Metabolic Brain Disease

, Volume 30, Issue 3, pp 747–754 | Cite as

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

  • Ghorbangol Ashabi
  • Leila KhalajEmail author
  • Fariba Khodagholi
  • Mahdi Goudarzvand
  • Alireza Sarkaki
Research Article


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 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.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Ghorbangol Ashabi
    • 1
  • Leila Khalaj
    • 2
    • 5
    Email author
  • Fariba Khodagholi
    • 3
    • 4
  • Mahdi Goudarzvand
    • 2
  • Alireza Sarkaki
    • 1
  1. 1.Department of PhysiologyFaculty of Medicine, Jundishapour Medical Sciences UniversityAhwazIran
  2. 2.Medical SchoolAlborz University of Medical SciencesAlborzIran
  3. 3.NeuroBiology Research CenterShahid Beheshti University of Medical SciencesTehranIran
  4. 4.Neuroscience Research CenterShahid Beheshti University of Medical SciencesTehranIran
  5. 5.Physiology-Pharmacology Department, Medical SchoolAlborz University of Medical SciencesKarajIran

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