Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia
- 1.5k Downloads
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.
KeywordsMetformin AMPK Nrf2 Antioxidant Inflammation Global cerebral ischemia
We thank the research council of Alborz Medical University for the funding of this project. We are also grateful to Neuroscience Research Center of Shahid Beheshti University for providing experimental facilities. The authors declare that there are no conflicts of interest.
- Dulovic M, Jovanovic M, Xilouri M, Stefanis L, Harhaji-Trajkovic L, Kravic-Stevovic T, Paunovic V, Ardah MT, El-Agnaf OM, Kostic V, Markovic I, Trajkovic V (2013) The protective role of AMP-activated protein kinase in alpha-synuclein neurotoxicity in vitro. Neurobiol Dis 63:1–11CrossRefPubMedGoogle Scholar
- Grisouard J, Dembinski K, Mayer D, Keller U, Muller B, Christ-Crain M (2011) Targeting AMP-activated protein kinase in adipocytes to modulate obesity-related adipokine production associated with insulin resistance and breast cancer cell proliferation. Diabetol Metab Syndr 3:16CrossRefPubMedCentralPubMedGoogle Scholar
- Jing H, Yao J, Liu X, Fan H, Zhang F, Li Z, Tian X, Zhou Y (2013) Fish-oil emulsion (omega-3 polyunsaturated fatty acids) attenuates acute lung injury induced by intestinal ischemia-reperfusion through Adenosine 5′-monophosphate-activated protein kinase-sirtuin1 pathway. J Surg Res 187:252–261CrossRefPubMedGoogle Scholar
- Joya-Galeana J, Fernandez M, Cervera A, Reyna S, Ghosh S, Triplitt C, Musi N, DeFronzo RA, Cersosimo E (2011) Effects of insulin and oral anti-diabetic agents on glucose metabolism, vascular dysfunction and skeletal muscle inflammation in type 2 diabetic subjects. Diabetes Metab Res Rev 27:373382CrossRefGoogle Scholar
- Labuzek K, Liber S, Gabryel B, Okopien B (2009) AICAR (5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside) increases the production of toxic molecules and affects the profile of cytokines release in LPS-stimulated rat primary microglial cultures. Neurotoxicology 31:134–146CrossRefPubMedGoogle Scholar
- Li XM, Yang JM, Hu DH, Hou FQ, Zhao M, Zhu XH, Wang Y, Li JG, Hu P, Chen L, Qin LN, Gao TM (2007) Contribution of downregulation of L-type calcium currents to delayed neuronal death in rat hippocampus after global cerebral ischemia and reperfusion. J Neurosci 27:5249–5259CrossRefPubMedGoogle Scholar
- Mohagheghi F, Khalaj L, Ahmadiani A, Rahmani B (2012) Gemfibrozil pretreatment affecting antioxidant defense system and inflammatory, but not Nrf-2 signaling pathways resulted in female neuroprotection and male neurotoxicity in the rat models of global cerebral ischemia-reperfusion. Neurotox Res 23:225–237CrossRefPubMedGoogle Scholar
- Niimura M, Takagi N, Takagi K, Mizutani R, Ishihara N, Matsumoto K, Funakoshi H, Nakamura T, Takeo S (2006) Prevention of apoptosis-inducing factor translocation is a possible mechanism for protective effects of hepatocyte growth factor against neuronal cell death in the hippocampus after transient forebrain ischemia. J Cereb Blood Flow Metab 26:1354–1365CrossRefPubMedGoogle Scholar
- Vazquez-Medina JP, Popovich I, Thorwald MA, Viscarra JA, Rodriguez R, Sonanez-Organis JG, Lam L, Peti-Peterdi J, Nakano D, Nishiyama A, Ortiz RM (2013) Angiotensin receptor-mediated oxidative stress is associated with impaired cardiac redox signaling and mitochondrial function in insulin-resistant rats. Am J Physiol Heart Circ Physiol 305:H599–607CrossRefPubMedCentralPubMedGoogle Scholar
- Yue W, Yang CS, Dipaola RS, Tan XL (2014) Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer Prev Res (Phila)Google Scholar