Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia

Abstract

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.

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

“…We clearly showed that metformin upregulated the Nrf2 system, while LPS treatment downregulated the Nrf2 system in both HFD-fed mice and HepG2 cells ( Figure 3C and 3D, Supplementary Figure 2 and 3). These results are in line with previous reports showing the interactions of the effects of metformin and LPS on the Nrf2 system [34,35] . The underlying regulatory mechanisms of LPS on the Nrf2 system were not addressed in the current study.…”

“…There is also a report showing that PTEN promotes Nrf2 phosphorylation-dependent degradation [34] , and therefore, LPS could promote Nrf2 degradation by upregulating PTEN expression. Interestingly, metformin has been shown to inhibit LPS-evoked inflammatory signaling through regulating ATF-3 [38,39] and has been recently found to activate Nrf2 to inhibit the inflammation response [35] . Whatever the specific mechanism involved, our data suggest that LPS-triggered Nrf2 dysfunction and the loss of redox balance could contribute to its detrimental effect on metformin and insulin action.…”

Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation

“…Recent animal studies have further demonstrated that long‐term metformin pretreatment can obviously alleviate the damage of ischemic stroke to brain tissue 12, 13, 14. In addition, metformin is also effective in treating global cerebral ischemia,15 intracerebral hemorrhage,16 epilepsy,17 Parkinson disease,18, 19 and Huntington disease 20. However, whether and how metformin treatment is effective in reducing brain injury after CA remain uninvestigated.…”

Effects of metformin on middle cerebral artery flow velocity in newly diagnosed type 2 Diabetic patients

“…Moreover, chronic metformin treatment significantly reduces infarct size in animal model [44]. The mechanism beyond that is chronic metformin therapy down-regulate AMPK in cerebral vessels and decreases lactate accumulation during ischemia [42][43][44][45]. However, acute metformin treatment during ischemic stroke may cause activation of AMPK which has harmful effects on neurons during ischemia with accumulation of lactate [44].…”