Neuroprotective effects of metformin on traumatic brain injury in rats is associated with the AMP-activated protein kina
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ORIGINAL ARTICLE
Neuroprotective effects of metformin on traumatic brain injury in rats is associated with the AMP-activated protein kinase signaling pathway Siavash Rahimi 1
&
Ahmadreza Ferdowsi 1
&
Ali Siahposht-Khachaki 2
Received: 23 December 2019 / Accepted: 29 June 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Metformin is an activator of AMP-activated protein kinase (AMPK). Thus, it has the potential to restore energy in damaged neurons and attenuate secondary brain damage due to traumatic brain injury (TBI). This study aims to investigate the potential neuroprotective effects of metformin through the energy balance reestablishment in acute severe brain injury after TBI and explore the underlying mechanisms. Male Wistar rats were divided into eight groups. The veterinary coma scale (VCS) was used to assess short-term neurological deficits. Blood-Brain barrier (BBB) disruption was evaluated by Evans Blue method 6 h postinjury. Vestibulomotor function was evaluated by beam-walk and beam-balance methods. Brain water content and brain tissue phosphorylated and total AMPK were assessed by the wet/dry method and enzyme-linked immunosorbent assay (ELISA), respectively. In order to eliminate the effect of AMPK, compound C was used as an AMPK inhibitor. The presented study showed that TBI has led to significant brain edema, BBB disruption, neurological deficit, vestibulomotor dysfunction and decrease AMPK phosphorylation in the rat brain. Metformin (100 and 200 mg/kg doses) attenuated brain edema, improved BBB and vestibulomotor dysfunction compared to TBI or Vehicle groups (P < 0.001). Furthermore, the p-AMPK/AMPK ratio was increased by metformin administration compare to TBI or Vehicle groups (p < 0.0001). Inhibition of AMPK by compound C abolished Metformin neuroprotective effects (P < 0.05 compared to Met 200 group). This study suggests that metformin inhibits TBI-mediated secondary injury via phosphorylation of AMPK and improves neurobehavioral function following TBI, which provides a potential therapeutic opportunity in the treatment of TBI. Keywords Metformin . TBI . Neuroprotective . AMPK . BBB disruption . Compound C
Introduction Traumatic brain injury (TBI) is characterized as structural and physiological alterations in brain function caused by an external force, with an annual incidence of two million cases in the United States and several million more worldwide, has been regarded as a significant global health issue (Albrecht et al. 2016; Coronado et al. 2011). Induced by mechanical force, the complex pathophysiological process initiates. TBI is categorized by two phases of primary and secondary. The primary * Ali Siahposht-Khachaki [email protected] 1
Department of Physiology and Pharmacology, Ramsar Campus, Mazandaran University of Medical Sciences, Sari, Iran
2
Department of Physiology, Faculty of Medicine, Mazandaran University of Medical Sciences, P.O.Box: 48471-91971, Sari, Iran
injury is attributed to the mechanical force applied to the brain
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