A PHOSPHOLIPASE-C INHIBITOR AMELIORATES POSTISCHEMIC NEURONAL DAMAGE IN RATS

Background and Purpose: The hypothesis of calcium-induced neuronal damage has been proposed regarding brain ischemia. Phospholipase C is an enzyme that catalyzes the phosphodiesteratic cleavage of phosphatidylinositol. The cleavage of phosphatidylinositol 4,5-bisphosphate by phospholipase C yields 1,4,5-inositol triphosphate, which mediates intracellular release of calcium, and 1,2-diacylglycerol, which is an activator of protein kinase C. We examined the effect of phenylmethylsulfonyl fluoride, a phospholipase C inhibitor, on delayed neuronal damage after transient forebrain ischemia in the hippocampal CA1 subfield in rats to assess the role of phospholipase C in postischemic neuronal damage. Methods: Twenty-minute forebrain ischemia was induced using the method of Pulsinelli and Brierley. We measured the neuronal density of the hippocampal CA1 subfield 7 days after reperfusion. The effect of phenylmethylsulfonyl fluoride was tested in both pretreatment and posttreatment groups. Results: In the vehicle treatment group (n=13), neuronal density was 51+/-42/mm (mean+/-SD). The neuronal densities in the 50-mg/kg (n=12) and 100-mg/kg (n=14) phenylmethylsulfonyl fluoride pretreatment groups and the 100-mg/kg (n=10) phenylmethylsulfonyl fluoride posttreatment group were 99+/-50, 150+/-55, and 143+/-63/mm, respectively. These values were significantly higher than that of the vehicle treatment group (p<0.05, p<0.01, and p<0.01, respectively). Conclusions: It is suggested that the activation of phospholipase C has an important role in postischemic delayed neuronal damage.