Chemical preconditioning with 3-nitropropionic acid in gerbil hippocampal slices: therapeutic window and the participation of adenosine receptor

Abstract

Ischemic tolerance induced by a subtoxic dose of neurotoxin, 3-nitropropionic acid (3-NPA), was recently reported as "chemical preconditioning." We electrophysiologically investigated the therapeutic window and the effect via action at the adenosine receptor using a gerbil hippocampal slice model of the tolerance phenomenon. 3-NPA at the dose of 4 mg/kg was administered intraperitoneally at 3, 24, and 72 h prior to slice preparation. Prolonged delay to hypoxic depolarization (HD) and improvement of the field excitatory postsynaptic potential recovery following a fixed period of hypoxia (8 min) were observed in the groups pretreated at 3 and 24 h compared with the control (P < 0.05). Correlation between the delay to HD and the recovery was highly significant (r = 0.37, P < 0.001). These effects were completely reversed by administration of theophylline (20 mg/kg), an adenosine receptor blocker. These findings indicate that chemical preconditioning with 3-NPA induces early onset (3 h) and long-lasting (24 h) tolerance of hypoxic damage to excitatory synaptic mechanisms in the hippocampus by delayed calcium entry, and the activation of adenosine receptor contributes to this neuroprotective effect.