Posttreatment with lubeluzole, the S-isomer of a novel 3,4-difluoro benzothiazole, potently rescued tactile/proprioceptive hindlimb placing reactions contralateral to unilateral thrombotic infarcts in the hindlimb area of the parietal sensorimotor neocortex of rats. Administered at 5 min postinfarct, a single i.v. bolus of lubeluzole was three times as potent as the racemate, whereas the R-isomer was inactive. Neurological protection was near-maximal for treatment delays through 1 hr postinfarct, but declined with longer delays. However, when administered at 6 hr, 1.25 mg/kg i.v. still protected 60% of infarcted rats. An i.v. bolus followed by a 1-hr i.v. infusion produced equieffective neurologic protection at both 6- and 3-hr delays. This optimal lubeluzole regimen, started at 5 min postinfarct, reduced infarct volume by 22 to 24% at 4 hr postinfarct and by 28% at 7 days postinfarct. Again, the R-isomer was inactive. Down-regulation of the glutamate-activated nitric oxide synthase pathway leading to neurotoxicity and neuronal death may constitute a neuroprotective mechanism of action for lubeluzole.