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Metformin improves anxiety-like behaviors through AMPK-dependent regulation of autophagy following transient forebrain ischemia

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Abstract

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.

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Acknowledgments

This paper was extracted as a part of Ghorbangol Ashabi’s Ph.D thesis. The study was financially supported by research affairs of Ahvaz Jundishapur University of Medical Sciences (grant No. APRC-93-05) and was performed in Ahvaz Physiology Research Center. Authors have no conflict of interest.

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Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, Jundishapur University of Medical Sciences, P.O.box: 61357-19754, Ahvaz, Iran

    Alireza Sarkaki, Yaghoob Farbood, Mohammad Badavi & Ghorbangol Ashabi

  2. Ahvaz Physiology Research Center, Jundishapur University of Medical Sciences, Ahvaz, Iran

    Alireza Sarkaki, Yaghoob Farbood, Mohammad Badavi & Ghorbangol Ashabi

  3. Medical School, Alborz University of Medical Sciences, Alborz, Iran

    Leila Khalaj

  4. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fariba Khodagholi

  5. Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fariba Khodagholi

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  1. Alireza Sarkaki
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Sarkaki, A., Farbood, Y., Badavi, M. et al. Metformin improves anxiety-like behaviors through AMPK-dependent regulation of autophagy following transient forebrain ischemia. Metab Brain Dis 30, 1139–1150 (2015). https://doi.org/10.1007/s11011-015-9677-x

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  • DOI: https://doi.org/10.1007/s11011-015-9677-x

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