Abstract
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 (n = 5), the mRNA levels of both Abcb1a and Abcb1b were found to be increased in the hippocampus at day 1 (n = 5) and at day 5 (n = 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 (n = 5) and at day 5 (n = 5) post-injury compared with sham controls (n = 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.
Highlights
Traumatic brain injury (TBI) is a major health care problem in the United States, with more than 2 million new cases occurring annually.[1]
Abcb1a messenger RNA (mRNA) in the hippocampus was significantly increased in repeat mild closed head injury (rmCHI) animals as compared with sham (one-way analysis of variance (ANOVA), F(2,12) = 11.50) by 1 day post-injury ( p < 0.01), and was further increased to greater than twofold by 5 days post-injury ( p < 0.01; Fig. 2A)
Abcb1b mRNA showed a similar response after rmCHI (one-way ANOVA, F(2,12) = 10.39), with a significant increase observed by 1 day post-injury ( p < 0.05), and a greater response observed by 5 days post-injury ( p < 0.01; Fig. 2B)
Summary
Traumatic brain injury (TBI) is a major health care problem in the United States, with more than 2 million new cases occurring annually.[1] Brain injury can be classified by severity level (i.e., mild, moderate, or severe) and/or mechanism (e.g., direct impact, penetrating, or acceleration/deceleration).[2,3] It has been estimated that more than 75% of TBI cases are classified as mild (mTBI), commonly referred to as concussion.[4,5]. Most patients report the abatement of symptoms within 3 months, as many as 33% may experience persistent symptoms for months or years post-injury.[6] The mechanisms through which mTBI alters brain function and pathology at various time-points are not well understood and are an intense area of study. There are no effective therapeutics available to lessen TBI pathobiology and improve brain function.
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