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A Dual Inhibitor of Cyclooxygenase and 5-Lipoxygenase Protects Against Kainic Acid-Induced Brain Injury

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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.

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Acknowledgments

This study was granted by a departmental funding.

Conflict of interest

The authors declare that they have no conflict of interest.

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All applicable international, national and/or institutional guidelines for the care and use of animals were followed.

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    Authors and Affiliations

    1. Department of Clinical and Experimental Medicine, University of Messina, Torre Biologica, 5th Floor, AOU Policlinico “G. Martino”, Via C. Valeria Gazzi, 98125, Messina, Italy

      Letteria Minutoli, Herbert Marini, Mariagrazia Rinaldi, Alessandra Bitto, Natasha Irrera, Gabriele Pizzino, Giovanni Pallio, Vincenzo Trichilo, Monica Interdonato, Federica Galfo & Francesco Squadrito

    2. Department of Veterinary Sciences, University of Messina, Messina, Italy

      Margherita Calò

    3. Department of Experimental, Specialized Medical and Surgical and Odontostomatological Sciences, University of Messina, Messina, Italy

      Elena Bianca Adamo

    4. Department of Paediatric, Gynaecological, Microbiological and Biomedical Sciences, University of Messina, Messina, Italy

      Domenica Altavilla

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    1. Letteria Minutoli
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    2. Herbert Marini
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    Correspondence to Francesco Squadrito.

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    Letteria Minutoli and Herbert Marini have equally contributed to this paper.

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    Minutoli, L., Marini, H., Rinaldi, M. et al. A Dual Inhibitor of Cyclooxygenase and 5-Lipoxygenase Protects Against Kainic Acid-Induced Brain Injury. Neuromol Med 17, 192–201 (2015). https://doi.org/10.1007/s12017-015-8351-0

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    • DOI: https://doi.org/10.1007/s12017-015-8351-0

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