Cerebral ischemia induces the degradation of membrane glycerolipids and results in the accumulation of unesterified fatty acids. These alterations may be important factors in the CNS pathology associated with cerebral ischemia, since membrane integrity depends on the glycerolipids and is incompatible with free fatty acids. In fact, exogenous free fatty acids can mimic the effects of ischemia on cerebral membranes. Free fatty acids can induce cerebral edema and block mitochondrial energy production. The apparent relationship between ischemia produced free fatty acids and the loss of membrane dependent functions makes control of cerebral free fatty acid concentrations one approach to assessing therapeutic agents for the treatment of cerebral ischemia. Cytidine diphosphocholine (CDPcholine) and cytidine diphosphoethanolamine (CDP-ethanolamine) are able to prevent the ischemia induced degradation of membrane glycerophospholipids and the consequent increases of free fatty acids in brain. CDPcholine and CDPethanolamine (CDPamines) are able to stimulate lipid synthesis and cancel the effects of ischemia on lipid catabolism. The experiments in this proposal are designed to determine if the CDPamines will have similar effects when administered after the onset of ischemic trauma. Preliminary experiments with gerbils indicate that these compounds do have the ability to reverse some of the lipid changes associated with cerebral ischemia. The effects of ischemia and CPDamine treatment on membrane structure will be assessed by determining the concentrations and metabolism of the phospholipids, free fatty acids, triglycerides and diglycerides. The effects on membrane function will be assessed by measuring cerebral edema, neurological functions, survival/mortality and the activities of membrane associated enzymes.
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