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

Ischemic tolerance induced by a subtoxic dose of neurotoxin, 3-nitropropionic acid (3-NPA), was recently reported as "chemical preeonditioning." 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 held 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. (C) 2000 Academic Press.