Eeuroprotective effects of the selective COX-2 inhibitor--论文代写范文精选

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Abstract
Results from several studies indicate that cyclooxygenase-2 (COX-2) is involved ischemic brain injury. The purpose of this study was to evaluate the neuroprotective effects of the selective COX-2 inhibitor nimesulide on cerebral infarction and neurological deficits in a standardized model of transient focal cerebral ischemia in rats. Three doses of nimesulide (3, 6 and 12 mg/kg; i.p.) or vehicle were administered immediately after stroke and additional doses were given at 6, 12, 24, 36 and 48 h after ischemia. In other set of experiments, the effect of nimesulide was studied in a situation in which its first administration was delayed for 3 to 24 h after ischemia. Total, cortical and subcortical infarct volumes and functional outcome (assessed by neurological deficit score and rotarod performance) were determined 3 days after ischemia.

The effect of nimesulide on prostaglandin E2 (PGE2) levels in the injured brain was also investigated. Nimesulide dose-dependently reduced infarct volume and improved functional recovery when compared to vehicle. Of interest is the finding that neuroprotection conferred by nimesulide (reduction of infarct size and neurological deficits and improvement of rotarod performance) was also observed when treatment was delayed until 24 h after ischemia. Further, administration of nimesulide in a delayed treatment paradigm completely abolished PGE2 accumulation in the postischemic brain, suggesting that COX-2 inhibition is a promising therapeutic strategy for cerebral ischemia to target the late-occurring inflammatory events which amplify initial damage.

INTRODUCTION
Stroke is a leading cause of death and disability worldwide. Development of an effective therapeutic strategy for stroke has been a priority of neuroscientists for decades. Considerable research efforts have been devoted to the development of neuroprotective agents to save neurons from the biochemical and metabolic consequences of ischemic brain injury. Current approaches to treat acute ischemic stroke include thrombolytic therapy (reperfusion), neuroprotection, and administration of neurorestorative agents. Intravenous thrombolysis within 3 hours after symptoms onset represents the first therapeutical approach that can effectively treat acute ischemic stroke [70].

Although adequate treatment should be started as early as possible, most patients still arrive at the hospital too late to receive the maximum benefit from this emerging therapy [2]. Despite the recently published PROACT II clinical trial, which first demonstrated the efficacy of intra-arterial thrombolysis within 6 hours of stroke onset [28], until now, thrombolysis has not been approved for intravenous administration >3 hours after stroke onset because the risk of hemorrhage increases with time [2,28]. In search of an effective treatment of stroke, numerous studies have been conducted to understand the pathophysiological mechanisms that lead to neuronal death. Among the initial events in the ischemic cascade are the widespread neuronal depolarization and massive release of glutamate (excitotoxicity) leading to calcium influx.

Approaches focusing on blocking presynaptic glutamate release, ionotropic glutamate receptors, or voltage-sensitive calcium or sodium channels have so far failed to demonstrate a proven clinical efficacy [18,23,30]. Other therapeutic strategies for stroke include hypothermia [20,65,81], antioxidants [7,13,14,64], blockade of excessive synaptic Zn2+ release [75], antiapoptotic strategies [26,53], administration of growth factors [1,40], erythropoietin [67], recombinant human interleukin-1 receptor antagonist [47], statins [73], gene therapy [80,81] and approaches involving transfer of new cells, such as stem cells, and neuronal precursors cells [1,46,63]. Recent experimental evidences have shown that brain damage occurring after focal cerebral ischemia (FCI) develops over a relatively long period of time [34,51].

One of the processes that plays a pivotal role in the delayed progression of brain damage is postischemic inflammation [19,34,51]. Cerebral ischemia is followed by infiltration of neutrophils in the injured brain, an event initiated by the expression of proinflammatory cytokines, chemokines, and adhesion molecules (for review, see reference 19). In addition, the marked expression of inflammation-related enzymes such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) plays an important role in the secondary events that amplify cerebral damage after ischemia.

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 (No. 03/113). 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 in groups in a room whose environment was maintained at 21-25 ºC, 45-50 % humidity and 12-h light/dark cycle. They had free access to pellet chow and water.

DISCUSSION
Gone are the days when drugs that confer neuroprotection when given before or a short period after cerebral ischemia can be considered relevant for therapy of ischemic stroke. Several agents from this group have been evaluated clinically and failed.

COX-2 inhibition has emerged as a potential therapeutic strategy for cerebral ischemia, targeting critical late-occurring pathophysiological events which exacerbate the initial brain damage triggered by the ischemic episode. This study demonstrated that the COX-2 inhibitor nimesulide appreciably reduces cerebral infarction, PGE2 accumulation, and also improves functional outcome after transient MCAO in rats.

Interestingly, the effects of nimesulide on both histological and functional recovery were evident even when the first administration was delayed up to 24 h after stroke. Although a previous report demonstrated positive effects with a COX-2 selective inhibitor (NS-398) when given after FCI [51], results from the present study demonstrate for the first time the wide therapeutic window for nimesulide in a rat stroke model and more importantly demonstrated that nimesulide also markedly improved functional recovery. As previously suggested [40], pre-clinical studies directed toward demonstrating functional improvement of neurological function in addition to reduction of infarct size may improve the predictive value of animal models for clinical efficacy with novel neuroprotective agents.

Present results that nimesulide protects neurons when administered several hours after stroke is consistent with our previous studies which have found that COX-2 selective inhibitors have a wide therapeutic window for protection in global cerebral ischemia [9-12], thus extending our observations to a model of transient focal ischemic stroke. It is important to discuss the finding that nimesulide did not reduce damage to subcortical areas (mainly striatum) when administered in a delayed fashion and only slightly diminished infarct volume in striatum when given immediately after stroke at the highest dose (Table 2; Fig. 2).

The striatum is considered to be the core of the ischemic lesion, it lacks collateral circulation and has proved relatively refractory to neuroprotection [24]. In addition, results from a previous study [51] indicated that COX-2 protein expression is not upregulated in striatum after transient cerebral ischemia, suggesting that COX-2 seems not to be an important pathophysiological mediator of ischemic damage in this brain region. This probably helps to explain our present results. The mild positive effects seen with the highest dose of nimesulide (Table 2; Fig. 2) might be attributable to other pharmacological effects ohttp://www.51due.com/writing/essay/f this compound not related to COX-2 inhibition, although further studies are needed to support this notion. On the other hand, repeated treatments with nimesulide afforded a more remarkable neuroprotection than the administration of a single dose given immediately after ischemia (Tables 2 and 3).

These findings show the importance of a continuous long-term therapeutic regime after focal stroke in clinical trials to achieve the maximal beneficial effects of neuroprotection with nimesulide to target the delayed progression of tissue damage. According to our results, the lowest dose of nimesulide (3 mg/kg) reduced neurological deficits and motor impairment (Table 3 and Fig. 3) similarly to the highest dose of this COX-2 inhibitor (12 mg/kg), but these positive effects were not accompanied by a significant reduction in infarct volume (Table 2). This might reflect the fact that unlike ischemic injury to many other tissues, the severity of disability is not predicted well by the amount of brain tissue lost. For example, damage to a small area in the medial temporal lobe may lead to severe disability, while damage to a greater volume elsewhere had little effect on function [22]. The majority of studies directed toward determining neuroprotective efficacy have used reduction of infarct volume as a measure of a drug’s efficacy in animals subjected to focal ischemia. Although it is presumed that reduced lesion size will translate to improved functional outcome, a direct correlation is not always observed in animals models [32] or in stroke patients [68].（essay代写)

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