Neuro-cognitive deficits observed in chronic alcoholics often mirror those in individuals with HIV-1-associated dementia (HAD). It has been suggested that alcohol abuse may serve as a co-factor in the development of HAD and exacerbate the symptoms of HIV-1 encephalitis (HIVE). We have previously shown that ethanol affects macrophage function (antigen presentation) and the blood brain barrier (BBS) by enhancing monocyte infiltration via disruption of tight junctions. We further demonstrated that the combined effects of alcohol abuse and HIV-1 infection affect adaptive immune responses and augment neuroinflammation in a small animal model of HIVE. These evidences support the idea that alcohol abuse is an exacerbating factor in HIV-1 central nervous system (CMS) infection through BBB damage and augmented neuroinflammation leading to neuronal injury and diminished anti-viral adaptive immunity. We propose that activation of peroxisome proliferator-activated receptor gamma (PPARgamma, an anti-inflammatory regulatory pathway) diminishes inflammatory cell activation in the CMS, alters their neurotoxic potential and renders protective effects. PPARgamma stimulation in endothelial cells can prevent monocyte transmigration to the brain in the setting of alcohol abuse and HIV-1 infection. In this competing continuation, we will investigate the therapeutic potential of PPARgamma activation and the mechanisms involved in PPARgamma-mediated amelioration of the combined deleterious effects of alcohol abuse by addressing the following questions: 1) Can PPARgamma stimulation alter the neuroprotective/neurotoxic potential of HIV-1-infected, immune activated macrophages [through cytokine and glutamate production, activation of inducible nitric oxide synthase and generation of reactive oxygen species, (ROS)]? 2) Can PPARgamma stimulation attenuate neuroinflammation by decreasing monocyte migration across the BBB (via up-regulation of ROS scavenging enzyme, superoxide dismutase)? And 3) Can PPARgamma agonists diminish neuroinflammation, improve BBB dysfunction and restore impaired immune responses associated with alcohol abuse in an animal model for HIVE? These studies will use cellular models, BBB constructs and an animal model for HIVE to mechanistically address putative protective effects of PPARgamma stimulation on BBB and neurons damaged by alcohol and interactions with HIV-1-infected macrophages. Since the last submission, we obtained additional data (namely significant anti-inflammatory and anti-viral effects of PPARgamma agonists) in support of the hypothesis being tested. The availability of PPARgamma agonists approved for clinical use will permit rapid translation of experimental findings into therapeutic applications.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA015913-02
Application #
7127652
Study Section
Special Emphasis Panel (ZRG1-AARR-A (05))
Program Officer
Gentry, Thomas
Project Start
2005-09-30
Project End
2010-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$322,978
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Rom, Slava; Zuluaga-Ramirez, Viviana; Gajghate, Sachin et al. (2018) Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models. Mol Neurobiol :
Rom, Slava; Zuluaga-Ramirez, Viviana; Reichenbach, Nancy L et al. (2018) Secoisolariciresinol diglucoside is a blood-brain barrier protective and anti-inflammatory agent: implications for neuroinflammation. J Neuroinflammation 15:25
Persidsky, Yuri; Hill, Jeremy; Zhang, Ming et al. (2016) Dysfunction of brain pericytes in chronic neuroinflammation. J Cereb Blood Flow Metab 36:794-807
Rom, Slava; Zuluaga-Ramirez, Viviana; Reichenbach, Nancy L et al. (2016) PARP inhibition in leukocytes diminishes inflammation via effects on integrins/cytoskeleton and protects the blood-brain barrier. J Neuroinflammation 13:254
Persidsky, Yuri (2015) Insights into end-organ injury in HIV infection: dynamics of monocyte trafficking to the brain in SIV encephalitis. Am J Pathol 185:1548-51
Watters, Andrea K; Rom, Slava; Hill, Jeremy D et al. (2015) Identification and dynamic regulation of tight junction protein expression in human neural stem cells. Stem Cells Dev 24:1377-89
Rom, Slava; Dykstra, Holly; Zuluaga-Ramirez, Viviana et al. (2015) miR-98 and let-7g* protect the blood-brain barrier under neuroinflammatory conditions. J Cereb Blood Flow Metab 35:1957-65
Persidsky, Yuri; Fan, Shongshan; Dykstra, Holly et al. (2015) Activation of Cannabinoid Type Two Receptors (CB2) Diminish Inflammatory Responses in Macrophages and Brain Endothelium. J Neuroimmune Pharmacol 10:302-8
Rom, Slava; Zuluaga-Ramirez, Viviana; Dykstra, Holly et al. (2015) Poly(ADP-ribose) polymerase-1 inhibition in brain endothelium protects the blood-brain barrier under physiologic and neuroinflammatory conditions. J Cereb Blood Flow Metab 35:28-36
Zuluaga-Ramirez, Viviana; Rom, Slava; Persidsky, Yuri (2015) Craniula: A cranial window technique for prolonged imaging of brain surface vasculature with simultaneous adjacent intracerebral injection. Fluids Barriers CNS 12:24

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