• Tomohiro Matsui, Yukari Motoki, Takafumi Inomoto, Daisuke Miura, Yukiko Kato, Hiromi Suenaga, Keisuke Hino, and Junzo Nojima.
• Department of Laboratory Sciences, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan. giants@yamaguchi-u.ac.jp
• Neurocrit Care. 2012 Oct 1;17(2):293-300.

BackgroundTherapeutic hypothermia protects neurons after severe brain injury. Activated microglia produce several neurotoxic factors, such as pro-inflammatory cytokines and nitric oxide (NO), during neuron destruction. Hence, suppression of microglial release of these factors is thought to contribute partly to the neuroprotective effects of hypothermia. After brain insults, adenosine triphosphate (ATP) is released from injured cells and activates microglia. Here, we examined the acute effects of temperature on ATP-activated microglial production of inflammatory factors, and the possible involvement of p38 mitogen-activated protein kinase (p38) underlying such effects.MethodsMicroglia were cultured with ATP at 33, 37, and 39°C, or with ATP in the presence of a p38 inhibitor, SB203580, at 37°C. Cytokine and NO levels, and p38 activation were measured.ResultsCompared to 37°C, TNF-α was reduced at 33°C and augmented at 39°C for 1.5 h. IL-6 was reduced at 33°C for 6 h. NO was reduced at 33°C, but augmented at 39°C for 6 h. p38 was reduced at 33°C for 1 min. SB203580 inhibited ATP-induced TNF-α, IL-6, and NO production.ConclusionLowering temperature rapidly reduced p38 activation and the subsequent p38-regulated production of pro-inflammatory cytokines and NO in ATP-activated microglia, suggesting that attenuation of early phase inflammatory responses via suppression of p38 in microglia is one possible neuroprotective mechanism of therapeutic hypothermia. Temperature elevation increased TNF-α and NO production in these cells. These temperature-dependent changes imply that monitoring of TNF-α and NO in the cerebrospinal fluid during the early phase might be useful as biomarkers for responses to therapeutic hypothermia and hyperthermia.

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