secondary increase in FFA efflux at 8 to 10 days which corresponds with clinical vasospasm, while samples obtained from TBI and stroke patients do not. Preliminary evidence suggests that FFAs may be predictive of vasospasm in SAH and outcome in stroke and TBI. FFA concentrations may provide diagnostic markers for patients with tumors as levels are increased in patients with gliomas/primary brain tumors, but not in patients with metastases and lymphoma. Concentrations increase in patients with dementia and schizophrenia, but not in multiple sclerosis and epilepsy. Taken together, this data suggests that FFA efflux under ischemic conditions is coupled to Ca++-dependent PLA₂ activation which may be attenuated by inhibition of intracellular Ca++ and maintenance of acidotic pH. This study is the first to document CSF concentrations of FFAs in patients with neurological diseases and provides evidence that changes in FFAs play a role in cerebral insults.