Seizures accelerate anoxia-induced neuronal death in the neonatal rat hippocampus

Seizures occurring in infants with hypoxia are frequently associated with a n ominous prognosis. There is, however, no direct evidence that seizures ar e involved in the pathogenesis of hypoxia-induced neuronal damage. Here, we report that seizures significantly aggravate the hypoxic state by accelera ting rapid anoxic depolarization (AD) and associated neuronal death in prep arations of the intact hippocampus of neonatal rats in vitro. Under control conditions, prolonged episodes of anoxia/aglycemia induced rapid suppressi on of synaptic activity followed sequentially by brief bursts of epileptifo rm activity and then by rapid AD. AD was associated with irreversible neuro nal damage manifested by irreversible loss of the membrane potential, synap tic responses, and neuronal degeneration. Aggravation of electrographic sei zure activity during anoxic episodes by the adenosine A, receptor antagonis ts DPCPX and caffeine or the gamma-aminobutyric acid-A receptor antagonist bicuculline or pretreatment with 4-aminopyridine accelerated AD and associa ted neuronal death by up to twofold, whereas blockade of seizure activity b y the glutamate receptor antagonists or tetrodotoxin significantly delayed the onset of AD. This report provides direct evidence for the need to preve nt seizures during neonatal brain hypoxia.