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Buprenorphine as an adjunctive therapy for HIV associated neurocognitive disorders
Başlık:
Buprenorphine as an adjunctive therapy for HIV associated neurocognitive disorders
Yazar:
Jaureguiberry, Matias, author.
ISBN:
9780438059580
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (273 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Joan W. Berman.
Özet:
HIV entry into the CNS mediates viral seeding and chronic neuroinflammation that leads to HIV associated neurocognitive disorders, (HAND) in greater than 50% of HIV infected individuals, despite antiretroviral therapy (ART). One of the mechanisms by which HIV enters the CNS is by transmigration of infected monocytes across the blood brain barrier (BBB). A mature subpopulation of monocytes that expresses CD14, the LPS receptor, and CD16, the Fcylll receptor, is increased in number in the peripheral blood of HIV infected people. Mature monocytes can be productively infected with HIV, and they transmigrate preferentially across the BBB in response to CCL2, a chemokine elevated in the CNS of infected people despite ART. CCL2-mediated transmigration of monocytes across the BBB is a multistep, regulated process. Initially, monocytes loosely adhere to the brain microvascular endothelial cells (BMVEC) of the BBB. CCL2 presented on the surface of BMVEC will bind to its receptor, CCR2, on monocytes, activating the integrins LFA-1 and VLA-4. Activated LFA-1 will bind ICAM-1, and activated VLA-4 will bind VCAM-1, on the surface of BMVEC, promoting firm adhesion, that facilitates the chemotaxis of mature monocytes into the CNS.
Injection drug use is a major risk factor for HIV infection. One of the drugs frequently abused intravenously is heroin, which is an opioid. Opioids have been shown to exacerbate HIV CNS neuropathogensis, in part by modulating the functions of immune cells. Buprenorphine is an opiate derivate used as a therapeutic for heroin dependency. It is a partial agonist MOR, and a full antagonist of KOR, opioid receptors. Some studies showed that buprenorphine treatment results in better cognitive outcomes in substance abusers. This observation suggests that buprenorphine, despite being an opioid, could have beneficial effects in the context of HIV infection, but the effects of buprenorphine on different steps of CCL2 mediated mature monocyte transmigration across the BBB, critical for the development of HAND, have not been studied.
We examined the effects of buprenorphine on CCL2-mediated adhesion of mature monocytes to primary human BMVEC using an in vitro adhesion assay. We found that CCL2 significantly increased the adhesion of mature monocytes to BMVEC, and that concomitant treatment with buprenorphine decreased this process. To understand the mechanisms by which buprenorphine decreases adhesion to BMVEC, we used a similar adhesion assay with recombinant human ICAM-1 and VCAM-1. We found that buprenorphine decreased the adhesion of mature monocytes to ICAM-1 but not to VCAM-1. We also characterized the effects of buprenorphine on CCL2-mediated chemotaxis using a modified Boyden chamber. CCL2 increased mature monocyte chemotaxis, and buprenorphine decreased this chemotaxis. As a possible mechanism by which buprenorphine is mediating this decrease, we studied FROUNT association to CCR2. FROUNT is an adaptor protein of CCR2 that mediates early receptor signaling involved in monocyte chemotaxis. We showed by coimmunoprecipitation that FROUNT associates with CCR2 after CCL2 treatment of monocytes, and that buprenorphine decreases this interaction, suggesting an early mechanism by which buprenorphine regulates CCL2 mediated monocyte migration. Overall we showed that buprenorphine decreases CCL2 mediated transmigration of mature monocytes at different steps, which may contribute to decreased neuroinflammation and HAND in the context of HIV infection and opioid abuse.
We studied the effects of buprenorphine on monocyte migration and cognitive functions in vivo using a mouse model of HIV infection, EcoHIV, developed by our collaborator Dr. David Volsky. EcoHIV infection of mice mirrors many aspects of human HIV infection, including the development of cognitive impairment during chronic infection. Using a radial arm water maze we showed that buprenorphine treated EcoHIV infected mice did not develop cognitive impairment compared to infected untreated mice. Additionally, in a separate experiment using flow cytometry, we showed that EcoHIV increases inflammatory mouse monocyte migration into the CNS and that buprenorphine decreases this process. These novel exciting results suggest that in the context of HIV infection buprenorphine limits monocyte migration across the BBB, contributing to the reduction/ elimination of cognitive impairment in vivo.
Our results suggest that buprenorphine, despite being an opioid, may decrease neuroinflammation and subsequent cognitive impairment that contributes to HAND by limiting monocyte migration into the CNS. We propose that buprenorphine may be used as an adjunctive therapy for HAND in the context of HIV infection and opioid abuse. Additionally we showed that buprenorphine was able to mediate its effects on monocyte migration in the absence of heroin abuse. Thus buprenorphine treatment could also be beneficial in HIV infected non-opioid abusers.
Notlar:
School code: 0266
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(684735.1) | 684735-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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