Abstract
BackgroundTherapeutic hypothermia is one of the neuroprotective strategies that improve neurological outcomes after brain damage in ischemic stroke and traumatic brain injury. Microglial cells become activated following brain injury and play an important role in neuroinflammation and subsequent brain damage. The aim of this study was to determine the time-dependent effects of hypothermia on microglial cell activation and migration, which are accompanied by neuroinflammation.MethodsMicroglial cells in culture were subjected to mild (33 °C) or moderate (29 °C) hypothermic conditions before, during, or after lipopolysaccharide (LPS) or hypoxic stimulation, and the production of nitric oxide (NO), proinflammatory cytokines, reactive oxygen species, and neurotoxicity was evaluated. Effects of hypothermia on microglial migration were also determined in in vitro as well as in vivo settings.ResultsEarly-, co-, and delayed-hypothermic treatments inhibited microglial production of inflammatory mediators to varying degrees: early treatment was the most efficient, and delayed treatment showed time-dependent effects. Delayed hypothermia also suppressed the mRNA levels of proinflammatory cytokines and iNOS, and attenuated microglial neurotoxicity in microglia-neuron co-cultures. Furthermore, delayed hypothermia reduced microglial migration in the Boyden chamber assay and wound healing assay. In a stab injury model, delayed local hypothermia reduced migration of microglia toward the injury site in the rat brain.ConclusionTaken together, our results indicate that delayed hypothermia is sufficient to attenuate microglial activation and migration, and provide the basis of determining the optimal time window for therapeutic hypothermia. Delayed hypothermia may be neuroprotective by inhibiting microglia-mediated neuroinflammation, indicating the therapeutic potential of post-injury hypothermia for patients with brain damages exhibiting some of the inflammatory components.
Highlights
Brain injury can be classified as direct disruption of the brain tissue and as secondary damage
Inhibitory effect of hypothermia on microglial nitric oxide (NO) production To examine the effect of hypothermic conditions on NO synthesis in activated microglia cells, BV-2 mouse microglial cells were treated with Toll-like receptor 4 (TLR4) ligand LPS (100 ng/ml) under normothermic (37 °C) or hypothermic conditions (33 °C, 29 °C) for 0 to 48 hours, and nitrite production was measured
Hypothermic conditions led to a decrease in NO production in LPS-activated BV-2 microglial cells compared to normothermia (Figure 1A)
Summary
Brain injury can be classified as direct disruption of the brain tissue and as secondary damage. The protective mechanisms of mild or moderate hypothermia include the reductions in excitatory neurotransmitters, apoptotic cell death, dysfunctional mitochondria, and suppression of protein synthesis [13,14]. Previous reports have shown that hypothermia inhibits microglia and brain inflammation, which may be the underlying mechanism of the neuroprotective effects of mild hypothermia [15,16,17,18,19]. Several reports have suggested that neurological outcomes of therapeutic hypothermia may depend on the duration or initiation of the cooling time. Therapeutic hypothermia is one of the neuroprotective strategies that improve neurological outcomes after brain damage in ischemic stroke and traumatic brain injury. Microglial cells become activated following brain injury and play an important role in neuroinflammation and subsequent brain damage. The aim of this study was to determine the time-dependent effects of hypothermia on microglial cell activation and migration, which are accompanied by neuroinflammation
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