Methamphetamine alters microglial immune function through P2X7R signaling

Fernandes, Natália C.; Sriram, Uma; Gofman, Larisa; Cenna, Jonathan; Ramirez, Servio H.; Potula, Raghava

doi:10.1186/s12974-016-0553-3

Cited by 43 publications

(29 citation statements)

References 87 publications

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“…METH has been shown to increase IL-10 in human plasma [14]. Similarly, the evaluation of METH in microglial cell (ESdM) activation showed an increased IL-10 production following 48-hr METH treatment [52]. In a comprehensive gene array overview, macrophages stimulated over a time-dependent METH dose showed considerable upregulation of IL-10 at 6 hours post METH exposure [17].…”

Section: Il-10mentioning

confidence: 91%

Methamphetamine and its immune-modulating effects

et al. 2019

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Methamphetamine (METH, or ice) use is a global burden, which continues to pervade and plague contemporary society with estimates of up to 35 million users worldwide. METH is a psychotropic compound which acts on the central nervous system, and, in chronic doses, can induce psychotic behavior from its highly addictive nature. METH harbours the capacity to cause modulation of immune cells, enabling the drug to have lasting, long-term effects which may manifest into neuropsychiatric disorders, as well as leading to increased susceptibility to communicable diseases, such as HIV. In addition, changes to the cytokine balance have been associated with blood brain barrier compromise, resulting to alterations to brain plasticity, creating lasting neurotoxicity. Furthermore, immune-related signaling pathways are key to further evaluating how METH impacts the host immunity through these neurological and peripheral modifications. Layering this knowledge with current data on inflammatory responses can help facilitate a better understanding of how the host adaptive and innate immunity responds to METH, how this can activate premature-ageing processes and how METH exacerbates disturbances leading to non-communicable age-related diseases, including cardiovascular disease, stroke, depression and dementia.

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Section: Il-10mentioning

confidence: 91%

Methamphetamine and its immune-modulating effects

et al. 2019

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“…Although previous studies have demonstrated methamphetamine-induced microglial activation 11 , 12 , 37 , the molecular and cellular mechanisms involved in this process are not completely understood. Therefore, we demonstrated the vital role of the sigma-1 receptor in methamphetamine-mediated microglial activation in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 97%

“…Microglia are known to be actively involved in various neurological diseases, such as Parkinson’s disease 6 , stroke 7 and depression 8 . Accumulating evidence suggests that methamphetamine-induced neurotoxicity is associated with microglial activation 9 , and activated microglia are thought to participate in either pro-toxic or protective mechanisms in the brain 10 – 12 . The classic M1 and alternative M2 phenotypes, which are the two most polarized phenotypes, represent two extremes of a dynamic changing state of microglial activation.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms underlying the involvement of the sigma-1 receptor in methamphetamine-mediated microglial polarization

Chao

Zhang

et al. 2017

Sci Rep

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Our previous study demonstrated that the sigma-1 receptor is involved in methamphetamine-induced microglial apoptosis and death; however, whether the sigma-1 receptor is involved in microglial activation as well as the molecular mechanisms underlying this process remains poorly understood. The aim of this study is to demonstrate the involvement of the sigma-1 receptor in methamphetamine-mediated microglial activation. The expression of σ-1R, iNOS, arginase and SOCS was examined by Western blot; activation of cell signaling pathways was detected by Western blot analysis. The role of σ-1R in microglial activation was further validated in C57BL/6 N WT and sigma-1 receptor knockout mice (male, 6–8 weeks) injected intraperitoneally with saline or methamphetamine (30 mg/kg) by Western blot combined with immunostaining specific for Iba-1. Treatment of cells with methamphetamine (150 μM) induced the expression of M1 markers (iNOS) with concomitant decreased the expression of M2 markers (Arginase) via its cognate sigma-1 receptor followed by ROS generation. Sequential activation of the downstream MAPK, Akt and STAT3 pathways resulted in microglial polarization. Blockade of sigma-1 receptor significantly inhibited the generation of ROS and activation of the MAPK and Akt pathways. These findings underscore the critical role of the sigma-1 receptor in methamphetamine-induced microglial activation.

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“…for 2 min, rinsed in distilled water to remove excess stain, and imaged. Protein levels were normalized to Po-S as a loading control (100-140 kDa) [31]. After blocking, rabbit anti-CD11b antibody (127 kDa, 1:1000, ab133357, Abcam) was incubated at 4°C overnight.…”

Section: Western Blotmentioning

confidence: 99%

Serum IgG-induced microglial activation enhances neuronal cytolysis via the NO/sGC/PKG pathway in children with opsoclonus-myoclonus syndrome and neuroblastoma

Ding

Yang

et al. 2020

Preprint

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Background: Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disease. Some children with OMS also have neuroblastoma (NB). We and others have previously documented that serum IgG from children with OMS and NB induces neuronal cytolysis and activates several signaling pathways. However, the mechanisms underlying OMS remain unclear. Here we investigated whether nitric oxide (NO) from activated microglias and its cascade contribute to neuronal cytolysis in pediatric OMS.Methods: The activation of cultured cerebral cortical and cerebellar microglias incubated with sera or IgG isolated from sera of children with OMS and NB was measured by the expression of the activation marker, cytokines and NO. Neuronal cytolysis was determined after exposing to IgG-treated microglia conditioned media. Using inhibitors and activators, the effects of NO synthesis and its intracellular cascade, namely soluble guanylyl cyclase (sGC) and protein kinase G (PKG), on neuronal cytolysis were evaluated.Results: Incubation with sera or IgG from children with OMS and NB increased the activation of cerebral cortical and cerebellar microglias, but not the activation of astrocytes or the cytolysis of glial cells. Moreover, the cytolysis of neurons was elevated by conditioned media from microglias incubated with IgG from children with OMS and NB. Furthermore, the expression of NO, sGC and PKG was increased. Neuronal cytolysis was relieved by the inhibitors of NO signaling, while neuronal cytolysis was exacerbated by the activators of NO signaling but not proinflammatory cytokines. The cytolysis of neurons was suppressed by pretreatment with the microglial inhibitor minocycline, a clinically tested drug. Finally, increased microglial activation did not depend on the Fab fragment of serum IgG.Conclusions: Serum IgG from children with OMS and NB potentiates microglial activation, which induces neuronal cytolysis through the NO/sGC/PKG pathway, suggesting an applicability of microglial inhibitor as a therapeutic candidate.

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Methamphetamine alters microglial immune function through P2X7R signaling

Cited by 43 publications

References 87 publications

Methamphetamine and its immune-modulating effects

Methamphetamine and its immune-modulating effects

Molecular mechanisms underlying the involvement of the sigma-1 receptor in methamphetamine-mediated microglial polarization

Serum IgG-induced microglial activation enhances neuronal cytolysis via the NO/sGC/PKG pathway in children with opsoclonus-myoclonus syndrome and neuroblastoma

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