Bexarotene promotes microglia/macrophages - Specific brain - Derived Neurotrophic factor expression and axon sprouting after traumatic brain injury

  • Exp Neurol. 2020 Dec;334:113462. doi: 10.1016/j.expneurol.2020.113462.
Junchi He  1 ,  Yike Huang  2 ,  Han Liu  1 ,  Xiaochuan Sun  1 ,  Jingchuan Wu  1 ,  Zhaosi Zhang  1 ,  Liu Liu  1 ,  Chao Zhou  1 ,  Shaoqiu Jiang  3 ,  Zhijian Huang  1 ,  Jianjun Zhong  1 ,  Zongduo Guo  1 ,  Li Jiang  1 ,  Chongjie Cheng  4
Affiliations
  • 1. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2. Department of Ophthalmology, Army Medical Center (Daping Hospital), Army Medical University, Chongqing, China.
  • 3. Department of Ophthalmology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 4. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
PMID: 32916173 DOI: 10.1016/j.expneurol.2020.113462
Abstract

Traumatic brain injury (TBI) has been regarded as one of the leading cause of injury-related death and disability. White matter injury after TBI is characterized by axon damage and demyelination, resulting in neural network impairment and neurological deficit. Brain-derived neurotrophic factor (BDNF) can promote white matter repair. The activation of Peroxisome Proliferator-activated Receptor gamma (PPARγ) has been reported to promote microglia/macrophages towards anti-inflammatory state and therefore to promote axon regeneration. Bexarotene, an agonist of retinoid X receptor (RXR), can activate RXR/PPARγ heterodimers. The aim of the present study was to identify the effect of bexarotene on BDNF in microglia/macrophages and axon sprouting after TBI in mice. Bexarotene was administered intraperitoneally in C57BL/6 mice undergoing controlled cortical impact (CCI). PPARγ dependency was determined by intraperitoneal administration of a PPARγ Antagonist T0070907. We found that bexarotene promoted axon regeneration indicated by increased growth associated protein 43 (GAP43) expression, myelin basic protein (MBP) expression, and biotinylated dextran amine (BDA)+ axon sprouting. Bexarotene also increased microglia/macrophages-specific brain derived neurotrophic factor (BDNF) expression after TBI. In addition, bexarotene reduced the number of pro-inflammatory microglia/macrophages while increased the number of anti-inflammatory microglia/macrophages after TBI. Moreover, bexaortene inhibited pro-inflammatory cytokine secretion. In addition, bexarotene treatment improved neurological scores and cognitive function of CCI-injured mice. These effects of bexarotene were partially abolished by T0070907. In conclusion, bexarotene promotes axon sprouting, increases microglia/macrophages-specific BDNF expression, and induces microglia/macrophages from a pro-inflammatory state towards an anti-inflammatory one after TBI at least partially in a PPARγ-dependent manner.

Keywords
Axon sprouting; Brain derived neurotrophic factor; Microglia/macrophages; Traumatic brain injury.
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