Bexarotene promotes microglia/macrophages - Specific brain - Derived Neurotrophic factor expression and axon sprouting after traumatic brain injury
Bexarotene promotes microglia/macrophages - Specific brain - Derived Neurotrophic factor expression and axon sprouting after traumatic brain injury
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贝沙罗汀促进创伤性脑损伤后小胶质细胞/巨噬细胞特异性脑源性神经营养因子表达和轴突发芽
DOI：
10.1016/j.expneurol.2020.113462
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发表时间：
2020-12-01
影响因子：
5.3
通讯作者：
Cheng, Chongjie
中科院分区：
文献类型：
--
作者：
He, Junchi;Huang, Yike;Cheng, Chongjie
创伤性脑损伤（Traumatic brain injury，TBI）是导致损伤相关死亡和残疾的主要原因之一。脑外伤后白色物质损伤的特点是轴突损伤和脱髓鞘，导致神经网络受损和神经功能缺损。脑源性神经营养因子（BDNF）可促进白色物质修复。已报道过氧化物酶体增殖物激活受体γ（PPAR γ）的激活促进小胶质细胞/巨噬细胞朝向抗炎状态，并因此促进轴突再生。贝沙罗汀是一种维甲酸X受体（RXR）激动剂，可激活RXR/PPAR γ异源二聚体。本研究的目的是确定贝沙罗汀对小鼠TBI后小胶质细胞/巨噬细胞中BDNF和轴突发芽的影响。在经历受控皮质撞击（CCI）的C57 BL/6小鼠中腹膜内给予贝沙罗汀。通过腹膜内施用PPAR γ拮抗剂T0070907来确定PPAR γ依赖性。我们发现贝沙罗汀促进轴突再生，表现为生长相关蛋白43（GAP 43）表达、髓鞘碱性蛋白（MBP）表达和生物素化葡聚糖胺（BDA）（+）轴突发芽增加。贝沙罗汀还增加了TBI后小胶质细胞/巨噬细胞特异性脑源性神经营养因子（BDNF）的表达。此外，贝沙罗汀减少了促炎性小胶质细胞/巨噬细胞的数量，同时增加了TBI后抗炎性小胶质细胞/巨噬细胞的数量。此外，贝伐他汀抑制促炎细胞因子分泌。此外，贝沙罗汀治疗改善了CCI损伤小鼠的神经评分和认知功能。贝沙罗汀的这些作用被T0070907部分消除。总之，贝沙罗汀促进轴突发芽，增加小胶质细胞/巨噬细胞特异性BDNF表达，并诱导小胶质细胞/巨噬细胞从促炎状态到抗炎状态，至少部分以PPAR γ依赖性方式。
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 (PPAR gamma) 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/PPAR gamma 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). PPAR gamma dependency was determined by intraperitoneal administration of a PPAR gamma 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 PPAR gamma-dependent manner.