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

• Published in: European journal of pharmacology Vol. 453; no. 2-3; pp. 189 - 195
• Main Authors: Candelario-Jalil, Eduardo, Álvarez, Dalia, González-Falcón, Armando, Garcı́a-Cabrera, Michel, Martı́nez-Sánchez, Gregorio, Merino, Nelson, Giuliani, Attilia, León, Olga Sonia
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 25.10.2002; Elsevier
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Death - drug effects; Cerebral ischemia; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Cyclooxygenase Inhibitors - therapeutic use; Delayed neuronal death; Dose-Response Relationship, Drug; Gerbillinae; Gerbils; Hippocampal CA1 sector; Hippocampus - drug effects; Hippocampus - pathology; Ischemic Attack, Transient - drug therapy; Ischemic Attack, Transient - pathology; Ischemic Attack, Transient - physiopathology; Isoenzymes - antagonists & inhibitors; Male; Medical sciences; Neurodegeneration; Neurons - drug effects; Neurons - pathology; Neuropharmacology; Neuroprotection; Neuroprotective agent; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Nimesulide; Pharmacology. Drug treatments; Prosencephalon - blood supply; Prostaglandin-Endoperoxide Synthases; Pyramidal Cells - drug effects; Pyramidal Cells - pathology; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Time Factors; Neuroprotection; Cerebral ischemia; Neurodegeneration; Hippocampal CA1 sector; Delayed neuronal death; Gerbils; Nimesulide; Prostaglandin-endoperoxide synthase; Intraperitoneal administration; Isozyme; Central nervous system; Cardiovascular disease; Vascular disease; Ischemia; Mechanism of action; Cerebrovascular disease; Nervous system diseases; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Neuroprotective agent; Cerebral disorder; Non steroidal antiinflammatory agent; Vertebrata; Mammalia; Neuron; Cell death; Animal; Central nervous system disease; Oxidoreductases; Antiïschemic; Gerbil; Hippocampus; Brain (vertebrata)
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(02)02422-6

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 min 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.