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The Journal of Neuroscience, June 30, 2004, 24(26):5909-5912; doi:10.1523/JNEUROSCI.1278-04.2004

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Neurobiology of Disease
Prophylactic Creatine Administration Mediates Neuroprotection in Cerebral Ischemia in Mice

Shan Zhu,^1 * Mingwei Li,^1 * Bryan E. Figueroa,¹ Aijian Liu,^2,3 Irina G. Stavrovskaya,^4,5 Piera Pasinelli,⁶ M. Flint Beal,⁷ Robert H. Brown, Jr,⁶ Bruce S. Kristal,^4,5 Robert J. Ferrante,^2,3 and Robert M. Friedlander¹

¹Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, ²Geriatric Research Education and Clinical Center, Bedford Veterans Affairs Medical Center, Bedford, Massachusetts 01730, ³Departments of Neurology, Pathology, and Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, ⁴Burke Medical Research Institute, White Plains, New York 10605, ⁵Departments of Biochemistry and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, ⁶Day Neuromuscular Research Laboratory, Neurology Department, Massachusetts General Hospital-East, Charlestown, Massachusetts 02129, and ⁷Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021

Creatine mediates remarkable neuroprotection in experimental models of amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and traumatic brain injury. Because caspase-mediated pathways are shared functional mechanistic components in these diseases, as well as in ischemia, we evaluated the effect of creatine supplementation on an experimental stroke model. Oral creatine administration resulted in a remarkable reduction in ischemic brain infarction and neuroprotection after cerebral ischemia in mice. Postischemic caspase-3 activation and cytochrome c release were significantly reduced in creatine-treated mice. Creatine administration buffered ischemia-mediated cerebral ATP depletion. These data provide the first direct correlation between the preservation of bioenergetic cellular status and the inhibition of activation of caspase cell-death pathways in vivo. An alternative explanation to our findings is that creatine is neuroprotective through other mechanisms that are independent of mitochondrial cell-death pathways, and therefore postischemic ATP preservation is the result of tissue spearing. Given its safety record, creatine might be considered as a novel therapeutic agent for inhibition of ischemic brain injury in humans. Prophylactic creatine supplementation, similar to what is recommended for an agent such as aspirin, may be considered for patients in high stroke-risk categories.

Key words: creatine; ischemia; caspase; cytochrome c; neuroprotection; bioenergetics

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Received April 5, 2004; revised May 12, 2004; accepted May 14, 2004.

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