Neuroprotective effects of metformin on traumatic brain injury in rats associated with NF-κB and MAPK signaling pathway

Brain Res Bull. 2018 Jun;140:154-161. doi: 10.1016/j.brainresbull.2018.04.008. Epub 2018 Apr 24.

Abstract

Traumatic brain injury (TBI) triggers a complex sequence of inflammatory responses that contribute to secondary injury. Metformin, a first-line drug used to treat type 2 diabetes, is reported to exhibit potent anti-inflammatory activity on diseases associated with the central nervous system (CNS). The aim of this study is to investigate the potential neuroprotective effects of metformin on acute brain injury after TBI and explore the underlying mechanisms. Male Sprague-Dawley (SD) rats were divided into four groups: sham group, TBI group, TBI + saline (NS) group and TBI + metformin group. A weight-dropping model was employed to induce TBI in rats. Modified neurological severity scores (mNSS) were employed to assess the short-term neurological deficits, neuronal degeneration and apoptosis in the brain tissues were assayed with Fluoro-Jade B and TUNEL staining, immunofluorescence was designed to investigate microglial activation. The mRNA and protein expression levels of pro-inflammatory cytokines such as necrosis factor-alpha (TNF-α), interleukin-beta (IL-1β) and nterleukin-6 (IL-6) were evaluated by real-time quantitative reverse transcriptase polymerase chain reaction (QPCR) and enzyme-linked immunosorbent assay (ELISA). Western blotting analysis was engaged to examine the expression of NF-κB p65 and phosphorylation of ERK1/2 and p38 MAPK. Our results showed that metformin significantly ameliorated neurological deficit, cerebral edema and neuronal apoptosis in rats following TBI. Moreover, metformin administration inhibited microglial activation and decreased the production of pro-inflammatory cytokines including TNF-α, IL-1β and IL-6. In addition, metformin inhibited the translocation of NF-κB p65 from cytoplasm into the nucleus, as well as the phosphorylation of ERK1/2 and p38 MAPK. This study suggests that metformin administration inhibits microglia activation-mediated inflammation via NF-κB and MAPK signaling pathway to improve neurobehavioral function following TBI, which provide a potential therapeutic benefit in treating brain injury.

Keywords: Inflammation; Metformin; Microglia activation; Traumatic brain injury.

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Brain Injuries, Traumatic / drug therapy*
  • Brain Injuries, Traumatic / metabolism
  • Brain Injuries, Traumatic / pathology
  • Disease Models, Animal
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Inflammation / pathology
  • MAP Kinase Signaling System / drug effects
  • Male
  • Metformin / pharmacology*
  • Microglia / drug effects
  • Microglia / metabolism
  • Microglia / pathology
  • NF-kappa B / metabolism*
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Random Allocation
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects

Substances

  • NF-kappa B
  • Neuroprotective Agents
  • Metformin
  • Extracellular Signal-Regulated MAP Kinases