P-glycoprotein Expression Is Upregulated in a Pre-Clinical Model of Traumatic Brain Injury

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.

Relationship Between Amyloid-β Deposition and Blood–Brain Barrier Dysfunction in Alzheimer’s Disease

“…In the brain, P-gP is mainly expressed on the lumen (blood-facing) surface of the BBB endothelium, and helps limit the entry of brain-active drugs into the CNS using ATP ( Chen et al, 2021 ). P-gP is also found in astrocytes, neurons, and microglia ( Chai et al, 2020b ; Vita et al, 2020 ). The expression and function of P-gP are compromised with age and in cases of AD ( Guerreiro and Bras, 2015 ).…”

Histological comparison of repeated mild weight drop and lateral fluid percussion injury models of traumatic brain injury (TBI) in female and male rats

“…We detected a modest, yet significant increase in claudin-5 reactivity in the in the dentate gyrus of females and males receiving LFP. While no reports were found in the literature describing similar changes; an upregulation of the claudin-5 gene has been reported in the hippocampus of male C57 mice at PID 5 following 4 repeated mild TBIs administered over 4 days 93 .…”

The impact of ATP-binding cassette transporters in the diseased brain: Context matters

“…Vita et al. 173 examined a mouse model of repeated mild blunt force TBI, noting increased Abcb1a and Abcb1b mRNA levels in the hippocampus over 5 days after injury. In contrast, Abcg2 and Abcc1 mRNA levels demonstrated a non-significant trend toward an increase and decrease, respectively.…”