Hypoglycemic Brain Injury: Phospholipids, Free Fatty Acids, and Cyclic Nucleotides in the Cerebellum of the Rat after 30 and 60 Minutes of Severe Insulin-Induced Hypoglycemia

Abstract

Previous results from this laboratory have shown that although prolonged severe hypoglycemia (30 or 60 min with cessation of electroencephalographic activity) leads to relatively extensive energy failure in the cerebellum. there is surprisingly little histopathologic evidence of cell damage and virtually complete sparing of the Purkinje cells. In the present study, we induced hypoglycemia of the above-mentioned durations and compared metabolic alterations in the cerebral cortex (a structure which shows extensive cell damage) and the cerebellum. The experiments were performed on rats ventilated on 70% N₂O and 30% O₂, and hypoglycemia was induced by insulin administration. After 30 and 60 min of hypoglycemia the majority of animals showed changes in cerebellar energy state considerably less pronounced than in the cerebral cortex. In some animals. useful amounts of glycogen remained even after 60 min of hypoglycemic coma. It is suggested that part of the resistance of the cerebellum in hypoglycemia is due to a better preserved substrate supply, probably since the cerebellum contains a higher density of glucose transport sites. However, this alone cannot explain the higher resistance of the tissue. Thus, in all 30-min animals the cerebellum showed some deterioration of cellular energy state, and after 60 min the majority had relatively extensive energy failure. Furthermore, the results obtained after 60 min of hypoglycemia suggested that some decrease in phospholipid content occurred. During hypoglycemia. the cerebellar concentrations of cyclic AMP and cyclic GMP rose. The concentration of cyclic GMP, but not that of cyclic AMP, showed an inverse relationship to the energy charge. In cerebellum, cyclic GMP rose to higher values than in the cerebral cortex, and in contrast to that in the cerebral cortex, cyclic AMP concentration in the cerebellum showed no tendency to secondary reduction with progressive deterioration of tissue energy state. During hypoglycemia, the concentrations of free fatty acids increased in the cerebellum, the values showing an inverse relationship to cellular energy state. However, the accumulation seemed less pronounced than in the cerebral cortex, even when the two structures were compared at similar degrees of deterioration of energy state. Since accumulation of polyenoic free fatty acids has been implicated in tissue damage in several adverse situations, the results hint that part of the resistance of the cerebellum to the hypoglycemic insult may be due to a better preserved Ca²⁺homeostasis and/or a less pronounced activation of phospholipase A₂.