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

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 CX3CR1^GFP 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.

Keywords: Cell death; Inflammation; Ischemic stroke; Microglia; Targeted temperature management.