Therapeutic hypothermia is a useful intervention against brain injury in experimental models and patients, but
its therapeutic applications are limited due to its ill-defined mode of action. Glia cells maintain homeostasis and protect
the central nervous system from environmental change, but after brain injury, glia are activated and induce glial scar formation
and secondary injury. On the other hand, therapeutic hypothermia has been shown to modulate glial hyperactivation
under various brain injury conditions. We considered that knowledge of the effect of hypothermia on the molecular
profiles of glia and on their phenotypes would improve our understanding of the neuroprotective mechanism of hypothermia.
Here, we review the findings of recent studies that examined the effect of hypothermia on proteome changes in reactive
glial cells in vitro and in vivo. The therapeutic effects of hypothermia are associated with the inhibition of reactive
oxygen species generation, the maintenance of ion homeostasis, and the protection of neurovascular units in cultured glial
cells. In an animal model, a distinct pattern of protein alterations was detected in glia following hypothermia under
ischemic/reperfusion conditions. In particular, hypothermia was found to exert a neuroprotective effect against ischemic
brain injury by regulating specific glial signaling pathways, such as, glutamate signaling, cell death, and stress response,
and by influencing neural dysfunction, neurogenesis, neural plasticity, cell differentiation, and neurotrophic activity. Furthermore,
the proteins that were differentially expressed belonged to various pathways and could mediate diverse phenotypic
changes of glia in vitro or in vivo. Therefore, hypothermia-modulated glial proteins and subsequent phenotypic
changes may form the basis of the therapeutic effects of hypothermia.