Cannabinoid receptor expression in HIV encephalitis and HIV‐associated neuropathologic comorbidities

Cosenza-Nashat, Melissa A.; Bauman, Avital; Zhao, Meng‐Liang; Morgello, Susan; Suh, Hyeon-Sook; Lee, Sunhee C.

doi:10.1111/j.1365-2990.2011.01177.x

Cited by 41 publications

(34 citation statements)

References 62 publications

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“…For example, in neuropathic pain and multiple sclerosis, increases in CBR expression is associated with reductions of symptoms and/or dampened disease progression, suggesting a neuroprotective role (Pertwee, 2009). A recent HIV-1 human study, conducting immunohistological analysis in the cerebral cortex and white matter of HIV-1-infected patients showed an increase in CB 1 R and CB 2 R expression in HIV-1 encephalitis brains compared to brains of HIV negative cases (Cosenza-Nashat et al, 2011). Our findings of increased CB 1 R expression following Tat exposure are consistent with these observations in humans.…”

Section: Discussionmentioning

confidence: 99%

Endocannabinoids exert CB 1 receptor-mediated neuroprotective effects in models of neuronal damage induced by HIV-1 Tat protein

Hermes

Nwanguma

et al. 2017

Molecular and Cellular Neuroscience

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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-arachidonoyl ethanolamine (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.

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Section: Discussionmentioning

confidence: 99%

Endocannabinoids exert CB 1 receptor-mediated neuroprotective effects in models of neuronal damage induced by HIV-1 Tat protein

Hermes

Nwanguma

et al. 2017

Molecular and Cellular Neuroscience

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“…with LPS or PBS (Suh et al, ; Sun et al, ) were utilized for this study. Immunohistochemistry and immunofluorescence were performed as previously described (Cosenza‐Nashat et al, ), using antigen retreival and ImmPress secondary antibody methods. In brief, deparaffinized sections were subjected to antigen retrieval in citrate buffer, pH 6.1 (Target Retrieval Solution: DAKO, Carpinteria, CA) at 95°C for 10 min.…”

Section: Methodsmentioning

confidence: 99%

LPS and IL‐1 differentially activate mouse and human astrocytes: Role of CD14

Tarassishin

Suh

Lee

2014

Glia

170

126

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Treatment of cultures with toll-like receptor (TLR) ligands or cytokines has become a popular approach to investigate astrocyte neuroinflammatory responses and to simulate the neural environment in various CNS disorders. However, despite much effort, the mechanism of astrocyte activation such as their responses to the TLR ligands and IL-1 remain highly debated. We compared highly pure primary mouse and human astrocyte cultures in their ability to produce proinflammatory mediators (termed “A1”) and immunoregulatory mediators (termed “A2”) in response to LPS, poly IC and IL-1 stimulation. In human astrocytes, IL-1 induced both A1 and A2 responses, poly IC induced mostly A2, and LPS induced neither. In mouse astrocytes, LPS induced mostly an A1 predominant response, poly IC induced both A1 and A2, and IL-1 neither. In addition, mouse astrocytes produce abundant IL-1 protein while human astrocytes did not, despite robust IL-1 mRNA expression. Of the TLR4 receptor complex proteins, human astrocytes expressed TLR4 and MD2 but not CD14, while mouse astrocytes expressed all three. Mouse astrocyte CD14 (cell-associated and soluble) was potently upregulated by LPS. Silencing TLR4 or CD14 by siRNA suppressed LPS responses in mouse astrocytes. In vivo, astrocytes in LPS-injected mouse brains also expressed CD14. Our results show striking differences between human and mouse astrocytes in the use of TLR/IL-1R and subsequent downstream signaling and immune activation. IL-1 translational block in human astrocytes may be a built-in mechanism to prevent autocrine and paracrine cell activation and neuroinflammation. These results have important implications for translational research of human CNS diseases.

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“…(B) HIVE brain showing colocalization of PGRN (green) with the macrophage and microglial marker CD68 (red). Methods: Double immunofluorescence study was performed as described previously (Cosenza-Nashat et al, 2011). Also see Figure 2 legend.…”

Section: Figurementioning

confidence: 99%

Potential Roles of Microglial Cell Progranulin in HIV-Associated CNS Pathologies and Neurocognitive Impairment

Suh

Gelman

Lee

2013

J Neuroimmune Pharmacol

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Progranulin (PGRN) is a highly unusual molecule with both neuronal and microglial expression with two seemingly unrelated functions, i.e., as a neuronal growth factor and a modulator of neuroinflammation. Haploinsufficiency due to loss of function mutations lead to a fatal presenile dementing illness (frontotemporal lobar degeneration), indicating that adequate expression of PGRN is essential for successful aging. PGRN might be a particularly relevant factor in the pathogenesis of HIV encephalitis (HIVE) and HIV-associated neurocognitive disorders (HAND). We present emerging data and a review of the literature which show that cells of myeloid lineage such as macrophages and microglia are the primary sources of PGRN and that PGRN expression contributes to pathogenesis of CNS diseases. We also present evidence that PGRN is a macrophage antiviral cytokine. For example, PGRN mRNA and protein expression are significantly upregulated in brain specimens with HIVE, and in HIV-infected microglia in vitro. Paradoxically, our preliminary CHARTER data analyses indicate that lower PGRN levels in CSF trended towards an association with HAND, particularly in those without detectable virus. Based upon these findings, we introduce the hypothesis that PGRN plays dual roles in modulating antiviral immunity and neuronal dysfunction in the context of HIV infection. In the presence of active viral replication, PGRN expression is increased functioning as an anti-viral factor as well as a neuroprotectant. In the absence of active HIV replication, ongoing inflammation or other stressors suppress PGRN production from macrophages/microglia contributing to neurocognitive dysfunction. We propose CSF PGRN as a candidate surrogate marker for HAND.

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Cannabinoid receptor expression in HIV encephalitis and HIV‐associated neuropathologic comorbidities

Cited by 41 publications

References 62 publications

Endocannabinoids exert CB 1 receptor-mediated neuroprotective effects in models of neuronal damage induced by HIV-1 Tat protein

Endocannabinoids exert CB 1 receptor-mediated neuroprotective effects in models of neuronal damage induced by HIV-1 Tat protein

LPS and IL‐1 differentially activate mouse and human astrocytes: Role of CD14

Potential Roles of Microglial Cell Progranulin in HIV-Associated CNS Pathologies and Neurocognitive Impairment

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