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ABC efflux transporters at blood-central nervous system barriers and their implications for treating spinal cord disorders.

ABSTRACT: The barriers present in the interfaces between the blood and the central nervous system form a major hurdle for the pharmacological treatment of central nervous system injuries and diseases. The family of ATP-binding cassette (ABC) transporters has been widely studied regarding efflux of medications at blood-central nervous system barriers. These efflux transporters include P-glycoprotein (abcb1), 'breast cancer resistance protein' (abcg2) and the various 'multidrug resistance-associated proteins' (abccs). Understanding which efflux transporters are present at the blood-spinal cord, blood-cerebrospinal fluid and cerebrospinal fluid-spinal cord barriers is necessary to determine their involvement in limiting drug transfer from blood to the spinal cord tissue. Recent developments in the blood-brain barrier field have shown that barrier systems are dynamic and the profile of barrier defenses can alter due to conditions such as age, disease and environmental challenge. This means that a true understanding of ABC efflux transporter expression and localization should not be one static value but instead a range that represents the complex patient subpopulations that exist. In the present review, the blood-central nervous system barrier literature is discussed with a focus on the impact of ABC efflux transporters on: (i) protecting the spinal cord from adverse effects of systemically directed drugs, and (ii) limiting centrally directed drugs from accessing their active sites within the spinal cord.

SUBMITTER: Koehn LM

PROVIDER: S-EPMC7047801 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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ABC efflux transporters at blood-central nervous system barriers and their implications for treating spinal cord disorders.

Koehn Liam M LM

Neural regeneration research 20200701 7

The barriers present in the interfaces between the blood and the central nervous system form a major hurdle for the pharmacological treatment of central nervous system injuries and diseases. The family of ATP-binding cassette (ABC) transporters has been widely studied regarding efflux of medications at blood-central nervous system barriers. These efflux transporters include P-glycoprotein (abcb1), 'breast cancer resistance protein' (abcg2) and the various 'multidrug resistance-associated protein ...[more]

PMID: 31960802

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Project description:ATP-binding cassette (ABC) drug efflux transporters could contribute to low intracellular concentrations of antiretroviral drugs in HIV-1 cell reservoirs and sanctuary sites. Furthermore, the functional expression of these transporters could be induced in activated T-cells. Therefore, we investigated the expression of ABC drug efflux transporters in human T-cells exposed to an HIV pseudotype virus (pHIVNL4-3), and further examined the potential involvement of the mammalian target of rapamycin (mTOR) signaling pathway in regulating their expression following exposure to pHIVNL4-3. Additionally, we investigated the contribution of the drug efflux transporters to the inflammatory response following pHIVNL4-3-induced T-cell activation. Human peripheral blood mononuclear cells (PBMCs) were exposed to HIV-1 envelope glycoprotein gp120IIIB, pHIVNL4-3 and/or mTOR inhibitors. The expression of ABC transporters, T-cell activation marker CD69, mTOR and pHIVNL4-3 was assessed in CD4+ T-cells by Flow cytometry. mRNA and protein levels of proinflammatory cytokines (IL6, TNFα and INFγ) were examined in PBMCs by qPCR and ELISA analyses, respectively, following exposure to pHIVNL4-3 with or without inhibitors of mTOR or ABC transporters. The expression of ABC transporters (P-glycoprotein, breast cancer resistance protein and multi-drug resistance associated protein-1) was significantly increased in CD4+ T-cells exposed to pHIVNL4-3. Treatment with mTOR inhibitors attenuated pHIVNL4-3-induced transporter expression, as well as mRNA and protein levels of IL6, TNFα and INFγ. Additionally, inhibition of P-gp or MRP1 activity resulted in lower concentrations of proinflammatory cytokines in supernatants of PBMC exposed to pHIVNL4-3. Herein we present novel data demonstrating that upregulation of ABC drug efflux transporters could involve the mTOR signaling pathway in CD4+ T-cells exposed to an HIV pseudotype. These transporters could limit antiretroviral drug penetration in HIV target T-cells. Furthermore, ABC transporters could potentially contribute to HIV-associated proinflammatory cytokine secretion.

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ABC efflux transporters at blood-central nervous system barriers and their implications for treating spinal cord disorders.

Publications

ABC efflux transporters at blood-central nervous system barriers and their implications for treating spinal cord disorders.

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