Dataset Information

Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV.

ABSTRACT: Many HIV infected individuals with suppressed viral loads experience chronic immune activation frequently developing neurological impairment designated as HIV associated neurocognitive disorder (HAND). Adjunctive therapies may reduce HIV associated inflammation and therefore decrease the occurrence of HAND.We have conducted in vitro, animal and clinical studies of the neurokinin 1 receptor (NK1R) antagonist aprepitant in HIV/SIV infection.Aprepitant inhibits HIV infection of human macrophages ex vivo with an ED50 ~ 5 µM. When administered at 125 mg once daily for 12 months to SIV-infected rhesus macaques, aprepitant reduced viral load by approximately tenfold and produced anti-anxiolytic effects. The anti-viral and anti-anxiolytic effects occur at approximately the third month of dosing; and the effects are sustained throughout the duration of drug administration. Protein binding experiments in culture media and animal and human plasma indicate that the free fraction of aprepitant is lower than previously reported supporting usage of higher doses in vivo. The analysis of blood samples from HIV positive individuals treated for 2 weeks with aprepitant at doses up to 375 mg demonstrated reduced levels of pro-inflammatory cytokines including G-CSF, IL-6, IL-8 and TNF?. Decreased pro-inflammatory cytokines may reduce HIV comorbidities associated with chronic inflammation.Our results provide evidence for a unique combination of antiretroviral, anti-inflammatory and behavioral modulation properties of aprepitant in vitro and in vivo. These results provide robust support for a clinical exposure target above that recommended for chemotherapy-induced nausea and vomiting. Doses up to 375 mg once daily in HIV-infected patients still elicit sub-therapeutic exposure of aprepitant though effective plasma concentrations can be achievable by proper dose modulation.

SUBMITTER: Barrett JS

PROVIDER: S-EPMC4880976 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV.

Barrett Jeffrey S JS Spitsin Sergei S Moorthy Ganesh G Barrett Kyle K Baker Kate K Lackner Andrew A Tulic Florin F Winters Angela A Evans Dwight L DL Douglas Steven D SD

Journal of translational medicine 20160526 1

<h4>Background</h4>Many HIV infected individuals with suppressed viral loads experience chronic immune activation frequently developing neurological impairment designated as HIV associated neurocognitive disorder (HAND). Adjunctive therapies may reduce HIV associated inflammation and therefore decrease the occurrence of HAND.<h4>Methods</h4>We have conducted in vitro, animal and clinical studies of the neurokinin 1 receptor (NK1R) antagonist aprepitant in HIV/SIV infection.<h4>Results</h4>Aprepi ...[more]

PMID: 27230663

Similar Datasets

Project description:Background Pyroptosis is a programmed cell death mediated by inflammasomes. Previous studies have reported that inhibition of neurokinin receptor 1 (NK1R) exerted neuroprotection in several neurological diseases. Herein, we have investigated the role of NK1R receptor inhibition using Aprepitant to attenuate NLRC4-dependent neuronal pyroptosis after intracerebral hemorrhage (ICH), as well as the underlying mechanism. Methods A total of 182 CD-1 mice were used. ICH was induced by injection of autologous blood into the right basal ganglia. Aprepitant, a selective antagonist of NK1R, was injected intraperitoneally at 1 h after ICH. To explore the underlying mechanism, NK1R agonist, GR73632, and protein kinase C delta (PKCδ) agonist, phorbol 12-myristate 13-acetate (PMA), were injected intracerebroventricularly at 1 h after ICH induction, and small interfering ribonucleic acid (siRNA) for NLRC4 was administered via intracerebroventricular injection at 48 h before ICH induction, respectively. Neurobehavioral tests, western blot, and immunofluorescence staining were performed. Results The expression of endogenous NK1R and NLRC 4 were gradually increased after ICH. NK1R was expressed on neurons. Aprepitant significantly improved the short- and long-term neurobehavioral deficits after ICH, which was accompanied with decreased neuronal pyroptosis, as well as decreased expression of NLRC4, Cleaved-caspase-1, GSDMD (gasdermin D), IL-1β, and IL-18. Activation of NK1R or PKCδ abolished these neuroprotective effects of Aprepitant after ICH. Similarly, knocking down NLRC4 using siRNA produced similar neuroprotective effects. Conclusion Aprepitant suppressed NLRC4-dependent neuronal pyroptosis and improved neurological function, possibly mediated by inhibition of NK1R/PKCδ signaling pathways after ICH. The NK1R may be a promising therapeutic target for the treatment of ICH. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02558-z.

Dataset Information

Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV.

Publications

Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets