Minocycline protects developing brain against ethanol-induced damage

NEUROPHARMACOLOGY

卷:129

Article

Wang, Xin¹  Zhang, Kai¹  Yang, Fanmuyi¹  Ren, Zhenhua^1,2  Xu, Mei¹  Frank, Jacqueline A.¹  Ke, Zu-ji³  Luo, Jia^1,3 

[1] Univ Kentucky, Dept Pharmacol & Nutr Sci, Coll Med, 132 Hlth Sci Res Bldg,1095 Vet Dr, Lexington, KY 40536 USA

[2] Anhui Med Univ, Sch Basic Med, Dept Anat, Hefei 230032, Anhui, Peoples R China

[3] Shanghai Univ Tradit Chinese Med, Dept Biochem, Shanghai 201203, Peoples R China

关键词: Apoptosis;    Development;    Fetal alcohol syndrome;    Inflammation;    Microglia;    Neurodegeneration;   

DOI  :  10.1016/j.neuropharm.2017.11.019

来源: Elsevier

【 摘 要 】

Fetal alcohol spectrum disorders (FASD) are caused by ethanol exposure during the pregnancy and is the leading cause of mental retardation. Ethanol exposure during the development results in the loss of neurons in the developing brain, which may underlie many neurobehavioral deficits associated with FASD. It is important to understand the mechanisms underlying ethanol-induced neuronal loss and develop appropriate therapeutic strategies. One of the potential mechanisms involves neuroimmune activation. Using a third trimester equivalent mouse model of ethanol exposure, we demonstrated that ethanol induced a wide-spread neuroapoptosis, microglial activation, and neuroinflammation in C57BL/6 mice. Minocycline is an antibiotic that inhibits microglial activation and alleviates neuroinflammation. We tested the hypothesis that minocycline may protect neurons ethanol-induced neuron death by inhibiting microglial activation and neuroinflammation. We showed that minocycline significantly inhibited ethanol-induced caspase-3 activation, microglial activation, and the expression of pro inflammatory cytokines. In contrast, minocycline reversed ethanol inhibition of anti-inflammatory cytokines. Minocycline blocked ethanol-induced activation of GSK3 beta, a key mediator of neuroinflammation and microglial activation in the developing brain. Consistent with the in vivo observations, minocycline inhibited ethanol-induced the expression of pro-inflammatory cytokines and activation of GSK3 beta in a microglia cell line (SIM-9). GSK3 beta inhibitor eliminated ethanol activation of pro-inflammatory cytokines in SIM-9 cells. Co-cultures of cortical neurons and SIM-9 microglia cells sensitized neurons to alcohol induced neuronal death. Minocycline protected neurons against ethanol-induced neuronal death in neurons/microglia co-cultures. Together, these results suggest that minocycline may ameliorate ethanol neurotoxicity in the developing by alleviating GSK3 beta-mediated neuroinflammation. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

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