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

摘要

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.