4-Amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl)pyrimidine (
BW619C89) is a
sodium channel antagonist which when administered parenterally reduces neurological deficit and
infarct volume after
middle cerebral artery occlusion in rats. We have investigated whether
BW619C89 administered orally before
middle cerebral artery occlusion is cerebroprotective when rats are assessed at one day after
stroke, and whether cerebroprotection is long lasting and related to functional recovery. A cerebroprotective oral dose of
BW619C89 (20 mg/kg) was used to determine whether reduction in
infarct volume is long lasting and can be enhanced with continued
therapy, and whether behavioural deficits occurring after
middle cerebral artery occlusion such as disturbances in cognition and motor coordination are ameliorated by treatment with
BW619C89. Rats received
sham surgery or
middle cerebral artery occlusion with a single treatment of
BW619C89 (20 mg/kg) 1 h before
middle cerebral artery occlusion, a double treatment group receiving 20 mg/kg
BW619C89 1 h before and 10 mg/kg 5 h after
middle cerebral artery occlusion, or continued treatment with
BW619C89 for up to five days. Neurological deficit, assessed from days 1 to 21, and at 70 days after
middle cerebral artery occlusion, was reduced to a similar extent in all three groups of rats treated with
BW619C89, compared with vehicle-treated controls. At 70 days after
middle cerebral artery occlusion, all groups performed at control level. Vehicle-treated rats were impaired in the Morris water maze and step-through passive avoidance paradigm five to eight weeks after
middle cerebral artery occlusion, when neurological deficit was minimal. These deficits were partially alleviated, to a similar extent, by all of the three treatments with
BW619C89. Total volumes of brain damage, assessed at 70 days after
middle cerebral artery occlusion in
Luxol Fast Blue- and
Cresyl Violet-stained coronal sections, were reduced in all three groups of BW619C89-treated rats, to 46% in the single, 50% in the double and 58% in the continued treatment group, compared with vehicle-treated rats. Extent of brain damage correlated with extent of impairment of the rats in the water maze. These findings suggest that
BW619C89 has long-lasting cerebroprotective effects with advantageous functional consequences after single
oral administration in a rodent model of
stroke. Prolonged treatment with
BW619C89 did not significantly enhance the cerebroprotective effects. Deficits in performance of rats in the water maze and step-through passive avoidance tasks indicate sustained
cognitive impairment after
middle cerebral artery occlusion. The reductions in brain damage by
BW619C89 correlated with significant long-term functional improvement.