Abstract
We previously revealed that long-term treatment with nicotine suppresses microglial activation, resulting in a protective effect against thrombin-induced shrinkage of the striatal tissue in organotypic slice cultures. Here, the effect of nicotine on impaired M1 and protective M2 microglial polarization was investigated using the BV-2 microglial cell line in the presence or absence of thrombin. Following nicotine treatment, α7 nicotinic acetylcholine receptor expression transiently increased and then gradually decreased until 14 days. Treatment with nicotine for 14 days slightly polarized M0 microglia to M2b and d subtypes. Co-exposure of thrombin and low concentration of interferon-γ recruited inducible NO synthase (iNOS)- and interleukin-1β-double-positive M1 microglia in a thrombin-concentration-dependent manner. Treatment with nicotine for 14 days significantly decreased the thrombin-induced increase of iNOS mRNA levels and conversely showed a tendency to increase arginase1 mRNA levels. Moreover, treatment with nicotine for 14 days suppressed thrombin-induced phosphorylation of p38 MAPK through the α7 receptor. Repeated intraperitoneal administration of α7 agonist PNU-282987 for 14 days selectively evoked the apoptosis of iNOS-positive M1 microglia at the perihematomal area and showed a neuroprotective effect in an in vivo intracerebral hemorrhage model. These findings revealed that long-term stimulation of α7 receptor causes suppression of thrombin-induced activation of p38 MAPK followed by apoptosis in neuropathic M1 microglia.
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Acknowledgements
This study was funded by the Smoking Research Foundation. We thank T. Shigemasa and Dr. T. Nakamura (Fukuyama University, Hiroshima, Japan) for technical support.
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Conducted experiments: MO, AM, MD, NT, YK. Contributed new reagents or analytic tools: MO, AI. Performed data analysis: MO, MD, NT, YK. Wrote or contributed to the writing and editing of the manuscript: MO.
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The methods in the present study were approved by the Institutional Animal Care and Use Committee of Fukuyama University (2021-A-13; March 16th, 2021), and animals were treated in accordance with the guidelines of the United States National Institutes of Health regarding the care and use of animals for experimental procedures.
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Ohnishi, M., Machida, A., Deguchi, M. et al. Long-term Stimulation of α7 Nicotinic Acetylcholine Receptor Rescues Hemorrhagic Neuron Loss via Apoptosis of M1 Microglia. J Neuroimmune Pharmacol 18, 160–168 (2023). https://doi.org/10.1007/s11481-023-10065-y
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DOI: https://doi.org/10.1007/s11481-023-10065-y