br Introduction The period around birth is a risky time

Introduction The period around birth is a risky time for stroke in infants. Ischemic stroke has been diagnosed in about 1/4000 full-term infants (Nelson and Lynch, 2004) and perinatal stroke represents the second most frequent cause of acute seizures in this age group (Levy et al., 1985). Furthermore, stroke is responsible for long-term cognitive and/or neurological sequelae, including epilepsy (Lynch et al., 2002). Clinical studies have yielded inconsistent results on these questions. For example, McBride et al. (2000) reported that prolonged or frequent seizures in the context of impaired blood flow may exacerbate ischemic β-Sitosterol receptor damage in the developing brain. Likewise, Shah et al. (2014) have demonstrated that a higher seizure burden in neonates with hypoxic/ischemic encephalopathy was correlated with greater damage on MRI. On the other hand, the multicenter study reported by Kwon et al. (2011) came to the conclusion that clinical seizures in neonatal hypoxic/ischemic encephalopathy have no independent impact on neurodevelopmental outcome. Experimental studies have been equally inconclusive. Wirrell et al. (2001) reported that seizures induced by kainate in P10 rats following carotid ligation significantly exacerbated brain injury. These results contrast with the studies of Cataltepe et al. (1995) in which status epilepticus, induced by bicuculline after hypoxic/ischemic insult, did not exacerbate brain damage in P7 rats. It is unclear what the reasons may be for these differing experimental results, but it is clear that the experimental approaches involved different mechanisms for inducing ischemia and different independent agents for inducing seizures. An animal model that better mimics the human situation in which his seizures occur as a natural outcome of focal ischemia would provide a more rational experimental approach to answering these questions concerning the relationships among hypoxic/ischemic insult, seizures, brain damage and neurological/cognitive outcome. We believe that the model of focal cerebral ischemia induced by the infusion of the vasoconstrictive agent endothelin-1 (ET-1) into the brain parenchyma satisfies this criterion. In animals, this model has been shown to be highly reproducible and to mimic human stroke (Gilmour et al., 2004). Intracerebral infusion of ET-1 causes a substantial reduction of local blood flow (Fuxe et al., 1997) and ischemia-related changes in aminoacids level concentrations (Van Hemelrijck et al., 2005), induces convulsive behavior (Gross and Weaver, 1993, Nagasaka et al., 1999) and produces morphological damage (Driscoll et al., 2008, Tsenov et al., 2007). Furthermore, unilateral intrahippocampal injection of ET-1 in immature animals leads to the development of electrical seizures with behavioral manifestations and produces morphological damage within the treated hippocampus (Mateffyova et al., 2006, Tsenov et al., 2007). Simonson and Herman (1993) have shown that ET-1 acts through the G-protein linked receptors ETA and ETB. Furthermore, these two receptors have been demonstrated to have different localization within nervous tissue. ETA receptors are located predominantly in cerebrovascular smooth muscle cells (Pierre and Davenport, 1998), while ETB receptors are distributed on vascular endothelial cells (Stenman et al., 2002), on astrocytes (Baba, 1998) and on microglia (McLarnon et al., 1999). The consequences of ET-1 injection into the brain parenchyma, as well as the roles of the endothelin receptors, ETA and ETB, in cerebral ischemia and ischemia-induced changes have been relatively well described in the brains of adult animals (Hama et al., 1997, Schaller, 2006). However, similar studies concerning the role of ETA and ETB in ischemia-induced effects in immature brains are largely lacking. In the present study, we focus on the following questions:
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