Gatson Joshua W, Simpkins James W, Uteshev Victor V
UT Southwestern Medical Center, Department of Surgery, Department of Neurosurgery, 5323 Harry Hines Blvd, Dallas, TX 75390-9160, United States.
University of West Virginia, Center for Basic and Translational Stroke Research, Department of Physiology and Pharmacology, Morgantown, WV 26506, United States.
Brain Res Bull. 2015 Mar;112:35-41. doi: 10.1016/j.brainresbull.2015.01.008. Epub 2015 Jan 31.
There are currently no clinically efficacious drug therapies to treat brain damage secondary to traumatic brain injury (TBI). In this proof-of-concept study, we used a controlled cortical impact model of TBI in young adult rats to explore a novel promising approach that utilizes PNU-120596, a previously reported highly selective Type-II positive allosteric modulator (α7-PAM) of α7 nicotinic acetylcholine receptors (nAChRs). α7-PAMs enhance and prolong α7 nAChR activation, but do not activate α7 nAChRs when administered without an agonist. The rational basis for the use of an α7-PAM as a post-TBI treatment is tripartite and arises from: (1) the intrinsic ability of brain injury to elevate extracellular levels of choline (a ubiquitous cell membrane-building material and a selective endogenous agonist of α7 nAChRs) due to the breakdown of cell membranes near the site and time of injury; (2) the ubiquitous expression of functional α7 nAChRs in neuronal and glial/immune brain cells; and (3) the potent neuroprotective and anti-inflammatory effects of α7 nAChR activation. Therefore, both neuroprotective and anti-inflammatory effects can be achieved post-TBI by targeting only a single player (i.e., the α7 nAChR) using α7-PAMs to enhance the activation of α7 nAChRs by injury-elevated extracellular choline. Our data support this hypothesis and demonstrate that subcutaneous administration of PNU-120596 post-TBI in young adult rats significantly reduces both brain cell damage and reactive gliosis. Therefore, our results introduce post-TBI systemic administration of α7-PAMs as a promising therapeutic intervention that could significantly restrict brain injury post-TBI and facilitate recovery of TBI patients.
目前尚无临床有效的药物疗法来治疗创伤性脑损伤（TBI）继发的脑损伤。在这项概念验证研究中，我们在年轻成年大鼠中使用了TBI的控制性皮质撞击模型，以探索一种新的有前景的方法，该方法利用PNU-120596，一种先前报道的α7烟碱型乙酰胆碱受体（nAChRs）的高度选择性II型正变构调节剂（α7-PAM）。α7-PAMs可增强并延长α7 nAChR的激活，但在没有激动剂的情况下给药时不会激活α7 nAChRs。将α7-PAM用作TBI后治疗的合理依据是三方的，源于：（1）脑损伤由于损伤部位和时间附近的细胞膜破裂而提高细胞外胆碱水平（一种普遍存在的细胞膜构建材料和α7 nAChRs的选择性内源性激动剂）的内在能力；（2）功能性α7 nAChRs在神经元和神经胶质/免疫脑细胞中的普遍表达；（3）α7 nAChR激活的强大神经保护和抗炎作用。因此，通过使用α7-PAMs仅靶向单个靶点（即α7 nAChR）来增强损伤升高的细胞外胆碱对α7 nAChRs的激活，可在TBI后实现神经保护和抗炎作用。我们的数据支持这一假设，并表明在年轻成年大鼠TBI后皮下注射PNU-120596可显著减少脑细胞损伤和反应性胶质增生。因此，我们的结果引入了TBI后全身给予α7-PAMs作为一种有前景的治疗干预措施，可显著限制TBI后脑损伤并促进TBI患者的恢复。
