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Neuroinflammation is a key element in the ischemic cascade after cerebral ischemia that results in cell damage and death in the subacute phase. However, anti-inflammatory drugs do not improve outcome in clinical settings suggesting that the neuroinflammatory response after an ischemic stroke is not entirely detrimental. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. Because of its inhibitory influence on several pathways of the ischemic cascade, hypothermia has been introduced as a promising neuroprotective strategy. This review also discusses the influence of hypothermia on the neuroinflammatory response. We conclude that hypothermia exerts both stimulating and inhibiting effects on different aspects of neuroinflammation and hypothesize that these effects are key to neuroprotection.

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System x cϪ exchanges intracellular glutamate for extracellular cystine, giving it a potential role in intracellular glutathione synthesis and nonvesicular glutamate release. We report that mice lacking the specific xCT subunit of system x c Ϫ (xCT Ϫ/Ϫ ) do not have a lower hippocampal glutathione content, increased oxidative stress or brain atrophy, nor exacerbated spatial reference memory deficits with aging. Together these results indicate that loss of system x c Ϫ does not induce oxidative stress in vivo. Young xCT Ϫ/Ϫ mice did however display a spatial working memory deficit. Interestingly, we observed significantly lower extracellular hippocampal glutamate concentrations in xCT Ϫ/Ϫ mice compared to wild-type littermates. Moreover, intrahippocampal perfusion with system x c Ϫ inhibitors lowered extracellular glutamate, whereas the system x c Ϫ activator N-acetylcysteine elevated extracellular glutamate in the rat hippocampus. This indicates that system x c Ϫ may be an interesting target for pathologies associated with excessive extracellular glutamate release in the hippocampus. Correspondingly, xCT deletion in mice elevated the threshold for limbic seizures and abolished the proconvulsive effects of N-acetylcysteine. These novel findings sustain that system x c Ϫ is an important source of extracellular glutamate in the hippocampus. System x c Ϫ is required for optimal spatial working memory, but its inactivation is clearly beneficial to decrease susceptibility for limbic epileptic seizures.

Vagus nerve stimulation (VNS) is an adjunctive treatment for refractory epilepsy in patients who are unsuitable candidates for epilepsy surgery (Ben-Menachem 2002). Worldwide, more than 50 000 epilepsy patients have been treated with VNS. Several studies, including two large double-blind randomized clinical trials (Ben-Menachem et al. 1994;DeGiorgio et al. 2000), have confirmed the efficacy of VNS in different types of epilepsy. Seizure reduction as a result of VNS ranges from 25% to 55%, and varies considerably from patient to patient. In responders, VNS causes either a rapid or a delayed reduction in seizure frequency. However, a significant fraction (approximately one third) of patients do not respond to VNS. Because the mechanism of action of VNS in epilepsy is currently unknown, it is not clear which factors determine the patient's response to the treatment, nor what the most optimal stimulation parameters are.The vagus nerve is a mixed nerve consisting of 20% efferent (motor) and 80% afferent (sensory) fibers. The nucleus of the solitary tract receives the largest number of vagal afferents. The nucleus of the solitary tract in turn Received July 5, 2010; revised manuscript received January 18, 2011; accepted February 8, 2011.Address correspondence and reprint requests to Robrecht Raedt, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. E-mail: robrecht.raedt@ugent.be 1 These authors contributed equally to this work.

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Malfunctioning of system x(c)(-), responsible for exchanging intracellular glutamate for extracellular cystine, can cause oxidative stress and excitotoxicity, both important phenomena in the pathogenesis of Parkinson's disease (PD). We used mice lacking xCT (xCT(-/-) mice), the specific subunit of system x(c)(-), to investigate the involvement of this antiporter in PD. Although cystine that is imported via system x(c)(-) is reduced to cysteine, the rate-limiting substrate in the synthesis of glutathione, deletion of xCT did not result in decreased glutathione levels in striatum. Accordingly, no signs of increased oxidative stress could be observed in striatum or substantia nigra of xCT(-/-) mice. In sharp contrast to expectations, xCT(-/-) mice were less susceptible to 6-hydroxydopamine (6-OHDA)-induced neurodegeneration in the substantia nigra pars compacta compared to their age-matched wild-type littermates. This reduced sensitivity to a PD-inducing toxin might be related to the decrease of 70% in striatal extracellular glutamate levels that was observed in mice lacking xCT. The current data point toward system x(c)(-) as a possible target for the development of new pharmacotherapies for the treatment of PD and emphasize the need to continue the search for specific ligands for system x(c)(-).