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The Journal of Neuroscience, May 15, 2002, 22(10):3921-3928

Influence of Mild Hypothermia on Inducible Nitric Oxide Synthase Expression and Reactive Nitrogen Production in Experimental Stroke and Inflammation

Hyung Soo Han^{1, 2}, Yanli Qiao^{1, 3}, Murat Karabiyikoglu², Rona G. Giffard³, and Midori A. Yenari^{1, 2}

Departments of ¹ Neurology, ² Neurosurgery, and ³ Anesthesia, Stanford University Medical Center, Stanford, California 94305

Mild hypothermia is neuroprotective, but the reasons are not well known. Inflammation contributes to ischemic damage; therefore, we examined whether the protection by hypothermia may be attributable to alterations in the inflammation. We examined whether hypothermia might alter the inflammatory cell-associated inducible nitric oxide synthase (iNOS) and subsequent nitric oxide (NO) and peroxynitrite generation in experimental stroke and inflammation. Rats underwent 2 hr of middle cerebral artery occlusion (MCAO). Brain inflammation was modeled by intravenous lipopolysaccharide (LPS) (2 mg/kg) injection. Temperature was maintained at 33°C for 2 hr immediately after MCAO and LPS injection, delayed 2 hr after MCAO or maintained at 38°C. Cultured microglia were activated with LPS and then incubated at 33 or 37°C. Both intraischemic and delayed mild hypothermia attenuated infarct size by 40% (p < 0.05). Immunohistochemistry was performed to identify cell type, iNOS, and peroxynitrite. The majority of iNOS- and peroxynitrite-positive cells were activated microglia-macrophages, and mild hypothermia significantly decreased the numbers of immunoreactive cells at 72 hr by >50% (p < 0.05). After ischemia, mild hypothermia decreased NO production by 40%. Similarly, hypothermia attenuated NO and iNOS in LPS-injected rats, as well as in cultured microglia. Aminoguanidine, an iNOS inhibitor, also attenuated infarct size and NO in ischemic and inflammation models. We conclude that mild hypothermia significantly inhibits the inflammatory response by affecting microglial iNOS-NO generation. Therapies directed against microglia or their activation may be useful in treating stroke.

Key words: focal cerebral ischemia; mild hypothermia; inducible nitric oxide synthase; microglia; peroxynitrite; lipopolysaccharide; inflammation

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22103921-08$05.00/0

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