Effects of delayed hypothermia on time-dependent microglial production of inflammatory and anti-inflammatory factors

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Therapeutic hypothermia protects neurons after severe brain damage. We have previously shown that immediate hypothermic culture reduces the temporal microglial production of inflammatory and anti-inflammatory factors. To better understand the therapeutic time window of this therapy for reducing these potential neurotoxic factors, we investigated the effects of delayed hypothermia on the temporal production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-10 and nitric oxide (NO) by toll-like receptor (TLR)-activated microglia.


Rat microglia were activated by TLR2 or TLR4 agonists under normothermic (37°C) conditions (time zero). Subsequently, the cells were divided into normothermic or hypothermic (33°C) groups. The hypothermic group was subdivided into two groups with the induction of hypothermia that was started either 1 or 2 h after the activation of microglia. TNF-α and IL-1β, and IL-10 and NO production in the culture supernatant were measured at 3–6 h and 24–48 h, respectively, after time zero.


Compared with normothermia, 1-h and 2-h delayed hypothermia decreased TNF-α and IL-1β (after TLR2 activation) production at 3–6 h and 6 h, respectively. Both IL-10 (after TLR2 activation) and NO (after TLR4 activation) production were decreased at 24–48 h by hypothermia that was started within 2 h.


Delayed (1–2 h) hypothermic culture decreased the production of early-phase TNF-α and IL-1β, and late-phase IL-10 and NO by TLR-activated microglia, as has been observed with immediate hypothermic culture, suggesting that therapeutic hypothermia that is started within 1–2 h is sufficient to elicit neuroprotective effects by reducing microglial production of these factors.

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