GP120, AN HIV-1 PROTEIN, INCREASES SUSCEPTIBILITY TO HYPOGLYCEMIC ANDISCHEMIC BRAIN INJURY IN PERINATAL RATS

Recent data suggest that gp120, a glycoprotein secreted by HIV-l-infec ted macrophages, is neurotoxic, and that toxicity is mediated, at leas t in part, by overactivation of NMDA-type excitatory amino acid recept ors, In experimental animals, considerable evidence indicates that hyp oglycemic and ischemic neuronal injury are mediated by endogenous exci tatory amino acids. We hypothesized that in the presence of gp120 the severity of brain injury resulting from hypoglycemia and cerebral isch emia would increase. To test this hypothesis in vivo, we evaluated the influence of gp120 on the extent of brain injury resulting from these two clinically relevant pathophysiological insults in 7-day old (P7) rats, the developmental stage of peak susceptibility to NMDA neurotoxi city. We compared the severity of hippocampal injury resulting from ri ght intrahippocampal injections of gp120 (50 ng) in P7 rats rendered m arkedly hypoglycemic (n = 10) and in controls (n = 12). We also determ ined the influence of gp120 administration on the severity of hypoxic- ischemic injury, using a perinatal rat stroke model. P7 rats received intrahippocampal injections of gp120 (50 ng) (n = 23) or saline (n = 1 8) and then underwent right carotid ligation, followed by 2 h exposure to 8% oxygen, Brain injury was evaluated 5 days later, based on neuro pathology evaluation and measurements of bilateral regional cross-sect ional areas. The severity of hippocampal injury, based on cross-sectio nal area measurements, was considerably greater in animals from the hy poglycemic group than in litter-mate gp120-injected controls. Among th e animals that underwent hypoxic-ischemic lesioning, the severity; of injury, based on histopathology scoring and regional volume measuremen ts, was considerably greater in animals that received gp120 than in th ose that received saline, These results provide support for the hypoth esis that locally secreted HIV peptides, such as gp120, may potentiate the neurotoxicity of endogenous excitatory amino acid neurotransmitte rs in HIV-infected brain. (C) 1995 Academic Press, Inc.