title: A dual inhibitor of cyclooxygenase and 5-lipoxygenase protects against kainic acid-induced brain injury.
abstract: Systemic administration of kainic acid causes inflammation and apoptosis in the brain, resulting in neuronal loss. Dual cyclooxygenase/5-lipoxygenase (COX/5-LOX) inhibitors could represent a possible neuroprotective approach in preventing glutamate excitotoxicity. Consequently, we investigated the effects of a dual inhibitor of COX/5-LOX following intraperitoneal administration of kainic acid (KA, 10 mg/kg) in rats. Animals were randomized to receive either the dual inhibitor of COX/5-LOX (flavocoxid, 20 mg/kg i.p.) or its vehicle (1 ml/kg i.p.) 30 min after KA administration. Sham brain injury rats were used as controls. We evaluated protein expression of phosphorylated extracellular signal-regulated kinase (p-ERK1/2) and tumor necrosis factor alpha (TNF-α) as well as levels of malondialdehyde (MDA), prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the hippocampus. Animals were also observed for monitoring behavioral changes according to Racine Scale. Finally, histological analysis and brain edema evaluation were carried out. Treatment with the dual inhibitor of COX/5-LOX decreased protein expression of p-ERK1/2 and TNF-α in hippocampus, markedly reduced MDA, LTB4 and PGE2 hippocampal levels, and also ameliorated brain edema. Histological analysis showed a reduction in cell damage in rats treated with the dual inhibitor of COX/5-LOX, particularly in hippocampal subregion CA3c. Moreover, flavocoxid significantly improved behavioral signs following kainic acid administration. Our results suggest that dual inhibition of COX/5-LOX by flavocoxid has neuroprotective effects during kainic acid-induced excitotoxicity.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Torre Biologica, 5th Floor, AOU Policlinico "G. Martino", Via C. Valeria Gazzi, 98125, Messina, Italy.
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.forename: Herbert
authors.initials: H
authors.lastname: Marini
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Rinaldi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Natasha
authors.initials: N
authors.lastname: Irrera
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pizzino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pallio
authors.forename: Margherita
authors.initials: M
authors.lastname: Calò
authors.forename: Elena Bianca
authors.initials: EB
authors.lastname: Adamo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Trichilo
authors.forename: Monica
authors.initials: M
authors.lastname: Interdonato
authors.forename: Federica
authors.initials: F
authors.lastname: Galfo
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001929:Brain Edema / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D002392:Catechin / Q000494:pharmacology / Q000627:therapeutic use*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015232:Dinoprostone / Q000032:analysis; D004338:Drug Combinations; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity; D007975:Leukotriene B4 / Q000032:analysis; D015227:Lipid Peroxidation / Q000187:drug effects; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009498:Neurotoxins / Q000633:toxicity; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016861:Cyclooxygenase Inhibitors; D004338:Drug Combinations; D016859:Lipoxygenase Inhibitors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D014409:Tumor Necrosis Factor-alpha; C544478:flavocoxid; D007975:Leukotriene B4; D008315:Malondialdehyde; D002392:Catechin; D015232:Dinoprostone; D007608:Kainic Acid