Conditional expression of HIV‐1 tat in the mouse alters the onset and progression of tonic, inflammatory and neuropathic hypersensitivity in a sex‐dependent manner

Bağdaş, Deniz; Paris, Jason J.; Carper, Moriah; Wodarski, Rachel; Rice, Andrew S.C.; Knapp, Pamela E.; Hauser, Kurt F.; Damaj, M. Imad

doi:10.1002/ejp.1618

Cited by 22 publications

(24 citation statements)

References 102 publications

(120 reference statements)

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“…Two-way mixed ANOVAs were conducted with treatment (4 levels: control, Tat 100 nM, MJN110 0.5 µM +Tat, MJN110 1 µM + Tat) as a between-subjects factor and time as a within-subjects factor. When MJN110 was applied to neuron cultures 30 min prior Tat 100 nM, results demonstrated a significant main effect for time [F (40,11,760) = 9.3, p GG < 0.001], a main effect of treatment [F (3, 294) = 10.6, p < 0.001], and a time x treatment interaction [F (120, 11,760) = 2.4, p = 0.001] (Figure 2A). A one-way ANOVA conducted on the last 10 min revealed a significant treatment effect [F (3, 294) = 5.5, p = 0.001], with Tat 100 nM treatment and pretreatment of MJN110 1 µM + Tat showing significantly higher [Ca 2+ ] i levels compared to the control condition (p = 0.001 and p = 0.036, respectively; Figure 2A').…”

Section: Tat-induced Dysregulation Of [Ca 2+ ] I Increase Was Mitigated By Pretreatment With Mjn110 In a Timeand Concentration-dependent mentioning

confidence: 99%

“…When MJN110 was pretreated 1 h prior Tat 100 nM exposure, a two-way mixed ANOVA demonstrated a significant main effect for time [F (40,11,840) = 6.4, p GG < 0.001], a main effect of treatment [F (3, 296) = 17.0, p < 0.001], and a time x treatment interaction [F (120, 11,840) = 2.7, p < 0.001] (Figure 2B). A oneway ANOVA conducted on the last 10 min of the experimental time course revealed a significant treatment effect [F (3, 296) = 6.0, p = 0.001], with only Tat 100 nM treatment displaying significantly higher [Ca 2+ ] i levels compared to the control condition (p < 0.001) and significantly differing from the MJN110 0.5 µM + Tat condition (p = 0.044; Figure 2B').…”

Section: Tat-induced Dysregulation Of [Ca 2+ ] I Increase Was Mitigated By Pretreatment With Mjn110 In a Timeand Concentration-dependent mentioning

confidence: 99%

“…Potential neuroprotective effects of the endocannabinoid system in the context of neuroHIV have been reviewed previously (33,34). Activation of CB 1 R and CB 2 R may downregulate the proinflammatory cytokine levels associated with synaptodendritic injury (35,36), behavioral disturbances observed in PWH and HIV-1 transgenic rats (36,37), and peripheral neuropathy (38)(39)(40). Nevertheless, therapeutic use of the CB 1 R agonists are limited due to associated pervasive psychoactive side effects including sensorimotor, affective, and cognitive disturbances (41).…”

Section: Introductionmentioning

confidence: 99%

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Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat

et al. 2021

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While current therapeutic strategies for people living with human immunodeficiency virus type 1 (HIV-1) suppress virus replication peripherally, viral proteins such as transactivator of transcription (Tat) enter the central nervous system early upon infection and contribute to chronic inflammatory conditions even alongside antiretroviral treatment. As demand grows for supplemental strategies to combat virus-associated pathology presenting frequently as HIV-associated neurocognitive disorders (HAND), the present study aimed to characterize the potential utility of inhibiting monoacylglycerol lipase (MAGL) activity to increase inhibitory activity at cannabinoid receptor-type 1 receptors through upregulation of 2-arachidonoylglycerol (2-AG) and downregulation of its degradation into proinflammatory metabolite arachidonic acid (AA). The MAGL inhibitor MJN110 significantly reduced intracellular calcium and increased dendritic branching complexity in Tat-treated primary frontal cortex neuron cultures. Chronic MJN110 administration in vivo increased 2-AG levels in the prefrontal cortex (PFC) and striatum across Tat(+) and Tat(–) groups and restored PFC N-arachidonoylethanolamine (AEA) levels in Tat(+) subjects. While Tat expression significantly increased rate of reward-related behavioral task acquisition in a novel discriminative stimulus learning and cognitive flexibility assay, MJN110 altered reversal acquisition specifically in Tat(+) mice to rates indistinguishable from Tat(–) controls. Collectively, our results suggest a neuroprotective role of MAGL inhibition in reducing neuronal hyperexcitability, restoring dendritic arborization complexity, and mitigating neurocognitive alterations driven by viral proteins associated with latent HIV-1 infection.

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Section: Tat-induced Dysregulation Of [Ca 2+ ] I Increase Was Mitigated By Pretreatment With Mjn110 In a Timeand Concentration-dependent mentioning

confidence: 99%

Section: Tat-induced Dysregulation Of [Ca 2+ ] I Increase Was Mitigated By Pretreatment With Mjn110 In a Timeand Concentration-dependent mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat

et al. 2021

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“…To address this concern, in future studies, we propose expanding our model to include the assessment of ingested cART combination regimens, in order to investigate the effects of various drug combinations. Secondly, cART is administered in the presence of HIV infection, and the expression of viral products is a potential confounding factor in PSN development 6,87–90 . This can partially be addressed in future studies by testing the effects of oral cART administration in mouse models of HIV gp120 administration or in mice genetically engineered to express viral products 88,90,91 .…”

Section: Discussionmentioning

confidence: 99%

Nucleoside reverse transcriptase inhibitors are the major class of HIV antiretroviral therapeutics that induce neuropathic pain in mice

Bush

Wairkar

Tang

2022

Preprint

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The development of combination antiretroviral therapy (cART) has transformed human immunodeficiency virus (HIV) infection from a lethal diagnosis into a chronic disease, and people living with HIV on cART can experience an almost normal life expectancy. However, these individuals often develop various complications that lead to decreased quality of life, one of the most significant of which is neuropathic pain and development of painful peripheral sensory neuropathy (PSN). Critically, although cART is thought to induce pain pathogenesis, the relative contribution of different classes of antiretrovirals has not been systematically investigated. In this study, we measured development of pathological pain and peripheral neuropathy in mice orally treated with distinct antiretrovirals at their translational dosages. Our results show that only nucleoside reverse transcriptases (NRTIs), but not other types of antiretrovirals, such as proteinase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase strand transfer inhibitors, and CCR5 antagonists, induce pathological pain and PSN. Thus, these findings suggest that NRTIs are the major class of antiretrovirals in cART that promote development of neuropathic pain. As NRTIs form the essential backbone of multiple different current cART regimens, it is of paramount clinical importance to better understand the underlying mechanism to facilitate design of less toxic forms of these drugs and or potential mitigation strategies.

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“…Our failure to detect this disorder could reflect the shorter duration of DOX exposure and TAT induction (2 weeks) or withdrawal of DOX for 2 weeks prior to tissue collection that could allow IENF time to regenerate. Finally, there is also a report of sex-dependent effects of TAT on responses to inflammatory or neuropathic insults ( 42 ) and while the prior report was limited to female mice, we included both sexes. However, in post-hoc exploratory analyses we identified no differences in PNS function or structure between sexes.…”

Section: Discussionmentioning

confidence: 99%

Prevention of HIV-1 TAT Protein-Induced Peripheral Neuropathy and Mitochondrial Disruption by the Antimuscarinic Pirenzepine

et al. 2021

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HIV-associated distal sensory polyneuropathy (HIV-DSP) affects about one third of people with HIV and is characterized by distal degeneration of axons. The pathogenesis of HIV-DSP is not known and there is currently no FDA-approved treatment. HIV trans-activator of transcription (TAT) is associated with mitochondrial dysfunction and neurotoxicity in the brain and may play a role in the pathogenesis of HIV-DSP. In the present study, we measured indices of peripheral neuropathy in the doxycycline (DOX)-inducible HIV-TAT (iTAT) transgenic mouse and investigated the therapeutic efficacy of a selective muscarinic subtype-1 receptor (M1R) antagonist, pirenzepine (PZ). PZ was selected as we have previously shown that it prevents and/or reverses indices of peripheral neuropathy in multiple disease models. DOX alone induced weight loss, tactile allodynia and paw thermal hypoalgesia in normal C57Bl/6J mice. Conduction velocity of large motor fibers, density of small sensory nerve fibers in the cornea and expression of mitochondria-associated proteins in sciatic nerve were unaffected by DOX in normal mice, whereas these parameters were disrupted when DOX was given to iTAT mice to induce TAT expression. Daily injection of PZ (10 mg/kg s.c.) prevented all of the disorders associated with TAT expression. These studies demonstrate that TAT expression disrupts mitochondria and induces indices of sensory and motor peripheral neuropathy and that M1R antagonism may be a viable treatment for HIV-DSP. However, some indices of neuropathy in the DOX-inducible TAT transgenic mouse model can be ascribed to DOX treatment rather than TAT expression and data obtained from animal models in which gene expression is modified by DOX should be accompanied by appropriate controls and treated with due caution.

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Conditional expression of HIV‐1 tat in the mouse alters the onset and progression of tonic, inflammatory and neuropathic hypersensitivity in a sex‐dependent manner

Cited by 22 publications

References 102 publications

Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat

Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat

Nucleoside reverse transcriptase inhibitors are the major class of HIV antiretroviral therapeutics that induce neuropathic pain in mice

Prevention of HIV-1 TAT Protein-Induced Peripheral Neuropathy and Mitochondrial Disruption by the Antimuscarinic Pirenzepine

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