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

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.

Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat

“…The effects observed with nimesulide in the present study were not related to modification of physiological variables since these parameters did not differ between nimesulide-treated and vehicle-treated rats (data not shown). These findings are in agreement with our previous results [9], suggesting that nimesulide does not significantly change major physiological variables.…”

“…Additional doses were given at 6, 12, 24, 36 and 48 h after stroke. This treatment schedule and dosage range were based on the pharmacokinetic profile of nimesulide [71] and on our previous experience with this compound in a model of global cerebral ischemia [9,12]. We also performed an experiment in which nimesulide was given as a single dose.…”

“…Moreover, administration of highly selective COX-2 inhibitors has been proven to reduce brain damage and prostaglandin accumulation following cerebral ischemia [9][10][11][12]50,51]. The observations that enhanced COX-2 activity contributes to amplify cerebral injury after stroke offer an interesting prospect for targeting the late phase of the damage with COX-2 inhibitors.…”

“…This compound has been widely used for 20 years to treat inflammatory conditions and fever and readily crosses the blood-brain barrier [16,69]. This study was prompted by our previous results with this COX-2 inhibitor in transient global cerebral ischemia [9,12] and in a model of in vivo kainate-induced excitotoxicity [8]. The present study used a standardized model of middle cerebral artery occlusion (MCAO) induced by an intraluminal suture and several measures of nimesulide's efficacy were considered (infarct volume, neurological deficits, motor impairment using the rotarod test, and accumulation of PGE 2 in infarcted cerebral cortex).…”

Protective Effect of Calendula officinalis L. Flowers Against Monosodium Glutamate Induced Oxidative Stress and Excitotoxic Brain Damage in Rats

“…Several anti-inflammatory compounds are known to protect against hippocampal neuronal loss in different animal models [31]. Owing to the fact that COE has anti-inflammatory action, this mode of action may be drawn for the observed neuroprotective effect of the extract.…”