Stroke leads to energy failure and subsequent neuronal cell loss. Creatine and phosphocreatine constitute a cellular energy buffering and transport system, and dietary creatine supplementation has been shown to protect neurons in several models of neurodegeneration. We examined whether creatine has beneficial effects in a mouse model of focal cerebral ischemia. Oral creatine administered three weeks before stroke reduced infarct sizes induced by MCA occlusion in a dose-dependent manner. However, no significant differences in the brain concentration of creatine, phosphocreatine and ATP were found in our HPLC analysis. In contrast to previous studies that linked neuroprotection with increased levels of creatine and/or phosphocreatine, we thus observed beneficial creatine effects in stroke that are independent of the concentrations of creatine and energy-rich phosphates in the brain. To investigate the role of perfusion-related protective mechanisms we measured vascular reactivity of isolated MCA and performed in vivo MR imaging (alternating Diffusion Weighted Imaging (DW-MRI) and Perfusion Weighted Imaging with FAIR (FAIR-MRI)) in the acute phase during and after MCA occlusion. At 30 min after MCAO, FAIR-MRI showed the same absolute perfusion of the ipsilateral hemisphere in creatine-fed and control animals (0.43 ± 0.18 / 0.39 ± 0.18 ml/g*min respectively). However, 30 min after reperfusion (90 min post MCAO) ipsilateral blood flow in creatine-fed animals was significantly higher than in control animals (0.51 ± 0.10 / 0.30 ± 0.15 ml/g*min respectively, p=0.01). DWI during ischemia at 50 min after MCAO showed no difference in ipsilateral absolute ADC reduction between creatine-fed animals and controls (0.69 ± 0.10 / 0.74 ± 0.16 × 10−3 mm2/s respectively). At 90 min after reperfusion (150 min post MCAO) ipsilateral ADC recovered significantly better in creatine-fed compared to control animals (0.84 ± 0.07 / 0.62 ± 0.17 × 10−3 mm2/s respectively, p=0.01). Our findings suggest a novel mechanism of creatine-induced neuroprotection through improvement of cerebrovascular function during cerebral ischemia.
