Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Chem Biol Interact. 2013 Mar 25;203(1):371-5. doi: 10.1016/j.cbi.2012.10.022. Epub 2012 Nov 15.
Cholinergic activity has been recognized as a major regulatory component of stress responses after traumatic brain injury (TBI). Centrally acting acetylcholinesterase (AChE) inhibitors are also being considered as potential therapeutic candidates against TBI mediated cognitive impairments. We have evaluated the expression of molecules involved in cholinergic and inflammatory pathways in various regions of brain after repeated blast exposures in mice. Isoflurane anesthetized C57BL/6J mice were restrained and placed in a prone position transverse to the direction of the shockwaves and exposed to three 20.6 psi blast overpressures with 1-30 min intervals. Brains were collected at the 6h time point after the last blast exposure and subjected to cDNA microarray and microRNA analysis. cDNA microarray analysis showed significant changes in the expression of cholinergic (muscarinic and nicotinic) and gammaaminobutyric acid and glutamate receptors in the midbrain region along with significant changes in multiple genes involved in inflammatory pathways in various regions of the brain. MicroRNA analysis of cerebellum revealed differential expression of miR-132 and 183, which are linked to cholinergic anti-inflammatory signaling, after blast exposure. Changes in the expression of myeloperoxidase in the cerebellum were confirmed by Western blotting. These results indicate that early pathologic progression of blast TBI involves dysregulation of cholinergic and inflammatory pathways related genes. Acute changes in molecules involved in the modulation of cholinergic and inflammatory pathways after blast TBI can cause long-term central and peripheral pathophysiological changes.
胆碱能活性已被认为是创伤性脑损伤 (TBI) 后应激反应的主要调节成分。中枢作用的乙酰胆碱酯酶 (AChE) 抑制剂也被认为是治疗 TBI 介导的认知障碍的潜在治疗候选药物。我们评估了在小鼠反复爆震暴露后，大脑各个区域中涉及胆碱能和炎症途径的分子的表达。异氟烷麻醉的 C57BL/6J 小鼠被束缚并置于与冲击波方向横切的俯卧位置，并暴露于三个 20.6 psi 的爆震超压，间隔 1-30 分钟。在最后一次爆震暴露后的 6 小时时间点收集大脑，并进行 cDNA 微阵列和 microRNA 分析。cDNA 微阵列分析显示，在中脑区域中，胆碱能（毒蕈碱和烟碱）和γ-氨基丁酸和谷氨酸受体的表达发生了显著变化，同时大脑各个区域中涉及炎症途径的多个基因的表达也发生了显著变化。小脑的 microRNA 分析显示，爆震暴露后，与胆碱能抗炎信号相关的 miR-132 和 183 的表达发生了差异。Western blot 验证了小脑髓过氧化物酶表达的变化。这些结果表明，爆震性 TBI 的早期病理进展涉及胆碱能和炎症途径相关基因的失调。爆震性 TBI 后调节胆碱能和炎症途径的分子的急性变化可导致中枢和外周长期的病理生理变化。
