Vita Sydney M, Redell John B, Maynard Mark E, Zhao Jing, Grill Raymond J, Dash Pramod K, Grayson Bernadette E
Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Department of Neurobiology and Anatomy, University of Texas McGovern Medical School, Houston, Texas, USA.
Neurotrauma Rep. 2020 Nov 18;1(1):207-217. doi: 10.1089/neur.2020.0034. eCollection 2020.
Athletes participating in contact sports are at risk for sustaining repeat mild traumatic brain injury (rmTBI). Unfortunately, no pharmacological treatment to lessen the pathophysiology of brain injury has received U.S. Food and Drug Administration (FDA) approval. One hurdle to overcome for potential candidate agents to reach effective therapeutic concentrations in the brain is the blood-brain barrier (BBB). Adenosine triphosphate (ATP)-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp), line the luminal membrane of the brain capillary endothelium facing the vascular space. Although these transporters serve to protect the central nervous system (CNS) from damage by effluxing neurotoxicants before they can reach the brain, they may also limit the accumulation of therapeutic drugs in the brain parenchyma. Thus, increased Pgp expression following brain injury may result in reduced brain availability of therapeutic agents. We therefore questioned if repeat concussive injury increases Pgp expression in the brain. To answer this question, we used a rodent model of repeat mild closed head injury (rmCHI) and examined the messenger RNA (mRN) and protein expression of both isoforms of rodent Pgp (Abcb1a and Abcb1b). Compared with sham-operated controls ( 5), the mRNA levels of both Abcb1a and Abcb1b were found to be increased in the hippocampus at day 1 ( 5) and at day 5 ( 5) post-injury. Using a validated antibody, we show increased immunolabeling for Pgp in the dorsal cortex at day 5 and in the hippocampus at day 1 ( 5) and at day 5 ( 5) post-injury compared with sham controls ( 6). Taken together, these results suggest that increased expression of Pgp after rmCHI may reduce the brain accumulation of therapeutic drugs that are Pgp substrates. It is plausible that including a Pgp inhibitor with a candidate therapeutic agent may be an effective approach to treat the pathophysiology of rmCHI.
参加接触性运动的运动员有遭受重复性轻度创伤性脑损伤（rmTBI）的风险。不幸的是，尚无减轻脑损伤病理生理的药物治疗获得美国食品药品监督管理局（FDA）的批准。潜在候选药物要在脑内达到有效治疗浓度需要克服的一个障碍是血脑屏障（BBB）。三磷酸腺苷（ATP）结合盒（ABC）转运蛋白，如P-糖蛋白（Pgp），排列在面向血管腔隙的脑毛细血管内皮细胞的腔膜上。虽然这些转运蛋白通过在神经毒性物质到达脑之前将其外排来保护中枢神经系统（CNS）免受损伤，但它们也可能限制治疗药物在脑实质中的蓄积。因此，脑损伤后Pgp表达增加可能导致治疗药物在脑内的可利用性降低。我们因此质疑重复性脑震荡损伤是否会增加脑内Pgp的表达。为回答这个问题，我们使用了重复性轻度闭合性颅脑损伤（rmCHI）的啮齿动物模型，并检测了啮齿动物Pgp两种亚型（Abcb1a和Abcb1b）的信使核糖核酸（mRNA）和蛋白表达。与假手术对照组（n = 5）相比，发现损伤后第1天（n = 5）和第5天（n = 5）海马中Abcb1a和Abcb1b的mRNA水平均升高。使用经过验证的抗体，我们发现与假手术对照组（n = 6）相比，损伤后第5天背侧皮质以及损伤后第1天（n = 5）和第5天（n = 5）海马中Pgp的免疫标记增加。综上所述，这些结果表明rmCHI后Pgp表达增加可能会减少作为Pgp底物的治疗药物在脑内的蓄积。在候选治疗药物中加入Pgp抑制剂可能是治疗rmCHI病理生理的一种有效方法，这似乎是合理的。
