The purpose of the present study was to examine the dose-response relationship and the therapeutic time window for the synthetic nonpsychotropic cannabinoid (HU-211) as a neuroprotective agent in transient, severe forebrain ischemia in the rat. Adult Sprague-Dawley rats were subjected to 20 min common carotid artery occlusion (CCAo) 24 h after coagulation of both vertebral arteries. Thirty minutes after the onset of CCAo, rats received an iv injection of HU-211 2, 4, or 8 mg/kg in HPCD (n = 12, 18, and 11, respectively), or the appropriate vehicle (n = 20). Neurological signs were scored daily for 3 d following ischemia. A significant improvement (p < 0.01, Kruskal-Wallis nonparametric test, followed by Mann-Whitney U-test, p < 0.05) of neurological deficits by the 4 mg/kg dose of HU-211, was observed 24, 48, and 72 h after insult. On the third day post-CCAo, the rat brain was taken for histopathological evaluation of the CA-1 sector of the hippocampus. Counts of viable neurons in the hippocampal CA1 field showed significantly more live cells in the HU-211 (4 mg/kg) treated animals (P < 0.001, ANOVA followed by Duncan's post-hoc test, p < 0.05). The drug was equally effective when given 30 and 60 min after ischemia, but neuroprotection was no longer significant after 3 h. We suggest that HU-211 may be a potential treatment for postischemic brain damage in human beings.