Global cerebral ischemia arises in patients who have a variety of clinical conditions including cardiac arrest, shock and asphyxia. In spite of advances in understanding of the brain ischemia and stroke etiology, therapeutic approaches to improve ischemic injury still remain limited. It has been established that metformin can attenuate cell death in cerebral ischemia. One of the main functions of metformin is proposed to be conducted via AMP-activated protein kinase (AMPK)-dependent pathway in the experimental cerebral ischemia model. It is also established that metformin can suppress inflammation and activate Nuclear factor erythroid 2-related factor (Nrf2) pathways in neurons. In the current study, the role of metformin in regulating inflammatory and antioxidant pathways in the global cerebral ischemia was investigated. Our results indicated that pretreatment of rats by metformin attenuated cellular levels of nuclear factor-κB, Tumor Necrosis Factor alpha and Cyclooxygenase-2 which are considered as three important proteins involved in the inflammation pathway. Pretreatment by metformin increased the level of Nrf2 and heme oxygenase-1 in the hippocampus of ischemic rats compared with untreated ischemic group. Moreover, pretreatment by metformin enhanced the level of glutathione and catalase activities compared with them in ischemic group. Such protective changes detected by metformin pretreatment were reversed by injecting compound c, an AMPK inhibitor. These findings suggested that metformin might protect cells through modulating inflammatory and antioxidant pathways via induction of AMPK. However, more experimental and clinical trial studies regarding neuroprotective potential of metformin and the involved mechanisms, especially in the context of cerebral ischemic injuries, are necessary.

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Here, we have investigated the effect of metformin pretreatment in the rat models of global cerebral ischemia. Cerebral ischemia which leads to brain dysfunction is one of the main causes of neurodegeneration and death worldwide. Metformin is used in clinical drug therapy protocols of diabetes. It is suggested that metformin protects cells under hypoxia and ischemia in non-neuronal contexts. Protective effects of metformin may be modulated via activating the AMP activated protein kinase (AMPK). Our results showed that induction of 30 min global cerebral I/R injury using 4-vesseles occlusion model led to significant cell death in the rat brain. Metformin pretreatment (200 mg kg/once/day, p.o., 2 weeks) attenuated apoptotic cell death and induced mitochondrial biogenesis proteins in the ischemic rats, analyzed using histological and Western blot assays. Besides, inhibition of AMPK by compound c showed that metformin resulted in apoptosis attenuation via AMPK activation. Interestingly, AMPK activation was also involved in the induction of mitochondrial biogenesis proteins using metformin, inhibition of AMPK by compound c reversed such effect, further supporting the role of AMPK upstream of mitochondrial biogenesis proteins. In summary, Metformin pretreatment is able to modulate mitochondrial biogenesis and apoptotic cell death pathways through AMPK activation in the context of global cerebral ischemia, conducting the outcome towards neuroprotection.

Stroke is one of the main threats to the public health worldwide. Metformin, an anti-diabetic drug, is an activator of AMP-activated protein kinase (AMPK). Metformin plays an important role on improving behavior in neurodegenerative diseases through diverse pathways. In the current study we aimed to investigate the probable effects of metformin on anxiety and autophagy pathway in global cerebral ischemia. Rats were divided into seven groups; Sham, ischemia (I/R), metformin (met), compound c (CC), CC+ischemia, met+ischemia, met+CC+ischemia. Metformin was pretreated for 2 weeks and CC administrated half an hour before global cerebral ischemia. Blood glucose, body weight, sensorimotor scores, elevated plus maze and open field test were evaluated after ischemia. Autophagy related factors were measured by Western blot and immunofluorescent assay in hippocampus of rats. Based on our results, pretreatment of rats by metformin improved sensory motor signs, anxiolytic behavior and locomotion in ischemic rats. CC injection in I/R rats attenuated the therapeutic effects of metformin. Autophagy factors such as light chain 3B, Atg7, Atg5-12 and beclin-1 decreased in ischemic rats compared to the sham group (P < 0.001 in all proteins). Level of autophagic factors increased in metformin pretreated rats compared to global cerebral ischemia (P < 0.001 in all proteins). These data indicated that the beneficial role of metformin in behavior and autophagy flux mediates via AMPK. Our results recommended that metformin therapy could improve psychological disorders and movement disability following I/R and profound understanding of AMPK-dependent autophagy would enhance its development as a promising target for intracellular pathway.

In the present study, we examined the effects of intracerebroventricular administration of extracellular signal-regulated protein kinase-(ERK) and p38-specific inhibitors, U0126 and PD169316, respectively, on apoptosis induced by amyloid beta (Ab) in rats. To investigate the effects of these compounds, we evaluated intracellular signalling pathways of apoptosis, as well as inflammatory and antioxidant pathways, 7 and 20 days after Ab injection. We found that caspase-3 and Bax/Bcl-2 ratio, two hallmarks of apoptosis, were significantly decreased in the rats pre-treated with U0126 and PD169316, 7 days after Ab injection. This observation was in agreement with the results of immunostaining analysis of the hippocampus that showed decreased levels of terminal transferase dUTP nick end labelling positive cells in the hippocampus of U0126 and PD169316 pre-treated rats, compared with the Ab-injected group. We also chased the changes in the levels of calpain-2 and caspase-12, two ER factors, in the Ab-injected and treatment groups. Decreased levels of calpain-2 and caspase-12 in U0126 and PD169316 pre-treated rats confirmed the protective effects of these inhibitors. Furthermore, we studied the effect of two stress-sensing transcription factors, nuclear-related factor-2 (Nrf2) and nuclear factor-кB (NF-кB), in Ab-injected as wells as U0126 and PD169316 pre-treated rats. U0126 and PD169316 activated Nrf2 and suppressed NF-кB pathways, 7 days after Ab injection. These antioxidant and inflammatory pathways restored to the vehicle level within 20 days. Taken together, our findings reinforce and extend the notion of the potential neuroprotective role of ERK and/or p38 inhibitors against the neuronal toxicity induced by Ab.

Context Metformin induced AMP-activated protein kinase (AMPK) and protected neurons in cerebral ischaemia. Objective This study examined pretreatment with metformin and activation of AMPK in molecular and behavioral levels associated with memory. Materials and methods Rats were pretreated with metformin (200 mg/kg) for 2 weeks and 4-vessels occlusion global cerebral ischaemia was induced. Three days after ischaemia, memory improvement was done by passive avoidance task and neurological scores were evaluated. The amount of Brain-Derived Neurotropic Factor (BDNF) and phosphorylated and total P70S6 kinase (P70S6K) were measured. Results Pretreatment with metformin (met) in the met + ischaemia/reperfusion (I/R) group reduced latency time for enter to dark chamber compared with the sham group (p50.001) and increased latency time compared with the I/R group (p50.001). Injection of Compound C (CC) (as an AMPK inhibitor) concomitant with metformin reduced latency time in I/R rats compared with the I/R + met group (p50.05). Neurological scores were reduced in met treated rats compared with the sham group. Pretreatment with metformin in I/R animals reduced levels of pro-BDNF compared with the I/R group (p50.001) but increased that compared with the sham group (p50.001). The level of pro-BDNF decreased in the met + CC + I/R group compared with the met + I/R group (p50.01). Pretreatment with metformin in I/R animals significantly increased P70S6K compared with the I/R group (p50.001). Conclusion Short-term memory in ischaemic rats treated with metformin increased step-through latency; sensory-motor evaluation was applied and a group of ischaemia rats that were pretreated with metformin showed high levels of BDNF, P70S6K that seemed to be due to increasing AMPK. ARTICLE HISTORY

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