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The Journal of Neuroscience, October 19, 2005, 25(42):9794-9806; doi:10.1523/JNEUROSCI.3163-05.2005

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Neurobiology of Disease
Akt Contributes to Neuroprotection by Hypothermia against Cerebral Ischemia in Rats

Heng Zhao,^1,2,4 Takayoshi Shimohata,¹ Jade Q. Wang,² Guohua Sun,² David W. Schaal,¹ Robert M. Sapolsky,^1,2,3,4 and Gary K. Steinberg^1,3,4

Departments of ¹Neurosurgery, ²Biological Sciences, and ³Neurology and Neurological Sciences and ⁴Stanford Stroke Center, Stanford University, Stanford, California 94305

Activation of the Akt/protein kinase B (PKB) kinase pathway can be neuroprotective after stroke. Akt is activated by growth factors via a phosphorylation-dependent pathway involving the kinases phosphoinositide 3 (PI3) kinase and phosphoinositide-dependent protein kinase-1 (PDK1) and is negatively regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Akt kinase blocks apoptosis by phosphorylating the substrates forkhead transcription factor (FKHR) and glycogen synthase kinase 3 (GSK3). We found that intra-ischemic hypothermia (30°C) reduced infarct size and improved functional outcomes up to 2 months. Changes in phosphorylation levels of Akt, as measured by Western blots and immunostaining, differed from levels of Akt activity measured in an in vitro assay in normothermic animals. Hypothermia blocked most of these changes and maintained Akt activity. Inhibition of PI3/Akt enlarged infarct size in hypothermic animals. Hypothermia improved phosphorylation of PDK1, PTEN, and FKHR. Hypothermia did not improve GSK3 (Ser9) phosphorylation but blocked the nuclear translocation of phosphorylated -catenin (Ser33/37/Thr41) downstream of GSK3. Phosphorylation levels of PTEN, Akt, and Akt substrate decreased before apoptotic cytochrome c release and degradation of microtubule-associated protein-2, a marker of neuronal survival. Hypothermia may protect from ischemic damage in part by preserving Akt activity and attenuating the apoptotic effects of PTEN, PDK1, and FKHR.

Key words: Akt/PKB; hypothermia; cerebral ischemia; GSK3; PTEN; -catenin

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Received July 29, 2005; revised September 8, 2005; accepted September 12, 2005.

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