Effects of the cyclooxygenase-2 inhibitor nimesulide on cerebral infarction and neurological deficits induced by permanent middle cerebral artery occlusion in the rat

Journal of Neuroinflammation BioMed Central Research Open Access Effects of the cyclooxygenase-2 inhibitor nimesulide on cerebral infarction and neurological deficits induced by permanent middle cerebral artery occlusion in the rat Eduardo Candelario-Jalil*1,2, Noël H Mhadu1, Armando González-Falcón1, Michel García-Cabrera1, Eduardo Muñoz3, Olga Sonia León1 and Bernd L Fiebich2,4 Address: 1Department of Pharmacology, University of Havana (CIEB-IFAL), Havana 10600, Cuba, 2Neurochemistry Research Group, Department of Psychiatry, University of Freiburg Medical School, Hauptstrasse 5, D-79104 Freiburg, Germany, 3Departamento de Biología Celular, Fisiología e Inmunología. Universidad de Córdoba, Avda Menéndez Pidal s/n. 14004, Córdoba, Spain and 4VivaCell Biotechnology GmbH, FerdinandPorsche-Str. 5, D-79211 Denzlingen, Germany Email: Eduardo Candelario-Jalil* - ; Noël H Mhadu - ; Armando GonzálezFalcón - ; Michel García-Cabrera - ; Eduardo Muñoz - ; Olga Sonia León - ; Bernd L Fiebich - * Corresponding author Published: 18 January 2005 Journal of Neuroinflammation 2005, 2:3 doi:10.1186/1742-2094-2-3 Received: 17 December 2004 Accepted: 18 January 2005 This article is available from: http://www.jneuroinflammation.com/content/2/1/3 © 2005 Candelario-Jalil et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Previous studies suggest that the cyclooxygenase-2 (COX-2) inhibitor nimesulide has a remarkable protective effect against different types of brain injury including ischemia. Since there are no reports on the effects of nimesulide on permanent ischemic stroke and because most cases of human stroke are caused by permanent occlusion of cerebral arteries, the present study was conducted to assess the neuroprotective efficacy of nimesulide on the cerebral infarction and neurological deficits induced by permanent middle cerebral artery occlusion (pMCAO) in the rat. Methods: Ischemia was induced by permanent occlusion of the middle cerebral artery in rats, via surgical insertion of a nylon filament into the internal carotid artery. Infarct volumes (cortical, subcortical and total) and functional recovery, assessed by neurological score evaluation and rotarod performance test, were performed 24 h after pMCAO. In initial experiments, different doses of nimesulide (3, 6 and 12 mg/kg; i.p) or vehicle were administered 30 min before pMCAO and again at 6, 12 and 18 h after stroke. In later experiments we investigated the therapeutic time window of protection of nimesulide by delaying its first administration 0.5–4 h after the ischemic insult. Results: Repeated treatments with nimesulide dose-dependently reduced cortical, subcortical and total infarct volumes as well as the neurological deficits and motor impairment resulting from permanent ischemic stroke, but only the administration of the highest dose (12 mg/kg) was able to significantly (P < 0.01) diminish infarct volume. The lower doses failed to significantly reduce infarction but showed a beneficial effect on neurological function. Nimesulide (12 mg/kg) not only reduced infarct volume but also enhanced functional recovery when the first treatment was given up to 2 h after stroke. Conclusions: These data show that nimesulide protects against permanent focal cerebral ischemia, even with a 2 h posttreatment delay. These findings have important implications for the therapeutic potential of using COX-2 inhibitors in the treatment of stroke. Page 1 of 11 (page number not for citation purposes) Journal of Neuroinflammation 2005, 2:3 Background The brain is highly sensitive to disturbance of its blood supply. Stroke is a devastating disease and is the third most common cause of death, and the most common cause of motor and mental disability in adults, in developing countries [1]. Complex pathophysiological events occur in brain during ischemic processes, and these are considered responsible for cell damage leading to neuronal death (for review see [2,3]). However, it is now generally accepted that the mammalian brain may be more resistant to ischemia than previously thought. This raises the possibility of therapeutic intervention before brain damage has become irreversible. http://www.jneuroinflammation.com/content/2/1/3 stroke induced by the transient (1 h) occlusion of the middle cerebral artery [12]. Since most cases of human ischemic stroke are caused by permanent occlusion of cerebral arteries [23-26], the present study was conducted to assess whether nimesulide would also show neuroprotective efficacy on the cerebral infarction induced by permanent middle cerebral artery occlusion (pMCAO) in the rat, a clinically relevant model of ischemic stroke. The effects of the COX-2 inhibitor nimesulide had not been previously investigated in a model of permanent ischemic stroke. Methods A number of interacting and sequentially evoked events tend to reinforce the initial ischemic insult. A key role in these processes is played by post-ischemic inflammation. The Ca2+-related activation of intracellular second messenger systems, the increase in reactive oxygen species formation, as well as hypoxia itself triggers the expression of a large number of pro-inflammatory genes following cerebral ischemia. Thus, mediators of inflammation such as platelet-activating factor (PAF), tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), chemokines (IL-8, monocyte chemoattractant protein-1) and other pro-inflammatory factors are produced by the ischemic brain tissue [3]. In addition, the expression of adhesion molecules with the subsequent infiltration of polymorphonuclear leukocytes occurs following ischemic stroke. Results from several studies also suggest that the marked and sustained 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 injury after ischemia [4-12]. Nimesulide (N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide) is a non-steroidal anti-inflammatory drug with potent effects. It shows a high affinity and selectivity for COX-2 with a COX-2/COX-1 IC50 selectivity ratio of 0.06 (whole blood assay) [13]. Nimesulide readily crosses the intact blood-brain barrier in both humans and rodents [13,14]. Several recent studies have demonstrated a marked neuroprotective effect of nimesulide on chronic cerebral hypoperfusion [15], kainate-induced excitotoxicity [16], quisqualic acid-induced neurodegeneration [17], diffuse traumatic brain injury [18,19], glutamate-mediated apoptotic damage [20] and induction of the expression of the B subunit of endogenous complement component C1q (C1qB) in transgenic mice with neuronal overexpressi (...truncated)