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Peroxisome Proliferator-activated Re...

Omeragic, Amila .

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Peroxisome Proliferator-activated Receptor-γ (PPARγ) Agonists: Potential Novel Treatment for HIV-1 Associated Brain Inflammation.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Peroxisome Proliferator-activated Receptor-γ (PPARγ) Agonists: Potential Novel Treatment for HIV-1 Associated Brain Inflammation./
Author:	Omeragic, Amila .
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	204 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-01, Section: B.
Contained By:	Dissertations Abstracts International82-01B.
Subject:	Pharmaceutical sciences. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27666067
ISBN:	9798662390164

Peroxisome Proliferator-activated Receptor-γ (PPARγ) Agonists: Potential Novel Treatment for HIV-1 Associated Brain Inflammation.
Omeragic, Amila .

Peroxisome Proliferator-activated Receptor-γ (PPARγ) Agonists: Potential Novel Treatment for HIV-1 Associated Brain Inflammation. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 204 p.

Source: Dissertations Abstracts International, Volume: 82-01, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2020.

This item must not be sold to any third party vendors.

Despite the use of combinational antiretroviral therapy (cART) for the treatment of HIV-1 infection, cognitive impairments remain prevalent due to persistent viral replication and associated inflammation in the brain. Cellular targets in the brain include microglia and astrocytes which in response to infection release inflammatory markers and viral proteins. Peroxisome Proliferator Activated Receptor-gamma (PPARγ) is a ligand-activated transcription factor that plays a role in glucose and lipid homeostasis. Compelling evidence also suggests that PPARγ agonists can exert anti-inflammatory properties in animal models of neurological disorders. With no treatment currently available for HIV-1 associated neurocognitive disorders (HAND), it is critical to identify compounds that can permeate across the blood-brain barrier (BBB) and exert anti-inflammatory effects. The aim of this doctoral thesis was: i) to investigate the efficacy of PPARγ agonists, rosiglitazone and pioglitazone in reversing brain inflammation in vitro in primary cultures of mixed glial cells exposed to HIV-1ADA glycoprotein 120 (gp120) and in vivo in an intracerebroventricular (ICV) HIV-1ADA gp120 administered rat model, ii) to examine the efficacy of PPARγ agonists, rosiglitazone and pioglitazone in reversing brain inflammation in vitro in primary cultures of mixed glial cells exposed to EcoHIV and in vivo in an intracranial (IC) EcoHIV administered mouse model and iii) to assess the therapeutic potential of the selective PPARγ modulator (SPPARγM), INT131 in EcoHIV infection, and characterize its pharmacokinetic profile. We demonstrated that gp120 can induce an inflammatory response and decrease expression of glutamate transporter-1 (GLT-1) in vitro and in vivo. We then showed that these inflammatory responses could be partially or completely reversed with PPARγ agonists, rosiglitazone or pioglitazone treatment. Next, we successfully implemented a rodent model of HIV-1 associated brain inflammation using a chimeric virus, EcoHIV. Infection with EcoHIV in vitro and/or in vivo, resulted in a potent upregulation of several inflammatory genes that could be partially or completely reversed by rosiglitazone, pioglitazone or INT131. Finally, we characterized in mice the pharmacokinetic profile of INT131 systemically and in the brain. Overall, our data demonstrated that PPARγ agonists could serve as a promising novel therapeutic approach for treatment/prevention of HIV-1 associated brain inflammation.

ISBN: 9798662390164Subjects--Topical Terms:

3173021
Pharmaceutical sciences.
Subjects--Index Terms:

Combinational antiretroviral therapy

Peroxisome Proliferator-activated Receptor-γ (PPARγ) Agonists: Potential Novel Treatment for HIV-1 Associated Brain Inflammation.
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