Dash Pramod K, Zhao Jing, Kobori Nobuhide, Redell John B, Hylin Michael J, Hood Kimberly N, Moore Anthony N
Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 77030
Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 77030.
J Neurosci. 2016 Mar 2;36(9):2809-18. doi: 10.1523/JNEUROSCI.3197-15.2016.
Traumatic brain injury (TBI) is a major human health concern that has the greatest impact on young men and women. The breakdown of the blood-brain barrier (BBB) is an important pathological consequence of TBI that initiates secondary processes, including infiltration of inflammatory cells, which can exacerbate brain inflammation and contribute to poor outcome. While the role of inflammation within the injured brain has been examined in some detail, the contribution of peripheral/systemic inflammation to TBI pathophysiology is largely unknown. Recent studies have implicated vagus nerve regulation of splenic cholinergic nicotinic acetylcholine receptor α7 (nAChRa7) signaling in the regulation of systemic inflammation. However, it is not known whether this mechanism plays a role in TBI-triggered inflammation and BBB breakdown. Following TBI, we observed that plasma TNF-α and IL-1β levels, as well as BBB permeability, were significantly increased in nAChRa7 null mice (Chrna7(-/-)) relative to wild-type mice. The administration of exogenous IL-1β and TNF-α to brain-injured animals worsened Evans Blue dye extravasation, suggesting that systemic inflammation contributes to TBI-triggered BBB permeability. Systemic administration of the nAChRa7 agonist PNU-282987 or the positive allosteric modulator PNU-120596 significantly attenuated TBI-triggered BBB compromise. Supporting a role for splenic nAChRa7 receptors, we demonstrate that splenic injection of the nicotinic receptor blocker α-bungarotoxin increased BBB permeability in brain-injured rats, while PNU-282987 injection decreased such permeability. These effects were not seen when α-bungarotoxin or PNU-282987 were administered to splenectomized, brain-injured rats. Together, these findings support the short-term use of nAChRa7-activating agents as a strategy to reduce TBI-triggered BBB permeability.
Breakdown of the blood-brain barrier (BBB) in response to traumatic brain injury (TBI) allows for the accumulation of circulating fluids and proinflammatory cells in the injured brain. These processes can exacerbate TBI pathology and outcome. While the role of inflammation in the injured tissue has been examined in some detail, the contribution of peripheral inflammation in BBB breakdown and ensuing pathology has not been well defined. We present experimental evidence to indicate that the stimulation of nicotinic acetylcholine α7 receptors (nAChRa7s) can reduce peripheral inflammation and BBB breakdown after TBI. These results suggest that activators of nAChRa7 may have therapeutic utility for the treatment of TBI.
创伤性脑损伤（TBI）是一个重大的人类健康问题，对年轻男性和女性影响最大。血脑屏障（BBB）的破坏是TBI的一个重要病理后果，它引发继发性过程，包括炎症细胞浸润，这会加剧脑部炎症并导致不良后果。虽然已经对损伤脑内炎症的作用进行了一些详细研究，但外周/全身炎症对TBI病理生理学的贡献在很大程度上尚不清楚。最近的研究表明，迷走神经对脾脏胆碱能烟碱型乙酰胆碱受体α7（nAChRa7）信号的调节在全身炎症的调节中起作用。然而，尚不清楚这种机制是否在TBI引发的炎症和BBB破坏中起作用。TBI后，我们观察到相对于野生型小鼠，nAChRa7基因敲除小鼠（Chrna7(-/-)）的血浆TNF-α和IL-1β水平以及BBB通透性显著增加。给脑损伤动物注射外源性IL-1β和TNF-α会使伊文思蓝染料外渗恶化，这表明全身炎症会导致TBI引发的BBB通透性增加。全身给予nAChRa7激动剂PNU-282987或正变构调节剂PNU-120596可显著减轻TBI引发的BBB损伤。支持脾脏nAChRa7受体的作用，我们证明向脑损伤大鼠脾脏注射烟碱受体阻滞剂α-银环蛇毒素会增加BBB通透性，而注射PNU-282987会降低这种通透性。当向脾切除的脑损伤大鼠给予α-银环蛇毒素或PNU-282987时，未观察到这些效应。总之，这些发现支持短期使用nAChRa7激活剂作为减少TBI引发的BBB通透性的策略。
创伤性脑损伤（TBI）导致的血脑屏障（BBB）破坏会使循环液体和促炎细胞在损伤脑内积聚。这些过程会加剧TBI病理和后果。虽然已经对损伤组织中炎症的作用进行了一些详细研究，但外周炎症在BBB破坏及随后病理过程中的贡献尚未明确界定。我们提供实验证据表明，刺激烟碱型乙酰胆碱α7受体（nAChRa7s）可减少TBI后的外周炎症和BBB破坏。这些结果表明，nAChRa7激活剂可能对TBI治疗具有治疗效用。
