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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. [ABSTRACT FROM AUTHOR]

Despite the introduction of combined antiretroviral therapy (cART) HIV-1 virus persists in the brain in a latent or restricted manner and viral proteins, such as gp120, continue to play a significant disease-inciting role. Gp120 is known to interact with N -methyl- D -aspartate (NMDA) receptors (NMDARs) resulting in neuronal injury. Glutamate is the main excitatory neurotransmitter in the brain and plays an important role in cognitive function and dysregulation of excitatory synaptic transmission impairs neurocognition. It is our hypothesis that gp120 may alter synaptic function via modulating glutamate function from a physiological molecule to a pathophysiological substance. To test this hypothesis, we studied the modulatory effects of gp120 and glutamate on NMDAR-mediated spontaneous excitatory postsynaptic current (sEPSC NMDAR ) and dynamic dendritic spine changes in rat cortical neuronal cultures. Our results revealed that gp120 and glutamate each, at low concentrations, had no significant effects on sEPSC NMDAR and dendritic spines, but increased sEPSC NMDAR frequency, decreased numbers of dendritic spines when tested in combination. The observed effects were blocked by either a CXCR4 blocker or an NMDAR antagonist, indicating the involvements of chemokine receptor CXCR4 and NMDARs in gp120 modulation of glutamate effects. These results may imply a potential mechanism for HIV-1-associated neuropathogenesis in the cART era., Competing Interests: None., (IJPPP Copyright © 2023.)

Despite the introduction of vaccines and drugs for SARS-CoV-2, the COVID-19 pandemic continues to spread throughout the world. In severe COVID-19 patients, elevated levels of proinflammatory cytokines have been detected in the blood, lung cells, and bronchoalveolar lavage, which is referred to as a cytokine storm, a consequence of overactivation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome and resultant excessive cytokine production. The hyperinflammatory response and cytokine storm cause multiorgan impairment including the central nervous system, in addition to a detriment to the respiratory system. Hyperactive NLRP3 inflammasome, due to dysregulated immune response, is the primary cause of COVID-19 severity. The severity could be enhanced due to viral evolution leading to the emergence of mutated variants of concern, such as delta and omicron. In this review, we elaborate on the inflammatory responses associated with the NLRP3 inflammasome activation in COVID-19 pathogenesis, the mechanisms for the NLRP3 inflammasome activation and pathway involved, cytokine storm, and neurological complications as long-term consequences of SARS-CoV-2 infection. Also discussed is the therapeutic potential of NLRP3 inflammasome inhibitors for the treatment of COVID-19., Competing Interests: None., (IJPPP Copyright © 2022.)