Methamphetamine augments HIV-1 gp120 inhibition of synaptic transmission and plasticity in rat hippocampal slices: Implications for methamphetamine exacerbation of HIV-associated neurocognitive disorders

Zheng, Ya; Reiner, Benjamin C.; Liu, Jianuo; Xu, Linda; Xiong, Huangui

doi:10.1016/j.nbd.2022.105712

Cited by 6 publications

(9 citation statements)

References 83 publications

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“…We have previously reported that Meth augmented the gp120-induced enhancement of microglial outward K + current, leading to increased production of proinflammatory molecules and consequent neuronal injury [31]. We have also shown, in another study, that the microglial nucleotide-binding domain, leucinerich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome was involved in Meth-induced enhancement of gp120 inhibition of long-term potentiation, a widely accepted synaptic mechanism for learning and memory, implying a potential mechanism for the Meth-induced exacerbation of HANDs seen clinically [32].…”

Section: Introductionmentioning

confidence: 84%

Methamphetamine Enhancement of HIV-1 gp120-Mediated NLRP3 Inflammasome Activation and Resultant Proinflammatory Responses in Rat Microglial Cultures

Dutta,

Liu,

et al. 2024

IJMS

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Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders (HANDs) remain prevalent in HIV-1-infected individuals despite the evident success of combined antiretroviral therapy (cART). The mechanisms underlying HAND prevalence in the cART era remain perplexing. Ample evidence indicates that HIV-1 envelope glycoprotein protein 120 (gp120), a potent neurotoxin, plays a pivotal role in HAND pathogenesis. Methamphetamine (Meth) abuse exacerbates HANDs, but how this occurs is not fully understood. We hypothesize that Meth exacerbates HANDs by enhancing gp120-mediated neuroinflammation. To test this hypothesis, we studied the effect of Meth on gp120-induced microglial activation and the resultant production of proinflammatory cytokines in primary rat microglial cultures. Our results show that Meth enhanced gp120-induced microglial activation, as revealed by immunostaining and Iba-1 expression, and potentiated gp120-mediated NLRP3 expression and IL-1β processing and release, as assayed by immunoblotting and ELISA. Meth also augmented the co-localization of NLRP3 and caspase-1, increased the numbers of NLRP3 puncta and ROS production, increased the levels of iNOS expression and NO production, and increased the levels of cleaved gasderminD (GSDMD-N; an executor of pyroptosis) in gp120-primed microglia. The Meth-associated effects were attenuated or blocked by MCC950, an NLRP3 inhibitor, or Mito-TEMPO, a mitochondrial superoxide scavenger. These results suggest that Meth enhances gp120-associated microglial NLRP3 activation and the resultant proinflammatory responses via mitochondria-dependent signaling.

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Section: Introductionmentioning

confidence: 84%

Methamphetamine Enhancement of HIV-1 gp120-Mediated NLRP3 Inflammasome Activation and Resultant Proinflammatory Responses in Rat Microglial Cultures

Dutta,

Liu,

et al. 2024

IJMS

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“…Neuropathic protein accumulation was recently recognized as one of the major characteristics of Meth-induced neuronal degenerative disease (Mizoguchi et al 2019 , Zheng et al 2022 ); however, the potential mechanisms remain poorly understood. however, the potential mechanisms remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Key roles of autophagosome/endosome maturation mediated by Syntaxin17 in methamphetamine-induced neuronal damage in mice

Wang,

Hu,

Chen

et al. 2024

Mol Med

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Background Autophagic defects are involved in Methamphetamine (Meth)-induced neurotoxicity. Syntaxin 17 (Stx17), a member of the SNARE protein family, participating in several stages of autophagy, including autophagosome-late endosome/lysosome fusion. However, the role of Stx17 and potential mechanisms in autophagic defects induced by Meth remain poorly understood. Methods To address the mechanism of Meth-induced cognitive impairment, the adenovirus (AV) and adeno-associated virus (AAV) were injected into the hippocampus for stereotaxis to overexpress Stx17 in vivo to examine the cognitive ability via morris water maze and novel object recognition. In molecular level, the synaptic injury and autophagic defects were evaluated. To address the Meth induced neuronal damage, the epidermal growth factor receptor (EGFR) degradation assay was performed to evaluate the degradability of the “cargos” mediated by Meth, and mechanistically, the maturation of the vesicles, including autophagosomes and endosomes, were validated by the Co-IP and the GTP-agarose affinity isolation assays. Results Overexpression of Stx17 in the hippocampus markedly rescued the Meth-induced cognitive impairment and synaptic loss. For endosomes, Meth exposure upregulated Rab5 expression and its guanine-nucleotide exchange factor (GEF) (immature endosome), with a commensurate decreased active form of Rab7 (Rab7-GTP) and impeded the binding of Rab7 to CCZ1 (mature endosome); for autophagosomes, Meth treatment elicited a dramatic reduction in the overlap between Stx17 and autophagosomes but increased the colocalization of ATG5 and autophagosomes (immature autophagosomes). After Stx17 overexpression, the Rab7-GTP levels in purified late endosomes were substantially increased in parallel with the elevated mature autophagosomes, facilitating cargo (Aβ42, p-tau, and EGFR) degradation in the vesicles, which finally ameliorated Meth-induced synaptic loss and memory deficits in mice. Conclusion Stx17 decrease mediated by Meth contributes to vesicle fusion defects which may ascribe to the immature autophagosomes and endosomes, leading to autophagic dysfunction and finalizes neuronal damage and cognitive impairments. Therefore, targeting Stx17 may be a novel therapeutic strategy for Meth-induced neuronal injury.

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“…The mechanisms for Meth potentiation of HIV-1gp120-associated neurotoxicity are multifaceted, including, but not limited to, activation of microglial NLRP3 inflammasome. Studies have shown that NLRP3 inflammasome is involved in HIV-1 gp120-associated microglia activation [ 20 , 59 ] and resultant neuronal injury [ 32 ]. In agreement with the abovementioned studies, our results showed that Meth enhanced pro-IL-1β/IL-1β expression, processing and release in HIV-1 gp120-primed microglial cultures which were attenuated or blocked by MCC950, a specific NLRP3 inflammasome inhibitor, demonstrating Meth-induced potentiation of gp120-primed microglial activation via NLRP3 inflammasome signaling in cultured rat microglial cells.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that Meth potentiated gp120 enhancement of microglial outward K + current, leading to increased production of proinflammatory molecules and consequent neuronal injury [ 31 ]. We also showed in another study that microglial nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome was involved in Meth potentiation of gp120 inhibition of long-term potentiation, a widely accepted synaptic mechanism for learning and memory, implying a potential mechanism for Meth exacerbation of HAND seen clinically [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Methamphetamine enhancement of HIV-1 gp120-mediated NLRP3 inflammasome activation and resultant proinflammatory responses in rat microglial cultures

Dutta,

Liu,

et al. 2023

Preprint

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Background Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain prevalent in HIV-1-infected individuals despite the evident success of combined antiretroviral therapy (cART). The mechanisms under HAND prevalence in the cART era remain perplexing. Ample evidence indicates that HIV-1 envelope glycoprotein protein 120 (gp120), a potent neurotoxin, plays a pivotal role in the HAND pathogenesis. Methamphetamine (Meth) abuse exacerbates HAND. How Meth exacerbates HAND is not fully understood. This study was to test the hypothesis that Meth exacerbates HAND by enhancing gp120-mediated proinflammatory responses in the brain, worsening the pathogenesis of HAND. Methods Experiments were carried out on primary microglial cultures prepared from neonatal SD rats. The purity of microglia was determined by staining with anti-CD11b. Meth and gp120 were applied to microglial cultures. Microglial activation was revealed by immunostaining and Iba-1 expression. The protein expression levels of Pro-IL-1β, Il-1β, Iba-1, iNOS, NLRP3, GSDMD and GSDMD-N were detected by western blotting analyses. The levels of proinflammatory cytokine and NO production in the microglia culture supernatants were assayed by ELISA and Griess reagent systems, respectively. NLRP3 activation was uncovered by fluorescent microscopy images displaying NLRP3 puncta labeled by anti-NLRP3 antibody. NLRP3 co-localization with caspase-1 was labeled with antibodies. One-way ANOVA with post hoc Tukey’s multiple comparison tests was employed for statistical analyses. Results Meth enhanced gp120-induced microglia activation revealed by immunostaining and Iba-1 expression, and potentiated gp120-mediated NLRP3 expression, IL-1β processing and release assayed by immunoblot and ELISA. Meth also augmented the co-localization of NLRP3 and caspase-1, increased the numbers of NLRP3 puncta and ROS production, elevated levels of iNOS expression and NO production, and enhanced levels of cleaved gasderminD (GSDMD-N, an executor of pyroptosis) in gp120-primed microglia. The Meth-associated effects were attenuated or blocked by MCC950, an NLRP3 inhibitor, or Mito-TEMPO, a mitochondrial superoxide scavenger, indicating the involvement of mitochondria in Meth enhancement of NLRP3 inflammasome activation in gp120-primed microglia. Conclusions These results suggest that Meth enhanced gp120-associated microglial NLRP3 activation and resultant proinflammatory responses via mitochondria-dependent signaling.

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Methamphetamine augments HIV-1 gp120 inhibition of synaptic transmission and plasticity in rat hippocampal slices: Implications for methamphetamine exacerbation of HIV-associated neurocognitive disorders

Cited by 6 publications

References 83 publications

Methamphetamine Enhancement of HIV-1 gp120-Mediated NLRP3 Inflammasome Activation and Resultant Proinflammatory Responses in Rat Microglial Cultures

Methamphetamine Enhancement of HIV-1 gp120-Mediated NLRP3 Inflammasome Activation and Resultant Proinflammatory Responses in Rat Microglial Cultures

Key roles of autophagosome/endosome maturation mediated by Syntaxin17 in methamphetamine-induced neuronal damage in mice

Methamphetamine enhancement of HIV-1 gp120-mediated NLRP3 inflammasome activation and resultant proinflammatory responses in rat microglial cultures

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