National Trauma Research Institute, Alfred Hospital, Victoria, Australia.
J Neurotrauma. 2012 May 1;29(7):1410-25. doi: 10.1089/neu.2011.2188. Epub 2012 Apr 16.
Neurogenesis is stimulated following injury to the adult brain and could potentially contribute to tissue repair. However, evidence suggests that microglia activated in response to injury are detrimental to the survival of new neurons, thus limiting the neurogenic response. The aim of this study was to determine the effect of the anti-inflammatory drug minocycline on neurogenesis and functional recovery after a closed head injury model of focal traumatic brain injury (TBI). Beginning 30 min after trauma, minocycline was administered for up to 2 weeks and bromodeoxyuridine was given on days 1-4 to label proliferating cells. Neurological outcome and motor function were evaluated over 6 weeks using the Neurological Severity Score (NSS) and ledged beam task. Microglial activation was assessed in the pericontusional cortex and hippocampus at 1 week post-trauma, using immunohistochemistry to detect F4/80. Following immunolabeling of bromodeoxyuridine, double-cortin, and NeuN, cells undergoing distinct stages of neurogenesis, including proliferation, neuronal differentiation, neuroblast migration, and long-term survival, were quantified at 1 and 6 weeks in the hippocampal dentate gyrus, as well as in the subventricular zone of the lateral ventricles and the pericontusional cortex. Our results show that minocycline successfully reduced microglial activation and promoted early neurological recovery that was sustained over 6 weeks. We also show for the first time in the closed head injury model, that early stages of neurogenesis were stimulated in the hippocampus and subventricular zone; however, no increase in new mature neurons occurred. Contrary to our hypothesis, despite the attenuation of activated microglia, minocycline did not support neurogenesis in the hippocampus, lateral ventricles, or pericontusional cortex, with none of the neurogenic stages being affected by treatment. These data provide evidence that a general suppression of microglial activation is insufficient to enhance neuronal production, suggesting that further work is required to elucidate the relationship between microglia and neurogenesis after TBI.
神经发生在成年大脑受伤后会受到刺激，并且可能有助于组织修复。然而，有证据表明，受伤后被激活的小胶质细胞对新神经元的存活有害，从而限制了神经发生反应。本研究的目的是确定抗炎药物米诺环素对闭合性颅脑损伤（TBI）局灶性创伤性脑损伤模型后神经发生和功能恢复的影响。创伤后 30 分钟开始，米诺环素治疗长达 2 周，并在第 1-4 天给予溴脱氧尿苷以标记增殖细胞。使用神经损伤严重程度评分（NSS）和突出梁任务在 6 周内评估神经功能和运动功能。在创伤后 1 周，使用免疫组织化学检测 F4/80 评估损伤周围皮质和海马中的小胶质细胞激活。在溴脱氧尿苷、双皮质素和 NeuN 免疫标记后，在海马齿状回以及侧脑室室下区和损伤周围皮质中定量分析处于不同神经发生阶段的细胞，包括增殖、神经元分化、神经前体细胞迁移和长期存活，在 1 周和 6 周时。我们的结果表明，米诺环素成功地减少了小胶质细胞的激活，并促进了早期神经恢复，这种恢复持续了 6 周。我们还首次在闭合性颅脑损伤模型中表明，在海马和室下区刺激了神经发生的早期阶段；然而，没有新的成熟神经元增加。与我们的假设相反，尽管激活的小胶质细胞减少，但米诺环素并没有支持海马、侧脑室或损伤周围皮质的神经发生，治疗没有影响任何一个神经发生阶段。这些数据提供的证据表明，普遍抑制小胶质细胞的激活不足以增强神经元的产生，这表明需要进一步的工作来阐明 TBI 后小胶质细胞与神经发生之间的关系。
