Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice.
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 sparing. 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.
Zhu
Shan
S
Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Li
Mingwei
M
Figueroa
Bryan E
BE
Liu
Aijian
A
Stavrovskaya
Irina G
IG
Pasinelli
Piera
P
Beal
M Flint
MF
Brown
Robert H
RH
Kristal
Bruce S
BS
Ferrante
Robert J
RJ
Friedlander
Robert M
RM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003401:Creatine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011292:Premedication
D018696:Neuroprotective Agents; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003401:Creatine