Previous studies suggest that treatment with icariin (ICA) combined with Panax notoginseng saponins (PNS) improved behavior and cholinergic system disorders followed by amyloid beta-peptide(25-35) lateral ventricle injection in rats. The present study investigated whether administration of ICA + PNS had preventive and therapeutic effects on bilateral common carotid arteries (CCA) occlusion-induced cerebral ischemia-reperfusion (IR) injury in rats. Male Sprague-Dawley rats were divided randomly as follows: sham-operated, i.g. vehicle, ICA (5 mg/kg), PNS (40 mg/kg), ICA + PNS (2.5 + 20, 5 + 40 or 10 + 80 mg/kg), and ergoloid mesylate as a positive control (0.45 mg/kg) in model rats. Treatment was performed once a day for 7 days prior to ischemia. The rats were subjected to transient global IR induced by CCA occlusion in combination with intraperitoneal injection of sodium nitroprusside (2.0 mg/kg), then treated with ICA + PNS for another 14 days continuously. ICA + PNS significantly improved the rat passive avoidance task in step-down paradigms, and spatial cognition in the eight-arm radial maze, concomitant with an improvement of blood viscosity. Increased lipid peroxidation in brain after IR injury was observed, MDA being 0.56 +/- 0.10 nmol/mg prot vs 0.48 +/- 0.06 nmol/mg prot in the vehicle control (p < 0.05). Treatment with ICA + PNS 2.5 + 10, 5 + 40, 10 + 80 mg/kg produced a marked reduction in the MDA level to 0.46 +/- 0.06, 0.42 +/- 0.09 and 0.45 +/- 0.08 nmol/mg prot, respectively vs 0.56 +/- 0.10 nmol/mg prot in IR injury only control (p < 0.05, p < 0.01). A decrease in superoxide dismutase activity was observed in the brain of IR rats (the SOD activity being 72.75 +/- 4.62 U/mg prot vs 80.97 +/- 6.06 U/mg prot in control, p < 0.05). ICA + PNS 5 + 40 mg/kg prevented the IR injury mediated fall in superoxide dismutase activity being 78.90 +/- 6.61 U/mg prot versus 72.75 +/- 4.62 U/mg prot (p < 0.05). ICA + PNS tended to attenuate apoptosis in hippocampal CA1 pyramidal neurons. Either ICA or PNS treatment alone did not obviously improve cognitive impairment (except that lipid peroxidation was reduced by PNS-treatment). The results indicated that ICA + PNS may ameliorate learning and memory deficit and blood viscosity by protecting neurons from oxidative stress in ischemic brain.