Long-term metformin therapy improves neurobehavioral functions and antioxidative activity after cerebral ischemia/reperfusion injury in rats.

Metformin (MET),an antidiabetic drug, has shown antioxidative and neuroprotective effects. In the present investigation, we aimed to study the probable effects of MET on cerebral ischemia/reperfusion in rats. Rats underwent cerebral ischemia/reperfusion and MET was administered orally at doses of 100 and 200 mg/kg for 56 days. Anxiety- and depressive-like behaviors were evaluated by elevated plus-maze or forced swimming tests, respectively. was assessed by. Cognitive functions were assessed by Y-maze continuous alternation task and morris water maze. The activity of SOD and the level of BDNF were measured in brains samples. Our results showed that administration of 200 mg/kg MET reduced the percent of brain edema (84.00 ± 2.13) in comparison with the ischemic animals (91.25 ± 2.25) (p < 0.05). Administration of 200 mg/kg MET in ischemic animals improved anxiety-like behavior by increasing the percentage of the open arms entries (46.51 ± 3.13) and the percentage of the open arms time (32.70 ± 2.49) in comparison with the cerebral ischemia group (26.35 ± 7.02 and 15.32 ± 5.78, respectively) (all p < 0.001). MET treatment (200 mg/kg) increased the cognition index of correct alternations (90.20 ± 4.95) in comparison with the cerebral ischemia group (59.50 ± 8.01) (p < 0.05). MET at the both doses reduced escape latency compared to the cerebral ischemia animals (all p < 0.05). In addition, 200 mg/kg MET increased the time spent in the target quadrant (16.06 ± 0.58) in comparison with the ischemic animals (9.84 ± 0.92) (p < 0.001) and the both doses of the drug increased the number of crossing (5.42 ± 0.36 and 6.5 ± 0.42, respectively) compared to the cerebral ischemia group (3.75 ± 0.31) (p < 0.05 and p < 0.001, respectively). Moreover, 200 mg/kg MET reduced the immobility time (47.50 ± 9.00) in comparison with the cerebral ischemia group (93.43 ± 8.28) (p < 0.001). Furthermore, the both doses of MET increased the BDNF levels (4590 ± 197.6 and 4767 ± 44.10, respectively) in comparison with the ischemic animals (3807 ± 42.56) (p < 0.01 and p < 0.001, respectively). Also, the both doses of the drug increased the SOD activity of brain (52.67 ± 0.33 and 55.00 ± 0.57, respectively) compared to the ischemic animals (49.33 ± 0.33) (p < 0.01 and p < 0.001, respectively). Based on our data, long-term MET therapy may improve behavioral disorders following cerebral ischemia/reperfusion and can be considered as a novel therapeutic approach for the treatment of brain ischemic conditions.