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Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia

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Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia
  Published in FINAL edited form as: EUROPEAN JOURNAL OF PHARMACOLOGY 453(2-3): 189-95 (2002) Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia  Authors: Eduardo Candelario-Jalil a, *, Dalia Álvarez a , Armando González-Falcón a , Michel García-Cabrera a , Gregorio Martínez-Sánchez a  , Nelson Merino a , Attilia Giuliani b  , Olga Sonia León a   Affiliation: a  Department of Pharmacology, University of Havana (CIEB-IFAL), Apartado Postal 6079, Havana City 10600, Cuba. b Department of Chemistry and Medical Biochemistry, University of Milan, Italy. *Author to whom all correspondence should be addressed: Eduardo Candelario-Jalil, M.Sc. Department of Pharmacology University of Havana (CIEB-IFAL) Apartado Postal 6079 Havana City 10600 CUBA Tel.: +53-7-271-9536 Fax: +53-7-336-811 E-mail:   Candelario-Jalil et al., 2002 Eur. J. Pharmacol. 453(2-3):189-95 (2002)   2 ABSTRACT Cyclooxygenase-2 is involved in the inflammatory component of the ischemic cascade, playing an important role in the delayed progression of the brain damage. The present study evaluated the  pharmacological effects of the selective cyclooxygenase-2 inhibitor nimesulide on delayed neuronal death of hippocampal CA1 neurons following transient global cerebral ischemia in gerbils. Administration of therapeutically relevant doses of nimesulide (3, 6 and 12 mg/kg; i.p.) 30 minutes  before ischemia and at 6, 12, 24, 48 and 72 h after ischemia significantly (P<0.01) reduced hippocampal neuronal damage. Treatment with a single dose of nimesulide given 30 min before ischemia also resulted in a significant increase in the number of healthy neurons in the hippocampal CA1 sector 7 days after ischemia. Of interest is the finding that nimesulide rescued CA1 pyramidal neurons from ischemic death even when treatment was delayed until 24 h after ischemia (34 ±  9 % protection). Neuroprotective effect of nimesulide is still evident 30 days after the ischemic episode, providing the first experimental evidence that cyclooxygenase-2 inhibitors confer a long lasting neuroprotection. Oral administration of nimesulide was also able to significantly reduce brain damage, suggesting that protective effects are independent of the route of administration. The present study confirms the ability of cyclooxygenase-2 inhibitors to reduce brain damage induced by cerebral ischemia and indicates that nimesulide can  provide protection when administered for up to 24 h post-ischemia. Keywords: nimesulide; cerebral ischemia; delayed neuronal death; hippocampal CA1 sector; neuroprotection; gerbils; neurodegeneration  Candelario-Jalil et al., 2002 Eur. J. Pharmacol. 453(2-3):189-95 (2002)   3 1. INTRODUCTION Transient global cerebral ischemia is produced when the brain is deprived temporarily of oxygen and glucose. In humans after cardiac arrest with resuscitation or cardiopulmonary bypass surgery, cerebral ischemia can lead to problems with cognition and memory, to serious neurological problems such as sensorimotor deficits and seizures, and to death (Levy et al., 1985; Petito et al., 1987). In humans and in animals subjected to transient forebrain ischemia, specific neurons degenerate following the ischemic episode (Kirino, 1982, 2000; Pulsinelli et al., 1982; Petito et al., 1987). The cornu Ammonis 1 (CA1) neurons of the hippocampus are widely regarded as among the most vulnerable in the mammalian brain to ischemia (Pulsinelli et al., 1982; Kirino, 1982). Delayed hippocampal damage is observed 3 to 7 days after the insult in CA1 pyramidal neurons (Kirino, 1982), suggesting that mechanisms that develop slowly after ischemia have an important role in ischemic neuronal demise. Several lines of recent evidences have shown that several pro-inflammatory genes or mediators, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 and cytokines (e.g., tumor necrosis factor α  and interleukin-1 β ) are strongly expressed in the ischemic brain (Ohtsuki et al., 1996; Koistinaho and Hökfelt, 1997; Barone and Feuerstein, 1999). Inflammation is now recognized as a significant contributing mechanism in cerebral ischemia because anti-inflammatory compounds or inhibitors of iNOS and cyclooxygenase-2 have been proven to reduce ischemic brain damage (Nogawa et al., 1997; Iadecola, 1997; Nakayama et al., 1998).  Nimesulide (N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide) is a non-steroidal anti-inflammatory drug with potent effects, showing a high affinity and selectivity for cyclooxygenase-2 (Rabasseda, 1996; Cullen et al., 1998), but other mechanisms have been proposed to explain its mode of action: 1) inhibition of tumor necrosis factor α  production (Azab et al., 1998), 2) antioxidant properties (Facino et al., 1993), 3) inhibition of the production of platelet activating factor (Tool and Verhoeven, 1995) and 4) reduction of the release of superoxide anions and other toxic substances from neutrophils (Bevilacqua et al., 1994). Nimesulide readily crosses the intact blood-brain barrier in both humans and rodents (Taniguchi et al., 1997; Cullen et al., 1998) . Recently, several studies have demonstrated a marked neuroprotective effect of nimesulide on chronic cerebral hypoperfusion (Wakita et al., 1999), kainate-induced excitotoxicity (Candelario-Jalil et al., 2000) and quisqualic acid-induced neurodegeneration in rats (Scali et al., 2000).  Candelario-Jalil et al., 2002 Eur. J. Pharmacol. 453(2-3):189-95 (2002)   4In the light of these evidences, the present study was undertaken to investigate the effects of clinically relevant doses of nimesulide on the delayed neuronal death of CA1 pyramidal cells in the gerbil hippocampus following global ischemia. To our knowledge, there is no previous study on the effects of nimesulide against neuronal damage after focal or global cerebral ischemia. 2. MATERIALS AND METHODS 2.1. Animals and surgical procedures Studies were performed in accordance with the Declaration of Helsinki and with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by National Institutes of Health (Bethesda, MD, USA). Our institutional animal care and use committee approved the experimental protocol (No. 01/98). A total of 111 male Mongolian gerbils (  Meriones unguiculatus ) weighing 60-75 g at the time of surgery were used in this study. These animals were housed four per cage, exposed to a 12-h light: 12-h dark cycle, and had free access to food and water throughout the study period. The gerbils were anesthetized with chloral hydrate (300 mg/kg, i.p.) and subjected to transient forebrain ischemia exactly as in our previous reports (Candelario-Jalil et al., 2001, 2002; Martínez et al., 2001). Briefly, in the supine position, a midline ventral incision was made in the neck. Both common carotid arteries were exposed, separated carefully from the vagus nerve, and occluded for 5 minutes with microaneurysmal clips (Sugita, Japan), which consistently resulted in delayed neuronal death in the CA1 region of the hippocampus (Kirino, 1982; Candelario-Jalil et al., 2002). Blood flow during the occlusion and reperfusion after removal of the clips was visually confirmed and the incision was closed with 4-0 silk sutures. In sham-operated animals, the arteries were freed from connective tissue but were not occluded. The onset of cerebral ischemia was associated with a brief period of panting breathing and body movements followed by quiescence. Successful occlusion of both common carotid arteries was evident with the rapid onset of complete bilateral ptosis and the adoption of a ‘hunched’ posture. Only animals showing this behavior were considered in this study (Martí et al., 2001; Martínez et al., 2001). The rectal temperature was carefully monitored and maintained at 37 ±  0.5 ° C using an incandescent lamp and the animals were allowed to recover on an electrical heated blanket. In addition, rectal temperature was monitored at 6-h intervals for 3 days of reperfusion in all experimental groups. 2.2. Experimental protocols 2.2.1. Experiment 1: Dose-response study of nimesulide treatment  Candelario-Jalil et al., 2002 Eur. J. Pharmacol. 453(2-3):189-95 (2002)   5This experiment was undertaken to investigate the effects of different doses of nimesulide on neuronal damage after ischemia. Since nimesulide is usually administered to patients at a dosage between 3 and 6 mg/kg for the treatment of inflammatory conditions (Rabasseda, 1996; Cullen et al., 1998), the following experimental groups were prepared: a sham-operated group (n=5), an ischemic group treated with the vehicle of nimesulide (polyvinylpyrrolidone, n=7) and three groups of ischemic gerbils treated with nimesulide at doses of 3 (n=6), 6 (n=8) and 12 mg/kg (n=7) given intraperitoneally. Nimesulide or vehicle was administered 30 minutes before ischemia and again at 6, 12, 24, 48 and 72 h of reperfusion. This treatment schedule was based on our previous experience with another cyclooxygenase-2 inhibitor (Candelario-Jalil et al., 2002). In addition, we reasoned that if cyclooxygenase-2 is one of a select few  proteins that still remains upregulated in CA1 neurons even at 3 days after global ischemia (Nakayama et al., 1998; Koistinaho et al., 1999), the nimesulide treatment should be maintained for several days after the ischemic episode. We also performed an experiment in which nimesulide was given as a single dose. 2.2.2. Experiment 2: Effects of a single dose of nimesulide The effect of a single dose of nimesulide (6 mg/kg; i.p.) given 30 minutes before the onset of ischemia was examined (n=7). The dose of nimesulide used in this experiment was based on results obtained from Experiment 1 (see Fig. 1). A single injection vehicle-treated group was also included (n=7). 2.2.3. Experiment 3: Time window for nimesulide treatment in gerbils subjected to transient forebrain ischemia In this experiment, the effect of nimesulide was studied in a situation in which its first administration was delayed for 6 to 24 h after ischemia. Nimesulide (6 mg/kg; i.p.) was dosed 6 (n=9), 12 (n=9) and 24 h (n=7) after the induction of ischemia, followed by additional doses at 24, 48 and 72 h of reperfusion. 2.2.4. Experiment 4: Analysis of duration of the neuroprotective action of nimesulide This experiment was undertaken to examine whether the protective effect of nimesulide was transitory or long lasting. Nimesulide (6 mg/kg; i.p.) was administered as in Experiment 1, but gerbils were sacrificed 30 days after the onset of blood flow (n=7). A vehicle-treated ischemic control group was also included (n=7).
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