Postischemic treatment--论文代写范文精选

提供神经保护nimesulide，观察到治疗推迟，缺血的发病后6小时，证实多种治疗的cox-2抑制剂。另一方面,选择性抑制COX-1与血管评估参数无显著影响。这些数据表明是COX-2的活动,不是COX-1活动,导致局部缺血性脑损伤的发展。下面的essay代写范文进行详述。

Abstract 
Several studies suggest that cyclooxygenase (COX)-2 plays a pivotal role in the progression of ischemic brain damage. In the present study, we investigated the effects of selective inhibition of COX-2 with nimesulide (12 mg/kg) and selective inhibition of COX-1 with valeryl salicylate (VAS, 12-120 mg/kg) on prostaglandin E2 (PGE2) levels, myeloperoxidase (MPO) activity, Evans Blue (EB) extravasation and infarct volume in a standardized model of transient focal cerebral ischemia in the rat. Postischemic treatment with nimesulide markedly reduced the increase in PGE2 levels in the ischemic cerebral cortex 24 h after stroke and diminished infarct size by 48 % with respect to vehicle-treated animals after 3 days of reperfusion. Furthermore, nimesulide significantly attenuated the blood-brain barrier (BBB) damage and leukocyte infiltration (as measured by EB leakage and MPO activity, respectively) seen at 48 h after the initial ischemic episode. These studies provide the first experimental evidence that COX-2 inhibition with nimesulide is able to limit BBB disruption and leukocyte infiltration following transient focal cerebral ischemia. Neuroprotection afforded by nimesulide is observed even when the treatment is delayed until 6 h after the onset of ischemia, confirming a wide therapeutic window of COX-2 inhibitors in experimental stroke. On the other hand, selective inhibition of COX-1 with VAS had no significant effect on the evaluated parameters. These data suggest that COX-2 activity, but not COX-1 activity, contributes to the progression of focal ischemic brain injury, and that the beneficial effects observed with non-selective COX inhibitors are probably associated to COX-2 rather than to COX-1 inhibition. 
Key words: Cyclooxygenase; prostaglandin E2; stroke; blood-brain barrier; leukocyte infiltration; cerebral ischemia; vasogenic edema; cerebral infarct; neuroprotection

Introduction 
Ischemic stroke disrupts the quality of patients’ life, extracts an enormous emotional and physical strain on caregivers, and cost society billions of dollars every year (Taylor et al. 1996). Significant progress has been made in dissecting the molecular pathways of excitotoxicity, oxidative stress, apoptosis and neuroinflammation in ischemic neuronal cell death. However, translation of these preclinical results into clinically effective stroke treatments remains a major challenge for the stroke community. Although a significant amount of ischemic tissue dies in the core of the infarct within few hours after the vessel occlusion, there is evidence showing that the damage in the surrounding tissue (ischemic penumbra) progresses over a relative long period of time (Iadecola and Ross 1997;Dirnagl et al. 1999). Thus, pharmacological strategies limiting the delayed phase of the damage are probably more important in stroke therapy, since most of the patients arrive in the emergency room too late for preventing or minimizing the initial damage. Inflammation is one of the mechanisms known to participate in the progression of brain injury (Dirnagl et al. 1999;Dirnagl 2004). It has been shown that after several hours of the onset of ischemia, there is a significant disruption of the blood-brain barrier (BBB) followed by a massive infiltration of polymorphonuclear (PMN) leukocytes (Rosenberg et al. 1998;Batteur-Parmentier et al. 2000;Martin et al. 2006). 

This results in brain edema and microglial activation, and the production of large amounts of pro-inflammatory cytokines, ROS, nitric oxide, among other mediators of neuroinflammation, which exacerbate tissue damage. All these neuroinflammatory mechanisms have been demonstrated to contribute to ischemic brain injury (Barone and Feuerstein 1999;Dirnagl et al. 1999;Stanimirovic and Satoh 2000). A large number of studies indicates that blockade of the neuroinflammatory process dramatically reduces ischemic brain injury (Nogawa et al. 1997;Nogawa et al. 1998;Nagayama et al. 1999;Batteur-Parmentier et al. 2000;Candelario-Jalil et al. 2004;Candelario-Jalil et al. 2005;Ikeda-Matsuo et al. 2006;Kawano et al. 2006).

Materials and Methods 
All the experimental procedures were performed strictly according to the regulations of the Havana University’s animal ethical committee and the guidelines of the National Institutes of Health (Bethesda, MD, USA) for the care and use of laboratory animals for experimental procedures. Our institutional animal care and use committee approved the experimental protocol. Appropriate measures were taken to minimize pain and distress of animals used in this study. A total of 349 male Sprague-Dawley rats (CENPALAB, Havana, Cuba) weighing 270-320 g at the time of surgery were used in the present study. The animals were quarantined for at least 7 days before the experiment. Animals were housed on bagasse bedding in groups of 2-4 in polycarbonate cages in a room whose environment was maintained at 21-22ºC, 45-50 % humidity and 12 h light/dark cycle. They had free access to rodent pellet chow and water.

In summary, the present study sheds additional light on the neuroprotective effects of the COX-2 inhibitor nimesulide against ischemia-induced PGE2 formation, BBB damage, leukocyte infiltration, and vasogenic edema in a rat model of transient focal cerebral ischemia. It is important to note that this neuroprotective effect of nimesulide was demonstrated with postischemic treatment. Furthermore, this study also indicates that COX- 1 inhibition is unable to confer any protective effect in focal ischemic brain damage, demonstrating the major contribution of COX-2, rather than COX-1, to brain injury in this model of ischemic stroke. Inhibition of COX-2 may be a valuable therapeutic strategy targeted specifically to the delayed progression of the lesion that occurs in the postischemic phase.（essay代写)

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