Injury to developing brain is a major problem in critically ill neonates. Hypoglycemia is common in these infants, and can cause lifelong disability in severe cases. Hypoglycemic injury in mature brain is related to duration of coma, which heralds the onset of energy failure. It is associated with excessive levels of excitatory amino acids (EAA), which mediate neuronal injury. The role of EAA in hypoglycemic neuronal injury in relation to altered cerebral oxidative metabolism have not been evaluated in an immature animals. The goal of this project is to determine whether EAA mediate hypoglycemic neuronal injury in piglets, and what its relationship is to cerebral oxygen consumption (CMRO2) during coma.
Specific aims are to determine: 1) the distribution and severity of hypoglycemia-induced neuropathologic injury relative to the distribution of EAA receptors; 2) the appearance of EAA in cerebral microdialysate (EAA efflux) during hypoglycemic coma and recovery; 3) the effect of an EAA antagonist on EAA efflux, CMRO2, and histologic injury associated with hypoglycemic coma; 4) the effect of an adenosine antagonist on EAA efflux, CMRO2, and histologic injury associated with hypoglycemic coma. In acute experiments cerebral microdialysis will be performed concurrently with measures of regional cerebral blood flow (CBF) and CMRO2 by the radiolabeled microsphere technique during and after hypoglycemic coma (isoelectric electroencephalogram) of variable duration. Microdialysates will be analyzed by high performance liquid chromatography for amino acid neurotransmitters (glutamate, aspartate, glycine, gamma-amino butyric acid) and for metabolites of adenosine (inosine, hypoxanthine, xanthine), an endogenous inhibitory modulator of EAA synaptic activity. In chronic experiments, the anatomic distribution and severity of histologic injury will be measured as a function of duration of coma and recovery. The distribution and density of glutamate receptor subtypes determined by quantitative receptor autoradiography will be correlated with histologic injury. Results of chronic experiments are expected to define neuroanatomic regional vulnerability to injury. The effect on CMRO2 and on histologic injury of a glutamate receptor antagonist (MK-801) or an adenosine antagonist (dipropyl cyclopentyl xanthine) will be evaluated. If successful, these studies will lead to new insights into the timing, regional vulnerability and pathogenesis of hypoglycemic neuronal injury in immature brain. The results could provide rationales for neuroprotective interventions applicable to critically ill neonates with lifelong consequences.
| Bhardwaj, A; Northington, F J; Ichord, R N et al. (1997) Characterization of ionotropic glutamate receptor-mediated nitric oxide production in vivo in rats. Stroke 28:850-6; discussion 856-7 |
