Intracellular calcium accumulation during the evolution of hypoxic–ischemic brain damage in the immature rat

An excessive intracellular accumulation of calcium (Ca2+) in neurons and glia has been proposed to represent a major ‘final common pathway’ for cell death arising from hypoxia–ischemia. To clarify the role of altered calcium flux into the perinatal brain undergoing hypoxic–ischemic damage, 7-day postnatal rats underwent unilateral common carotid artery ligation followed by systemic hypoxia with 8% oxygen. This insult is known to produce brain damage in the form of selective neuronal death or infarction largely limited to the cerebral hemisphere ipsilateral to the arterial occlusion. Either prior to or following hypoxia–ischemia, the rat pups received a s.c. injection of 45CaCl2, and specimens of blood, cerebrospinal fluid (CSF), and brain were obtained for isotopic measurements and the calculation of the extent of brain intracellular radioactivity. During hypoxia–ischemia, there was a modest increase in intracellular Ca2+ radioactivity (+28–47%) in both cerebral hemispheres only after 2 h of hypoxia–ischemia. During recovery from 2 h of hypoxia–ischemia, intracellular Ca2+ accumulated progressively only in the ipsilateral cerebral hemisphere for up to 24 h, during which interval intracellular Ca2+ decreased in the contralateral hemisphere. No such progressive accumulation was noted during recovery in animals previously exposed to only 1 h of hypoxia–ischemia. The results suggest that a disruption of intracellular Ca2+ homeostasis is a major contributing factor in the evolution of perinatal hypoxic–ischemic brain damage. Ca2+ accumulation is a relatively modest and late event during the hypoxic–ischemic phase, and a progressive overload occurs during the recovery phase only if infarction occurs. The question remains as to whether or not the intracellular Ca2+ overload occurring during recovery is a contributor to or a consequence of the ultimate brain damage.