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Endocannabinoids exert CB1 receptor-mediated neuroprotective effects in models of neuronal damage induced by HIV-1 Tat protein.
Xu, Changqing; Hermes, Douglas J; Nwanguma, Blessing; Jacobs, Ian R; Mackie, Kenneth; Mukhopadhyay, Somnath; Lichtman, Aron H; Ignatowska-Jankowska, Bogna; Fitting, Sylvia.
Afiliação
  • Xu C; Department of Psychology & Neuroscience, University of North Carolina, Chapel Hill, NC, USA.
  • Hermes DJ; Department of Psychology & Neuroscience, University of North Carolina, Chapel Hill, NC, USA.
  • Nwanguma B; Department of Chemistry & Biochemistry, North Carolina Central University, Durham, NC, USA.
  • Jacobs IR; Department of Psychology & Neuroscience, University of North Carolina, Chapel Hill, NC, USA.
  • Mackie K; Department of Psychological & Brain Science, Indiana University, Bloomington, IN, USA.
  • Mukhopadhyay S; Department of Chemistry & Biochemistry, North Carolina Central University, Durham, NC, USA.
  • Lichtman AH; Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
  • Ignatowska-Jankowska B; Edmond and Lily Safra Center for Brain Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
  • Fitting S; Department of Psychology & Neuroscience, University of North Carolina, Chapel Hill, NC, USA. Electronic address: sfitting@email.unc.edu.
Mol Cell Neurosci ; 83: 92-102, 2017 09.
Article em En | MEDLINE | ID: mdl-28733129
ABSTRACT
In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is considered a chronic disease that specifically targets the brain and causes HIV-1-associated neurocognitive disorders (HAND). Endocannabinoids (eCBs) elicit neuroprotective and anti-inflammatory actions in several central nervous system (CNS) disease models, but their effects in HAND remain unknown. HIV-1 does not infect neurons, but produces viral toxins, such as transactivator of transcription (Tat), that disrupt neuronal calcium equilibrium and give rise to synaptodendritic injuries and cell death, the former being highly correlated with HAND. Consequently, we tested whether the eCBs N-arachidonoylethanolamine (anandamide/AEA) and 2-arachidonoyl-glycerol (2-AG) offer neuroprotective actions in a neuronal culture model. Specifically, we examined the neuroprotective actions of these eCBs on Tat excitotoxicity in primary cultures of prefrontal cortex neurons (PFC), and whether cannabinoid receptors mediate this neuroprotection. Tat-induced excitotoxicity was reflected by increased intracellular calcium levels, synaptodendritic damage, neuronal excitability, and neuronal death. Further, upregulation of cannabinoid 1 receptor (CB1R) protein levels was noted in the presence of HIV-1 Tat. The direct application of AEA and 2-AG reduced excitotoxic levels of intracellular calcium and promoted neuronal survival following Tat exposure, which was prevented by the CB1R antagonist rimonabant, but not by the CB2R antagonist AM630. Overall, our findings indicate that eCBs protect PFC neurons from Tat excitotoxicity in vitro via a CB1R-related mechanism. Thus, the eCB system possesses promising targets for treatment of neurodegenerative disorders associated with HIV-1 infection.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ácidos Araquidônicos / Fármacos Neuroprotetores / Receptor CB1 de Canabinoide / Endocanabinoides / Glicerídeos / Neurônios Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Mol Cell Neurosci Assunto da revista: BIOLOGIA MOLECULAR / NEUROLOGIA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ácidos Araquidônicos / Fármacos Neuroprotetores / Receptor CB1 de Canabinoide / Endocanabinoides / Glicerídeos / Neurônios Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Mol Cell Neurosci Assunto da revista: BIOLOGIA MOLECULAR / NEUROLOGIA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos