Bexarotene protects against neurotoxicity partially through a PPARγ-dependent mechanism in mice following traumatic brain injury

Neurobiol Dis. 2018 Sep:117:114-124. doi: 10.1016/j.nbd.2018.06.003. Epub 2018 Jun 7.

Abstract

Traumatic brain injury (TBI) causes a high rate of mortality and disability worldwide, and there exists almost none effective drugs to protect against TBI. Neurotoxicity occurring after TBI can be derived from microglia and astrocytes, and causes neuronal death and synapse loss. Bexarotene has been demonstrated to protect neurons in CNS diseases. In the present study, we aimed to investigate the potential role of bexarotene in protecting against neurotoxicity after TBI, as well as the underlying mechanism. The controlled cortical impact (CCI) model was established on adult C57BL/6 mice, followed by intraperitoneal administration of bexarotene for 14 consecutive days. We found that bexarotene improved sensorimotor function and cognitive recovery in CCI mice. In addition, bexarotene decreased neuronal death and synapse loss, as well as inhibited apoptotic cascade. Moreover, bexarotene treatment reduced M1 microglia polarization, microglia-derived pro-inflammatory cytokines, and the number of A1 astrocytes after CCI. These effects of bexarotene were partially abolished by T0070907, an antagonist of peroxisome proliferator-activated receptor gamma (PPARγ). Additionally, bexarotene enhanced nuclear translocation and transcriptional activity of PPARγ. These findings show that bexarotene inhibits neurotoxicity in mice after TBI, at least in part through a PPARγ-dependent mechanism.

Keywords: Astrocyte; Bexarotene; Microglia; Neuron; Peroxisome proliferator-activated receptor gamma; Traumatic brain injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / toxicity
  • Bexarotene / pharmacology
  • Bexarotene / therapeutic use*
  • Brain Injuries, Traumatic / metabolism*
  • Brain Injuries, Traumatic / prevention & control*
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • PPAR gamma / agonists
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / metabolism*
  • Pyridines / toxicity

Substances

  • Benzamides
  • Neuroprotective Agents
  • PPAR gamma
  • Pyridines
  • T 0070907
  • Bexarotene