Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia
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, Kirino, 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-1β), are strongly expressed in the ischemic brain Ohtsuki et al., 1996, Koistinaho and Hokfelt, 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, Nagayama et al., 1998a, Nakayama et al., 1998b.
Nimesulide (N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide) is a nonsteroidal 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).
In 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.
Section snippets
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
Effects of different doses of nimesulide on CA1 hippocampal injury (Experiment 1)
Seven days after the ischemic episode, widespread damage to the CA1 region of the hippocampus was evident in the brains of the vehicle-treated group. Pyramidal neurons either presented a densely stained shrunken appearance with minimal cytoplasm or, in many instances, had disappeared. Some of these animals displayed a nearly total necrosis or loss of the CA1 pyramidal cells.
Delayed neuronal death in CA1 hippocampal sector was significantly reduced (P<0.01) by administration of nimesulide at the
Discussion
The core finding of the present study is that administration of clinically relevant doses of nimesulide is remarkably neuroprotective in gerbils against transient cerebral ischemia. There is no previous report on the protective effects of this cyclooxygenase-2 inhibitor in brain ischemia. Nimesulide rescued CA1 pyramidal neurons from ischemic death even when treatment was delayed until 24 h after ischemia. Of special interest is the finding that the protection is still observed 30 days after
References (51)
- et al.
Nimesulide decreases superoxide production by inhibiting phosphodiesterase type IV
Eur. J. Pharmacol.
(1994) - et al.
Nimesulide limits kainate-induced oxidative damage in the rat hippocampus
Eur. J. Pharmacol.
(2000) - et al.
Time course of oxidative damage in different brain regions following transient cerebral ischemia in gerbils
Neurosci. Res.
(2001) - et al.
The highly selective cyclooxygenase-2 inhibitor DFU is neuroprotective when given several hours after transient cerebral ischemia in gerbils
Brain Res.
(2002) - et al.
Neuroprotective effect of aminoguanidine on transient focal ischaemia in the rat brain
Brain Res.
(2001) - et al.
Effect of propentofylline (HWA 285) on focal ischemia in rats: effect of treatment and posttreatment duration on infarct size
J. Neurol. Sci.
(2000) Bright and dark sides of nitric oxide in ischemic brain injury
Trends Neurosci.
(1997)- et al.
Neutrophil inhibitory factor treatment of focal cerebral ischemia in the rat
Brain Res.
(1998) Delayed neuronal death in the gerbil hippocampus following ischemia
Brain Res.
(1982)- et al.
Long term cerebroprotective effects of dexanabinol in a model of focal cerebral ischemia
Brain Res.
(2001)
Protective effects of the green tea polyphenol (−)-epigallocatechin gallate against hippocampal neuronal damage after transient global ischemia in gerbils
Neurosci. Lett.
Induction of cyclooxygenase-2 mRNA in gerbil hippocampal neurons after transient forebrain ischemia
Brain Res.
Induction of cyclooxygenase-2 mRNA and protein following transient focal ischemia in the rat brain
Neurosci. Lett.
Differential cellular distribution and dynamics of HSP70, cyclooxygenase-2, and c-Fos in the rat brain after transient focal ischemia or kainic acid
Neuroscience
Cycloheximide reduces infarct volume when administered up to 6 h after mild focal ischemia in rats
Brain Res.
Inhibition of brain cyclooxygenase-2 activity and the antipyretic action of nimesulide
Eur. J. Pharmacol.
Nimesulide prevents lipopolysaccharide-induced elevation in plasma tumor necrosis factor-alpha in rats
Life Sci.
Inflammatory mediators and stroke: new opportunities for novel therapeutics
J. Cereb. Blood Flow Metab.
Activation of cyclo-oxygenase-2 contributes to motor and cognitive dysfunction following diffuse traumatic brain injury in rats
Clin. Exp. Pharmacol. Physiol.
Continuing postischemic neuronal death in CA1: influence of ischemia duration and cytoprotective doses of NBQX and SNX-111 in rats
Stroke
Temperature modulation (hypothermic and hyperthermic conditions) and its influence on histological and behavioral outcomes following cerebral ischemia
Brain Pathol.
Selective cyclooxygenase-2 inhibition by nimesulide in man
J. Pharmacol. Exp. Ther.
Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia
Brain Pathol.
Neuronal expression of cyclooxygenase-2 increases stroke damage
Soc. Neurosci. Abstr.
Antioxidant activity of nimesulide and its main metabolites
Drugs
Cited by (45)
Time dependent dual effect of anti-inflammatory treatments on sarin-induced brain inflammation: Suggested role of prostaglandins
2019, NeuroToxicologyCitation Excerpt :In our study the most effective anti-inflammatory treatment was the COX-2 inhibitor nimesulide which significantly reduced all of the inflammatory markers both at 8 h and at 24 h post sarin. This is in accord with reports of the beneficial effect of COX-2 inhibitors in other models of brain injury (Candelario-Jalil et al., 2002, 2003; Candelario-Jalil, 2008; Polascheck et al., 2010). Further evaluation of various doses, time and duration of administration following exposure may reveal its beneficial effects on histopathology markers as well.
Effects of selective and non-selective cyclooxygenase inhibition against neurological deficit and brain oedema following closed head injury in mice
2013, Brain ResearchCitation Excerpt :In other models of brain injury, the role of COX-2 is also controversial. Although selective inhibition of COX-2 with NS-398 had no influence on infarct volume (Hara et al., 1998), a beneficial effect was induced by nimesulide, another COX-2 inhibitor, after ischaemic stroke in gerbils (Candelario-Jalil et al., 2002) and rats (Candelario-Jalil et al., 2007a, 2005, 2004). The post-ischaemic lesion volume was also significantly reduced in COX-2-deficient mice (Iadecola et al., 2001).
Anesthetics, Cerebral Protection and Preconditioning
2013, Revista Brasileira de AnestesiologiaCytoprotective effect of nonsteroidal antiinflammatory drugs in rat brain slices subjected to reoxygenation after oxygen-glucose deprivation
2012, European Journal of Pharmaceutical SciencesCitation Excerpt :Some NSAIDs have been tested in models of ischemia–reperfusion in vivo. Although it is difficult to compare the results obtained in vivo with the findings of the present study, a neuroprotective effect has been reported for acetylsalicylic acid (Zheng et al., 2007), piroxicam (Soliman et al., 2009), ketoprofen (Silva et al., 2007), ibuprofen (Park et al., 2005), flurbiprofen (Mishra et al., 2010), nimesulide (Candelario-Jalil et al., 2002, 2005, 2008) and mefenamic acid (Khansari and Halliwell, 2009). Comparisons of the results of experimental studies of stroke with those of human clinical studies can be problematic.
C-Phycocyanin is neuroprotective against global cerebral ischemia/reperfusion injury in gerbils
2011, Brain Research BulletinCitation Excerpt :The powerful anti-lipoperoxidative capacity of C-PC30% could be explained by its cyclooxygenase-2 inhibitory property [89], together with its ability to efficiently scavenge peroxyl, alcoxyl and hydroxyl radicals [15,93]. In this sense, it has been reported that selective cyclooxygenase-2 inhibitors are neuroprotective in different experimental models of ischemic stroke [22–24]. The PP and FRAP, indicators of total antioxidant capacity [47], were both up-regulated in the I/R vehicle-treated group.