[The protective effect of mannitol, vitamin E, and glucocorticoid in experimental cerebral ischemia--influence on lipid peroxidation, energy metabolism and brain edema]

Abstract

At present we apply the three-drug-combination therapy consisting of mannitol, vitamin E and glucocorticoid (betamethasone) in the treatment of cerebral infarction at acute stage with favorable results. However, much of the action mechanism of these drugs remains unelucidated. For the purpose to elucidate the mechanism by which they exert actions and moreover to evaluate the efficacy of this therapy, we conducted experiments using highly ischemic whole brain models of rats. In this model, chemiluminescence value, energy metabolism, water content and concentrations of Na+, K+ were determined with time. During ischemic period chemiluminescence level increased with time, and more remarkable increase was seen after recirculation of the blood flow. However, in the group with administration of the three drugs combination increase in chemiluminescence was inhibited remarkably. In the analysis of intensity of chemiluminescence by wavelengths, the peaks were observed at 480, 520 - 530, 570, 620 - 640 and 680 - 700 nm. These wavelengths were taken to suggest the release of energy (luminescence) associated with the transition of singlet oxygen to the grounded state during the breakdown of the lipid hydroperoxide. By addition of vitamin E or beta-carotene (quencher of singlet oxygen) on the brain homogenate in vitro, luminescence was remarkably inhibited over whole ranges of wavelength. Determination of adenine nucleotide and carbohydrate revealed that these three drugs combination promoted their recovery at the period of recirculation of the blood flow after ischemia. In particular, increase in lactate was inhibited from the period of ischemia with prevention of progression of lactic acidosis. Moreover, in the group with administration of the three drugs combination and the group with administration of 20% or isotonic mannitol the increase in the cortical water content following recirculation of the blood flow was inhibited. From these result it is considered that each of the three drugs shows not only inhibition of lipid peroxidation as radical scavengers but also protective effect on lowering of activities of ion channel (Na+, K+-ATPase, etc.) by the free radicals.