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Cannabinoid Receptor-2 and HIV-Associated Neurocognitive Disorders

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Abstract

Despite the wide spread use of highly active antiretroviral therapy (HAART), mild forms of HIV-associated neuro cognitive disorders (HAND) remain commonplace. HAART treated patients now show low levels of viremia and more subtle yet biologically important signs of brain macrophage and microglial activation. Adjunctive therapeutic strategies are required to eliminate HIV-1 infection and suppress immune activation and its associated neuroinflammation. In this regard, cannabinoid receptor-2(CB2) activation is a promising means to attenuate HAND by inhibiting HIV replication, down regulating inflammation, and suppressing chemokine-like activity of viral neurotoxic proteins (for example, Tat and HIV-1gp120), and thereby prevent neuronal and synaptic loss. Inhibiting even low level HIV replication can attenuate neuronal injury by decreasing the production of neurotoxins. Down regulation of inflammation by CB2 activation is mediated through blunted activation of peri vascular macrophages and microglia; decreased production of tumor necrosis factor-α, chemokines and virotoxins. Down regulated neuroinflammation can decrease blood brain barrier permeability and leukocyte infiltration resulting in reduced neuronal injury. It is suggested that CB2 agonists may further attenuate HAND in HIV-infected patients on HAART. In addition, CB2 activation may also blunt brain injury by attenuating drug addiction.

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References

  • Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, Mulligan K, Bacchetti P, McCune JM, Schambelan M (2003) Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial. Ann Intern Med 139:258–266

    Article  CAS  PubMed  Google Scholar 

  • Albini A, Benelli R, Giunciuglio D, Cai T, Mariani G, Ferrini S, Noonan DM (1998) Identification of a novel domain of HIV tat involved in monocyte chemotaxis. J Biol Chem 273:15895–15900

    Article  CAS  PubMed  Google Scholar 

  • Alfahad TB, Nath A (2013) Update on HIV-associated neurocognitive disorders. Current neurology and neuroscience reports. PMC 13(387):3784616

    Google Scholar 

  • An SF, Groves M, Gray F, Scaravilli F (1999) Early entry and widespread cellular involvement of HIV-1 DNA in brains of HIV-1 positive asymptomatic individuals. J Neuropathol Exp Neurol 58:1156–1162

    Article  CAS  PubMed  Google Scholar 

  • Aracil-Fernandez A, Trigo JM, Garcia-Gutierrez MS, Ortega-Alvaro A, Ternianov A, Navarro D, Robledo P, Berbel P, Maldonado R, Manzanares J (2012) Decreased cocaine motor sensitization and self-administration in mice overexpressing cannabinoid CB(2) receptors. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 37:1749-1763. PMC: 3358745

  • Ardila A, Rosselli M, Strumwasser S (1991) Neuropsychological deficits in chronic cocaine abusers. Int J Neurosci 57:73–79

    CAS  PubMed  Google Scholar 

  • Avison MJ, Nath A, Greene-Avison R, Schmitt FA, Bales RA, Ethisham A, Greenberg RN, Berger JR (2004) Inflammatory changes and breakdown of microvascular integrity in early human immunodeficiency virus dementia. J Neurovirol 10:223–232

    Article  CAS  PubMed  Google Scholar 

  • Beatty WW, Katzung VM, Moreland VJ, Nixon SJ (1995) Neuropsychological performance of recently abstinent alcoholics and cocaine abusers. Drug Alcohol Depend 37:247–253

    Article  CAS  PubMed  Google Scholar 

  • Bhaskaran K, Mussini C, Antinori A, Walker AS, Dorrucci M, Sabin C, Phillips A, Porter K, Collaboration C (2008) Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy. Ann Neurol 63:213–221

    Article  Google Scholar 

  • Burstein SH, Audette CA, Breuer A, Devane WA, Colodner S, Doyle SA, Mechoulam R (1992) Synthetic nonpsychotropic cannabinoids with potent antiinflammatory, analgesic, and leukocyte antiadhesion activities. J Med Chem 35:3135–3141

    Article  CAS  PubMed  Google Scholar 

  • Clifford DB, Ances BM (2013) HIV-associated neurocognitive disorder. Lancet Infect Dis 13:976–986

    Article  PubMed  Google Scholar 

  • Costantino CM, Gupta A, Yewdall AW, Dale BM, Devi LA, Chen BK (2012) Cannabinoid receptor 2-mediated attenuation of CXCR4-tropic HIV infection in primary CD4+ T cells. PloS one 7:e33961. PMC: 3309010

  • Davis LE, Hjelle BL, Miller VE, Palmer DL, Llewellyn AL, Merlin TL, Young SA, Mills RG, Wachsman W, Wiley CA (1992) Early viral brain invasion in iatrogenic human immunodeficiency virus infection. Neurology 42:1736–1739

    Article  CAS  PubMed  Google Scholar 

  • de Paulis A, De Palma R, Di Gioia L, Carfora M, Prevete N, Tosi G, Accolla RS, Marone G (2000) Tat protein is an HIV-1-encoded beta-chemokine homolog that promotes migration and up-regulates CCR3 expression on human Fc epsilon RI + cells. J Immunol 165:7171–7179

    Article  PubMed  Google Scholar 

  • Eden A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslen M (2007) Immune activation of the central nervous system is still present after >4 years of effective highly active antiretroviral therapy. J Infect Dis 196:1779–1783

    Article  CAS  PubMed  Google Scholar 

  • Ehrhart J, Obregon D, Mori T, Hou H, Sun N, Bai Y, Klein T, Fernandez F, Tan J, Shytle RD (2005) Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. Journal of neuroinflammation 2:29. PMC: 1352348

  • El-Hage N, Wu G, Wang J, Ambati J, Knapp PE, Reed JL, Bruce-Keller AJ, Hauser KF (2006) HIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines. Glia 53:132–146, PMC: 3077280

    Article  PubMed Central  PubMed  Google Scholar 

  • Facchinetti F, Del Giudice E, Furegato S, Passarotto M, Leon A (2003) Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide. Glia 41:161–168

    Article  PubMed  Google Scholar 

  • Fiala M, Gan XH, Zhang L, House SD, Newton T, Graves MC, Shapshak P, Stins M, Kim KS, Witte M, Chang SL (1998) Cocaine enhances monocyte migration across the blood–brain barrier. Cocaine's connection to AIDS dementia and vasculitis? Adv Exp Med Biol 437:199–205

    Article  CAS  PubMed  Google Scholar 

  • Fitting S, Ignatowska-Jankowska BM, Bull C, Skoff RP, Lichtman AH, Wise LE, Fox MA, Su J, Medina AE, Krahe TE, Knapp PE, Guido W, Hauser KF (2013) Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice. Biol Psychiatry 73:443–453, PMC: 3570635

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fraga D, Raborn ES, Ferreira GA, Cabral GA (2011) Cannabinoids inhibit migration of microglial-like cells to the HIV protein Tat. J NeuroImmune Pharm: Off J Soc NeuroImmune Pharm 6:566–577

    Article  Google Scholar 

  • Gannon P, Khan MZ, Kolson DL (2011) Current understanding of HIV-associated neurocognitive disorders pathogenesis. Curr Opin Neurol 24:275–283, PMC: 3683661

    Article  PubMed Central  PubMed  Google Scholar 

  • Gonzalez-Scarano F, Martin-Garcia J (2005) The neuropathogenesis of AIDS. Nat Rev Immunol 5:69–81

    Article  CAS  PubMed  Google Scholar 

  • Gorantla S, Makarov E, Roy D, Finke-Dwyer J, Murrin LC, Gendelman HE, Poluektova L (2010) Immunoregulation of a CB2 receptor agonist in a murine model of neuroAIDS. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 5:456–468, PMC: 3109320

    Article  Google Scholar 

  • Grant I (2008) Neurocognitive disturbances in HIV. Int Rev Psychiatry 20:33–47

    Article  PubMed  Google Scholar 

  • Heaton RK (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75:2087–2096, PMC: 2995535

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kim BO, Liu Y, Zhou BY, He JJ (2004) Induction of C chemokine XCL1 (lymphotactin/single C motif-1 alpha/activation-induced, T cell-derived and chemokine-related cytokine) expression by HIV-1 Tat protein. J Immunol 172:1888–1895

    Article  CAS  PubMed  Google Scholar 

  • Kim HJ, Martemyanov KA, Thayer SA (2008a) Human immunodeficiency virus protein Tat induces synapse loss via a reversible process that is distinct from cell death. The Journal of neuroscience : the official journal of the Society for Neuroscience 28:12604–12613, PMC: 2678679

    Article  CAS  Google Scholar 

  • Kim HJ, Waataja JJ, Thayer SA (2008b) Cannabinoids inhibit network-driven synapse loss between hippocampal neurons in culture. The Journal of pharmacology and experimental therapeutics 325:850–858, PMC: 2398764

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kim HJ, Shin AH, Thayer SA (2011) Activation of cannabinoid type 2 receptors inhibits HIV-1 envelope glycoprotein gp120-induced synapse loss. Mol Pharmacol 80:357–366, PMC: 3164336

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kraft-Terry SD, Buch SJ, Fox HS, Gendelman HE (2009) A coat of many colors: neuroimmune crosstalk in human immunodeficiency virus infection. Neuron 64:133–145, PMC: 2784686

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kraft-Terry SD, Stothert AR, Buch S, Gendelman HE (2010) HIV-1 neuroimmunity in the era of antiretroviral therapy. Neurobiol Dis 37:542–548, PMC: 2840259

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lafrenie RM, Wahl LM, Epstein JS, Yamada KM, Dhawan S (1997) Activation of monocytes by HIV-Tat treatment is mediated by cytokine expression. J Immunol 159:4077–4083

    CAS  PubMed  Google Scholar 

  • Larrat EP, Zierler S (1993) Entangled epidemics: cocaine use and HIV disease. J Psychoactive Drugs 25:207–221

    Article  CAS  PubMed  Google Scholar 

  • Levine AJ, Hardy DJ, Miller E, Castellon SA, Longshore D, Hinkin CH (2006) The effect of recent stimulant use on sustained attention in HIV-infected adults. J Clin Exp Neuropsychol 28:29–42

    Article  PubMed  Google Scholar 

  • Lu TS, Avraham HK, Seng S, Tachado SD, Koziel H, Makriyannis A, Avraham S (2008) Cannabinoids inhibit HIV-1 Gp120-mediated insults in brain microvascular endothelial cells. J Immunol 181:6406–6416, PMC: 3735224

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Maldarelli F, Palmer S, King MS, Wiegand A, Polis MA, Mican J, Kovacs JA, Davey RT, Rock-Kress D, Dewar R, Liu S, Metcalf JA, Rehm C, Brun SC, Hanna GJ, Kempf DJ, Coffin JM, Mellors JW (2007) ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog 3:e46, PMC: 1847689

    Article  PubMed Central  PubMed  Google Scholar 

  • McArthur JC, Steiner J, Sacktor N, Nath A (2010) Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol 67:699–714

    CAS  PubMed  Google Scholar 

  • Meade CS, Conn NA, Skalski LM, Safren SA (2011) Neurocognitive impairment and medication adherence in HIV patients with and without cocaine dependence. J Behav Med 34:128–138, PMC: 3049963

    Article  PubMed Central  PubMed  Google Scholar 

  • Mestre L, Docagne F, Correa F, Loria F, Hernangomez M, Borrell J, Guaza C (2009) A cannabinoid agonist interferes with the progression of a chronic model of multiple sclerosis by downregulating adhesion molecules. Mol Cell Neurosci 40:258–266

    Article  CAS  PubMed  Google Scholar 

  • Miller AM, Stella N (2008) CB2 receptor-mediated migration of immune cells: it can go either way. Br J Pharmacol 153:299–308, PMC: 2219538

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Minghetti L, Visentin S, Patrizio M, Franchini L, Ajmone-Cat MA, Levi G (2004) Multiple actions of the human immunodeficiency virus type-1 Tat protein on microglial cell functions. Neurochem Res 29:965–978

    Article  CAS  PubMed  Google Scholar 

  • Mitola S, Sozzani S, Luini W, Primo L, Borsatti A, Weich H, Bussolino F (1997) Tat-human immunodeficiency virus-1 induces human monocyte chemotaxis by activation of vascular endothelial growth factor receptor-1. Blood 90:1365–1372

    CAS  PubMed  Google Scholar 

  • Molina PE, Winsauer P, Zhang P, Walker E, Birke L, Amedee A, Stouwe CV, Troxclair D, McGoey R, Varner K, Byerley L, LaMotte L (2011) Cannabinoid administration attenuates the progression of simian immunodeficiency virus. AIDS Res Hum Retrovir 27:585–592, PMC: 3131805

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Palmer S, Maldarelli F, Wiegand A, Bernstein B, Hanna GJ, Brun SC, Kempf DJ, Mellors JW, Coffin JM, King MS (2008) Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A 105:3879–3884, PMC: 2268833

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD (2006) Blood–brain barrier: structural components and function under physiologic and pathologic conditions. J NeuroImmune Pharm: Off J Soc NeuroImmune Pharm 1:223–236

    Article  Google Scholar 

  • Peterson PK, Gekker G, Hu S, Cabral G, Lokensgard JR (2004) Cannabinoids and morphine differentially affect HIV-1 expression in CD4(+) lymphocyte and microglial cell cultures. J Neuroimmunol 147:123–126

    Article  CAS  PubMed  Google Scholar 

  • Pini A, Mannaioni G, Pellegrini-Giampietro D, Passani MB, Mastroianni R, Bani D, Masini E (2012) The role of cannabinoids in inflammatory modulation of allergic respiratory disorders, inflammatory pain and ischemic stroke. Curr Drug Targets 13:984–993

    Article  CAS  PubMed  Google Scholar 

  • Pu H, Tian J, Flora G, Lee YW, Nath A, Hennig B, Toborek M (2003) HIV-1 Tat protein upregulates inflammatory mediators and induces monocyte invasion into the brain. Mol Cell Neurosci 24:224–237

    Article  CAS  PubMed  Google Scholar 

  • Puffenbarger RA, Boothe AC, Cabral GA (2000) Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia 29:58–69

    Article  CAS  PubMed  Google Scholar 

  • Raborn ES, Cabral GA (2010) Cannabinoid inhibition of macrophage migration to the trans-activating (Tat) protein of HIV-1 is linked to the CB(2) cannabinoid receptor. J Pharmacol Exp Ther 333:319–327, PMC: 2846023

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Huffman JW, Csiszar A, Ungvari Z, Mackie K, Chatterjee S, Pacher P (2007) CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. American journal of physiology Heart and circulatory physiology 293:2210–2218, PMC: 2229632

    Article  Google Scholar 

  • Ramirez SH, Hasko J, Skuba A, Fan S, Dykstra H, McCormick R, Reichenbach N, Krizbai I, Mahadevan A, Zhang M, Tuma R, Son YJ, Persidsky Y (2012) Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. The Journal of neuroscience : the official journal of the Society for Neuroscience 32:4004–4016, PMC: 3325902

    Article  CAS  Google Scholar 

  • Ramirez SH, Reichenbach NL, Fan S, Rom S, Merkel SF, Wang X, Ho WZ, Persidsky Y (2013) Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonists. J Leukoc Biol 93:801–810, PMC: 3629438

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rock RB, Gekker G, Hu S, Sheng WS, Cabral GA, Martin BR, Peterson PK (2007) WIN55,212-2-mediated inhibition of HIV-1 expression in microglial cells: involvement of cannabinoid receptors. J NeuroImmune Pharmaco : Off J Soc NeuroImmune Pharmacol 2:178–183

    Article  Google Scholar 

  • Rosselli M, Ardila A, Lubomski M, Murray S, King K (2001) Personality profile and neuropsychological test performance in chronic cocaine-abusers. The International journal of neuroscience 110:55–72

    CAS  PubMed  Google Scholar 

  • Rumbaugh JA, Nath A (2006) Developments in HIV neuropathogenesis. Curr Pharm Des 12:1023–1044

    Article  CAS  PubMed  Google Scholar 

  • Sa MJ, Madeira MD, Ruela C, Volk B, Mota-Miranda A, Paula-Barbosa MM (2004) Dendritic changes in the hippocampal formation of AIDS patients: a quantitative Golgi study. Acta Neuropathol 107:97–110

    Article  CAS  PubMed  Google Scholar 

  • Sacktor N, McDermott MP, Marder K, Schifitto G, Selnes OA, McArthur JC, Stern Y, Albert S, Palumbo D, Kieburtz K, De Marcaida JA, Cohen B, Epstein L (2002) HIV-associated cognitive impairment before and after the advent of combination therapy. Journal of neurovirology 8:136-142. Schouten J, Cinque P, Gisslen M, Reiss P, Portegies P (2011) HIV-1 infection and cognitive impairment in the cART era: a review. Aids 25:561-575.

  • Shapshak P, Kangueane P, Fujimura RK, Commins D, Chiappelli F, Singer E, Levine AJ, Minagar A, Novembre FJ, Somboonwit C, Nath A, Sinnott JT (2011) Editorial neuroAIDS review. Aids 25:123–141

    Article  PubMed  Google Scholar 

  • Spudich S, Gisslen M, Hagberg L, Lee E, Liegler T, Brew B, Fuchs D, Tambussi G, Cinque P, Hecht FM, Price RW (2011) Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden. The Journal of infectious diseases 204:753–760, PMC: 3156103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Suh HS, Gelman BB, Lee SC (2014) Potential roles of microglial cell progranulin in HIV-associated CNS pathologies and neurocognitive impairment. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 9:117–132, PMC: 3930627

    Article  Google Scholar 

  • Tan IL, McArthur JC (2012) HIV-associated neurological disorders: a guide to pharmacotherapy. CNS Drugs 26:123–134

    Article  PubMed  Google Scholar 

  • Toggas SM, Masliah E, Rockenstein EM, Rall GF, Abraham CR, Mucke L (1994) Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature 367:188–193

    Article  CAS  PubMed  Google Scholar 

  • Verdejo-Garcia A, Perez-Garcia M (2007) Profile of executive deficits in cocaine and heroin polysubstance users: common and differential effects on separate executive components. Psychopharmacology 190:517–530

    Article  CAS  PubMed  Google Scholar 

  • Viviani B, Gardoni F, Bartesaghi S, Corsini E, Facchi A, Galli CL, Di Luca M, Marinovich M (2006) Interleukin-1 beta released by gp120 drives neural death through tyrosine phosphorylation and trafficking of NMDA receptors. J Biol Chem 281:30212–30222

    Article  CAS  PubMed  Google Scholar 

  • Webber MP, Schoenbaum EE, Gourevitch MN, Buono D, Klein RS (1999) A prospective study of HIV disease progression in female and male drug users. Aids 13:257–262

    Article  CAS  PubMed  Google Scholar 

  • Xi ZX, Peng XQ, Li X, Song R, Zhang HY, Liu QR, Yang HJ, Bi GH, Li J, Gardner EL (2011) Brain cannabinoid CB(2) receptors modulate cocaine’s actions in mice. Nat Neurosci 14:1160–1166, PMC: 3164946

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu H, Cheng CL, Chen M, Manivannan A, Cabay L, Pertwee RG, Coutts A, Forrester JV (2007) Anti-inflammatory property of the cannabinoid receptor-2-selective agonist JWH-133 in a rodent model of autoimmune uveoretinitis. J Leukoc Biol 82:532–541

    Article  CAS  PubMed  Google Scholar 

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  1. Chemistry and Physiological Systems Research Branch Division of Basic Neuroscience & Behavioral Research, National Institute on Drug Abuse National Institutes of Health, 6001 Executive Blvd., NSC Bldg. - Rm 4275, 20892, Bethesda, MD, USA

    Vishnudutt Purohit, Rao S. Rapaka & Joni Rutter

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Purohit, V., Rapaka, R.S. & Rutter, J. Cannabinoid Receptor-2 and HIV-Associated Neurocognitive Disorders. J Neuroimmune Pharmacol 9, 447–453 (2014). https://doi.org/10.1007/s11481-014-9554-0

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