Clonidine, a alpha(2)-adrenergic receptor agonist, has been demonstrated to be neuroprotective when administered during ischemia. It is not known whether clonidine can precondition brain against ischemia. We examined this possibility using a transient forebrain ischemia model. Rats received 40 microg/kg of clonidine intraperitoneally at 6, 18, 24 and 72 h as well as 1 week before the forebrain ischemia that was produced by bilateral common carotid arterial occlusion combined with hemorrhagic hypotension to mean arterial pressure 50 mm Hg for 30 min. They were intubated and ventilated with a gas mixture of 1.0% halothane in 30% O(2)/balance air during the procedure. Rats that received clonidine at 6, 18 and 24 h before the ischemia had significantly improved neurological deficit scores and reduced infarct sizes evaluated 3 days after the ischemia. A selective alpha(2)-adrenoceptor antagonist, yohimbine, abolished the neuroprotective effects of clonidine preconditioning. We conclude that there is time window for clonidine preconditioning to be neuroprotective and that alpha(2)-adrenoceptors are important in mediating clonidine preconditioning-induced neuroprotection.