Ischemic Stroke

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Stroke remains one of the major causes of death and a leading cause of functional impairment, resulting in long-term disability. The latter is manifest by neurological dysfunction and significant reduction in the ability to perform activities of daily living. There are greater than 20 million incident strokes worldwide each year, resulting in more than 5.5 million annual deaths (World Health Report, 2002). Ischemic stroke is by far the most prevalent, accounting for about 88% of all strokes. Despite the advent of treatment using intravenous tissue-type plasminogen activator and the promise of additional acute therapies, effective pre- and post-stroke prevention are paramount for reducing the burden of stroke (Adams et al., 2005; Sacco et al., 1997).

The maintenance of ion gradients across the neuronal cell membrane involves a significant degree of metabolic energy provided by ATP. Within minutes of reduced or lack of blood flow, a cascade of events occur resulting in failure of sodium/potassium pumps, influx of extracellular calcium ions, and subsequent excitotoxicity that ultimately results in neuronal death. Neurons most severely affected by hypoxic injury die rapidly by necrosis, while those neurons that are exposed to a lesser degree of hypoxia in the penumbral zone succumb via apoptosis (Tatsumi et al., 2003). Creatine supplementation may result in improved ability of the neuron to withstand ischemia-mediated energetic deficiency.

Creatine supplementation has been reported to be neuroprotective in an experimental model of anoxia in neonatal mice (Wilken et al., 2000). After 30 minutes of anoxia, both ATP and PCr concentrations were significantly higher in creatine-treated pups than unsupplemented controls, suggesting that hypoxic energy failure in neonatal mice can be prevented by creatine applied before hypoxic events. In a model of transient hypoxic ischemia, six-day-old rats received creatine (3 g/kg/d) for 3 days prior to unilateral common carotid artery ligation followed by hypoxia. The creatine-treated rats showed a significant reduction in volume of brain edema and an increased 'energy potential' as reflected by the ratio of PCr to inorganic phosphate that was measured by 31P-magnetic resonance spectroscopy (Adcock et al., 2002). Neuronal cell injury was significantly lower in the cortex of the animals that had received creatine. In a separate report, oral creatine administration resulted in a marked reduction in ischemic brain infarction and neuroprotection after cerebral ischemia in mice, with a direct correlation between the preservation of bioenergetic cellular status and the inhibition of activation of caspase cell-death pathways in vivo (Zhu et al., 2004). Post-ischemic caspase-3 activation and cytochrome c release were significantly reduced in creatine-treated mice. In addition, creatine administration buffered ischemia-mediated cerebral ATP depletion, suggesting that creatine may be neuroprotective in this experimental paradigm through mechanisms independent of mitochondrial cell-death pathways. With respect to the latter, it has been shown that creatine-mediated neuroprotection may involve improved cerebrovascular function (Prass et al., 2007). The authors found a 40% reduction in infarct volume from transient focal cerebral ischemia after 3 weeks of dietary creatine administration without any changes in bioenergetic status as reflected by brain creatine, PCr, and ATP concentrations. There were, however, increased cerebral blood flow and vasodilatory responses after stroke in creatine-treated mice, suggesting that creatine-mediated neuroprotection may be associated with improved cerebrovas-cular function. This experimental data demonstrates that there is increased ability to resist ischemic injury by creatine supplementation and that these findings correlate with improved maintenance of energy metabolism and cellular homeostasis. In ischemic stroke, creatine may be multimodal by also inhibiting hypoxia-mediated release of cytochrome c and downstream activation of caspase-3, and may improve cerebrovascular flow. Prophylactic creatine supplementation may be beneficial in patients at high risk for stroke in preventing neuronal damage and loss.

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