Mechanisms and Interventions for Methamphetamine and HIV-1 Induced CNS Injury

Summary

Principal Investigator: Yuri Persidsky
Abstract: ABSTRACT: Methamphetamine (METH), an addictive stimulant has long lasting toxic effects on the central nervous system (CNS). Clinical studies indicated that METH dependence has an additive effect on neuropsychological deficits associated with HIV-1 infection. Oxidative stress, excitotoxicity, BBB impairment and glial cell activation, all have been independently implicated in the mechanisms of METH- and HIV-1-associated neurotoxicity. This proposal will investigate specific mechanisms operative in HIV-1 CNS infection and METH abuse that lead to an overall increase in oxidative stress and NF-kB signaling resulting in impairment of astrocytes and endothelial cell function. We propose that METH-mediated oxidative stress in astrocytes leads to a down regulation exitotoxic amino acid transporter (EAAT) -2, the primary astrocyte glutamate scavenger, while in endothelial cells, such an increase in oxidative stress results in loss of BBB integrity. Indeed, our preliminary data suggest that METH exposure caused ROS generation in astrocytes and human primary BMVEC, diminished EAAT-2 expression, in astrocytes, decreased BBB integrity in vitro that was restored by antioxidant treatment, caused decreased expression/re-distribution of tight junction proteins, enhanced adhesion and migration of monocytes across endothelial monolayers and activated small GTPases in BMVEC that were previously implicated in the BBB injury during HIV-1 encephalitis (HIVE). New preliminary data demonstrated increased permeability of BBB in vivo in animals exposed to METH that was prevented by antioxidant treatment. This proposal will investigate a novel concept of mechanistic commonality, i.e. METH-mediated oxidative stress exerts its cell-specific effects in astrocytes and endothelial cells aggravating injury caused by HIV-1 CNS infection and delineate therapeutic options for these targets using in vivo studies. Using a combination of in vitro assays and METH/HIVE animal model, we will address the following questions: What is the role(s) of enhanced reactive oxygen species, ROS production and NF-kB signaling in diminished expression/function of EAAT-2 in astrocytes? (Aim 1) What are underlying mechanisms of BBB dysfunction and enhanced monocyte adhesion/migration across brain endothelium (via oxidative stress, interference with NF-kB and GTPase signaling)? (Aim 2);and Can therapeutics decreasing oxidative stress and normalizing EAAT-2 function ameliorate BBB dysfunction and neurotoxicity in an animal model for HIVE and METH abuse? (Aim 3) We will address these questions utilizing primary human astrocytes and brain microvascular cells, in vitro BBB models and evaluate combined effects of METH and HIV-1 relevant stimuli on EAAT-2 and BBB function. Antioxidants and specific signaling inhibitors will be utilized to delineate pathways involved in these effects. Our HIVE animal model will be employed to investigate the biological outcomes of these cell-specific mechanisms in cognitive function, BBB damage and neurotoxicity. We believe that the proposed works are highly significant, as they will uncover novel mechanisms involved in the combined effects of HIV-1 and METH in the CNS and propose therapeutic approaches based on these investigations.
Funding Period: 2009-04-01 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. pmc Methamphetamine disrupts blood-brain barrier function by induction of oxidative stress in brain endothelial cells
    Servio H Ramirez
    Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA
    J Cereb Blood Flow Metab 29:1933-45. 2009
  2. pmc Methamphetamine causes mitrochondrial oxidative damage in human T lymphocytes leading to functional impairment
    Raghava Potula
    Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
    J Immunol 185:2867-76. 2010
  3. pmc HIV-1 infection and alcohol abuse: neurocognitive impairment, mechanisms of neurodegeneration and therapeutic interventions
    Yuri Persidsky
    Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
    Brain Behav Immun 25:S61-70. 2011
  4. pmc Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions
    Servio H Ramirez
    Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
    J Neurosci 32:4004-16. 2012
  5. pmc HIV-1, methamphetamine and astrocyte glutamate regulation: combined excitotoxic implications for neuro-AIDS
    Irma E Cisneros
    University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA
    Curr HIV Res 10:392-406. 2012
  6. pmc Glycogen synthase kinase 3β inhibition prevents monocyte migration across brain endothelial cells via Rac1-GTPase suppression and down-regulation of active integrin conformation
    Slava Rom
    Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Am J Pathol 181:1414-25. 2012
  7. pmc Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation
    Slava Rom
    Department of Pathology and Laboratory Medicine, Temple University School of Medicine, 3401 N Broad St, Philadelphia, PA 19140, USA
    J Neuroimmune Pharmacol 8:608-20. 2013

Research Grants

  1. CNS &Peripheral Viral Reservoirs/SIV Model of HIV HAART
    Janice E Clements; Fiscal Year: 2013
  2. Macrophages, NR2B-containing NMDA Receptors and HIV Dementia
    HUANGUI HANK XIONG; Fiscal Year: 2013
  3. HIV NEUROBEHAVIORAL RESEARCH CENTER
    ROBERT KERNACHAN HEATON; Fiscal Year: 2013
  4. SPINAL CIRCUITS AND THE MUSCULOSKELETAL SYSTEM
    Arthur W English; Fiscal Year: 2013
  5. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013

Detail Information

Publications7

  1. pmc Methamphetamine disrupts blood-brain barrier function by induction of oxidative stress in brain endothelial cells
    Servio H Ramirez
    Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA
    J Cereb Blood Flow Metab 29:1933-45. 2009
    ..These observations provide a basis for antioxidant protection against brain endothelial injury caused by METH exposure...
  2. pmc Methamphetamine causes mitrochondrial oxidative damage in human T lymphocytes leading to functional impairment
    Raghava Potula
    Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
    J Immunol 185:2867-76. 2010
    ..Altogether, our data indicate that METH can cause T cell dysfunction via induction of oxidative stress and mitochondrial injury as underlying mechanism of immune impairment secondary to METH abuse...
  3. pmc HIV-1 infection and alcohol abuse: neurocognitive impairment, mechanisms of neurodegeneration and therapeutic interventions
    Yuri Persidsky
    Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
    Brain Behav Immun 25:S61-70. 2011
    ..Agonists of cannabinoid receptor 2 (CB₂) possess potent anti-inflammatory and neuroprotective properties. We address multifaceted beneficial effects of CB₂ activation in the setting of HIV-1 brain infection and alcohol abuse...
  4. pmc Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions
    Servio H Ramirez
    Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
    J Neurosci 32:4004-16. 2012
    ..Together, these results suggest that pharmacological CB2R ligands offer a new strategy for BBB protection during neuroinflammation...
  5. pmc HIV-1, methamphetamine and astrocyte glutamate regulation: combined excitotoxic implications for neuro-AIDS
    Irma E Cisneros
    University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA
    Curr HIV Res 10:392-406. 2012
    ..We hope to shed light on common cellular and molecular pathways astrocytes share in glutamate regulation during drug abuse and HIV-1 infection...
  6. pmc Glycogen synthase kinase 3β inhibition prevents monocyte migration across brain endothelial cells via Rac1-GTPase suppression and down-regulation of active integrin conformation
    Slava Rom
    Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19104, USA
    Am J Pathol 181:1414-25. 2012
    ..These results indicate that GSK3β inhibition in monocytes affects active integrin expression, cytoskeleton rearrangement, and adhesion via suppression of Rac1-diminishing inflammatory leukocyte responses...
  7. pmc Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation
    Slava Rom
    Department of Pathology and Laboratory Medicine, Temple University School of Medicine, 3401 N Broad St, Philadelphia, PA 19140, USA
    J Neuroimmune Pharmacol 8:608-20. 2013
    ..This review attempts to summarize recent advances in studies of CB(2) activation in the setting of neuroinflammation, immunomodulation and HIV-1 infection...

Research Grants30

  1. CNS &Peripheral Viral Reservoirs/SIV Model of HIV HAART
    Janice E Clements; Fiscal Year: 2013
    ..We will also test eradication strategies designed to eliminate these reservoirs. ..
  2. Macrophages, NR2B-containing NMDA Receptors and HIV Dementia
    HUANGUI HANK XIONG; Fiscal Year: 2013
    ....
  3. HIV NEUROBEHAVIORAL RESEARCH CENTER
    ROBERT KERNACHAN HEATON; Fiscal Year: 2013
    ..With these structures and processes the HNRC will continue to foster its national and international leadership role in neuro-HIV research, training, and treatment. ..
  4. SPINAL CIRCUITS AND THE MUSCULOSKELETAL SYSTEM
    Arthur W English; Fiscal Year: 2013
    ..This PPG brings together a team of established scientists from diverse backgrounds, with a common goal to continue to strengthen the science base underlying clinical rehabilitation. ..
  5. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..