Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Punjab, India We have investigated the neuroprotective potential of combination of poly (ADP-ribose) polymerase inhibitor (nicotinamide or 3-aminobenzamide) and antioxidant (melatonin) in middle cerebral artery occlusion (MCAo) induced focal ischemia in rats. MCAo of 2 h followed by 22 h reperfusion produced large volume of cerebral infarction (mean +/- SEM 211.38 +/- 8.35 mm3), volume of edema (60 +/- 2 mm3) and neurological deficits (4.45 +/- 0.25). Combination of nicotinamide (500 mg kg(-1), i.p.) and melatonin (10 mg kg(-1), i.p.) significantly decreased infarct volume to 48 +/- 2.58 mm3 as compared to their individual drug (nicotinamide 76 +/- 12.49mm3, melatonin 76.17 +/- 1.24 mm3). A significant improvement was observed in edema volume and neurological deficits with this combination. Combination of 3-aminobenzamide (20 mg kg(-1), i.p.) and melatonin (10 mg kg(-1), i.p.) also produced similar reduction in infarction, edema and neurological score. These results indicate that the combination of poly (ADP-ribose) polymerase inhibitor and antioxidant produce enhanced neuroprotection. Clinical availability and wide therapeutic margin of nicotinamide and melatonin make them a promising drug combination for clinical evaluation in stroke patients.