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Phenothiazine Inhibits Neuroinflammation and Inflammasome Activation Independent of Hypothermia After Ischemic Stroke

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Abstract

A depressive or hibernation-like effect of chlorpromazine and promethazine (C + P) on brain activity was reported to induce neuroprotection, with or without induced-hypothermia. However, the underlying mechanisms remain unclear. The current study evaluated the pharmacological function of C + P on the inhibition of neuroinflammatory response and inflammasome activation after ischemia/reperfusion. A total of 72 adult male Sprague–Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion. At the onset of reperfusion, rats received C + P (8 mg/kg) with temperature control. Brain cell death was detected by measuring CD68 and myeloperoxidase (MPO) levels. Inflammasome activation was measured by mRNA levels of NLRP3, IL-1β, and TXNIP, and protein quantities of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Activation of JAK2/STAT3 pathway was detected by the phosphorylation of STAT3 (p-STAT3) and JAK2 (p-JAK2), and the co-localization of p-STAT3 and NLRP3. Activation of the p38 pathway was assessed with the protein levels of p-p38/p38. The mRNA and protein levels of HIF-1α, FoxO1, and p-FoxO1, and the co-localization of p-STAT3 with HIF-1α or FoxO1 were quantitated. As expected, C + P significantly reduced cell death and attenuated the neuroinflammatory response as determined by reduced CD68 and MPO. C + P decreased ischemia-induced inflammasome activation, shown by reduced mRNA and protein expressions of NLRP3, IL-1β, TXNIP, cleaved-Caspase-1, and IL-18. Phosphorylation of JAK2/STAT3 and p38 pathways and the co-localization of p-STAT3 with NLRP3 were also inhibited by C + P. Furthermore, mRNA levels of HIF-1α and FoxO1 were decreased in the C + P group. While C + P inhibited HIF-1α protein expression, it increased FoxO1 phosphorylation, which promoted the exclusion of FoxO1 from the nucleus and inhibited FoxO1 activity. At the same time, C + P reduced the co-localization of p-STAT3 with HIF-1α or FoxO1. In conclusion, C + P treatment conferred neuroprotection in stroke by suppressing neuroinflammation and NLRP3 inflammasome activation. The present study suggests that JAK2/STAT3/p38/HIF-1α/FoxO1 are vital regulators and potential targets for efficacious therapy following ischemic stroke.

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Funding

This work was supported in part by the National Natural Science Foundation of China (81871838, 82001277, 82101436), the Beijing Tongzhou District Financial Fund (2021), the Laboratory Development Funds of Luhe Hospital (2021).

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Authors and Affiliations

  1. Luhe Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, 101100, China

    Sichao Guo & Xiaokun Geng

  2. Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Sichao Guo, Xiaokun Geng, Hangil Lee & Yuchuan Ding

  3. Department of Research & Development Center, John D. Dingell VA Medical Center, Detroit, MI, 48201, USA

    Sichao Guo & Yuchuan Ding

  4. Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, 101100, China

    Xiaokun Geng

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Conceptualization: Yuchuan Ding, Xiaokun Geng and Sichao Guo.; Methodology: Sichao Guo; Formal analysis and investigation: Sichao Guo; Writing—original draft preparation: Sichao Guo; Writing—review and editing: Yuchuan Ding, Xiaokun Geng and Hangil Lee; Funding acquisition: Xiaokun Geng; Resources: Yuchuan Ding and Xiaokun Geng; Supervision: Yuchuan Ding and Xiaokun Geng.

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Guo, S., Geng, X., Lee, H. et al. Phenothiazine Inhibits Neuroinflammation and Inflammasome Activation Independent of Hypothermia After Ischemic Stroke. Mol Neurobiol 58, 6136–6152 (2021). https://doi.org/10.1007/s12035-021-02542-3

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