Simultaneous glutamate and GABA(A) receptor agonist administration increases calbindin levels and prevents hippocampal damage induced by either agent alone in a model of perinatal brain injury

Abstract

Perinatal brain injury is associated with the release of amino acids, principally glutamate and GABA, resulting in massive increases in intracellular calcium and eventual cell death. We have previously demonstrated that independent administration of kainic acid (KA), an AMPA/kainate receptor agonist, or muscimol, a GABA(A) receptor agonist, to newborn rats results in hippocampal damage [Hilton, G.D., Ndubuizu, A., and McCarthy, M.M., 2004. Neuroprotective effects of estradiol in newborn female rat hippocampus. Dev. Brain Res. 150, 191-198; Hilton, G. D., Nunez, J.L. and McCarthy, M.M., 2003. Sex differences in response to kainic acid and estradiol in the hippocampus of newborn rats. Neuroscience. 116, 383-391; Nunez, J.L. and McCarthy, M.M., 2003. Estradiol exacerbates hippocampal damage in a model of preterm infant brain injury. Endocrinology. 144, 2350-2359; Nunez, J.L., Alt, J.J. and McCarthy, M.M., 2003. A new model for prenatal brain damage. I. GABA(A) receptor activation induces cell death in developing rat hippocampus. Exp. Neurol. 181, 258-269]. We now report that KA or muscimol alone administered to immature hippocampal neurons in culture induces significant cell death as evidenced by TUNEL assay. Surprisingly, simultaneous administration of equimolar quantities of these two agonists blocks the effect of either one alone. Moreover, treatment of newborn pups results in less damage compared to either muscimol or KA alone. We further observed that immunoreactivity for the calcium-binding protein, calbindin D(28K), is increased in the brains of pups simultaneously administered KA and muscimol as compared to either alone.