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Targeted Temperature Management at 36 °C Shows Therapeutic Effectiveness via Alteration of Microglial Activation and Polarization After Ischemic Stroke

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Abstract

Ischemic injury leads to cell death and inflammatory responses after stroke. Microglia especially play a crucial role in this brain inflammation. Targeted temperature management (TTM) at 33 °C has shown neuroprotective effects against many acute ischemic injuries. However, it has also shown some adverse effects in preclinical studies. Therefore, we explored the neuroprotective effect of TTM at 36 °C in the ischemic brain. To confirm the neuroprotective effects of hypothermia, mice were subjected to a permanent stroke and then treated with one of the TTM paradigms at 33 and 36 °C. For comparison of TTM at 33 and 36 °C, we examined neuronal cell death and inflammatory response, including activation and polarization of microglia in the ischemic brain. TTM at 33 and 36 °C showed neuroprotective effects in comparison with normal body temperature (NT) at 37.5 °C. Mice under TTM at 33 and 36 °C showed ~ 45–50% fewer TUNEL-positive cells than those under NT. In IVIS spectrum CT, the activation of microglia/macrophage in CX3CR1GFP mice reduced after TTM at 33 and 36 °C in comparison with that after NT on day 7 after ischemic stroke. The number of Tmem119-positive cells under TTM at 33 and 36 °C was ~ 45–50% lower than that in mice under NT. TTM at 33 and 36 °C also increased the ratio of CD206-/CD86-positive cells than the ratio of CD86-/CD206-positive cells by ~ 1.2-fold. Thus, TTM at 33 and 36 °C could equivalently decrease the expression of certain cytokines after ischemic stroke. Our study suggested that TTM at 33 or 36 °C produces equivalent neuroprotective effects by attenuating cell death and by altering microglial activation and polarization. Therefore, TTM at 36 °C can be considered for its safety and effectiveness in ischemic stroke.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding authors on reasonable request.

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Funding

This study was supported by a grant from the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science, ICT & Future Planning (NRF-2016M3C7A1905098 to JEL and NRF-2018R1C1B6006159 to JSY) and a faculty research grant from Yonsei University College of Medicine for 2019 (6–2019-0188).

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Authors and Affiliations

  1. Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea

    Jong Youl Kim, Joohyun Park & Jong Eun Lee

  2. Department of Emergency Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211 Eonju-ro, Gangnam-gu, Seoul, 06273, Republic of Korea

    Ju Hee Kim, Jin Ho Beom, Sung Phil Chung & Je Sung You

  3. BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro Seodaemun-gu, Medical School Building Room # 146, Seoul, 03722, Republic of Korea

    Jong Eun Lee

  4. Brain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea

    Jong Eun Lee

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  1. Jong Youl Kim
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Correspondence to Je Sung You or Jong Eun Lee.

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All animal experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) of Yonsei University Health System and the National Institutes of Health guidelines.

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Jong Youl Kim and Ju Hee Kim are co-first authors

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Kim, J.Y., Kim, J.H., Park, J. et al. Targeted Temperature Management at 36 °C Shows Therapeutic Effectiveness via Alteration of Microglial Activation and Polarization After Ischemic Stroke. Transl. Stroke Res. 13, 132–141 (2022). https://doi.org/10.1007/s12975-021-00910-8

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  • DOI: https://doi.org/10.1007/s12975-021-00910-8

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