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A Single Dose of Pirfenidone Attenuates Neuronal Loss and Reduces Lipid Peroxidation after Kainic Acid-Induced Excitotoxicity in the Pubescent Rat Hippocampus

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Abstract

Systemic administration of kainic acid (KA) in rodents triggers limbic seizures following selective neuronal loss in the hippocampus attributed to the excitotoxic process. Lipid peroxidation products, such as 4-hydroxynonenal, are produced by oxidative stress and are present on the hippocampus, which contribute to neuronal death in the KA excitotoxicity model. Several antioxidants are neuroprotective agents. The aim of the present study was to analyse whether pirfenidone (PFD, 5-methyl-1-phenyl-2-(1H)-pyridone), an antioxidant drug, protects the neurons in the hippocampus of pubescent rats administered with KA. We evaluated the neuroprotective effect of PFD by quantifying the surviving neurons under hematoxilin-eosin staining after using three different doses of 100, 250, and 325 mg/kg administered via an orogastric tube 90 min after KA intraperitoneal injection (12 mg/kg). Only 325 mg/kg of PFD-attenuated neuronal loss in the hippocampal areas cornu ammonis field 1 (CA1) and cornu ammonis field 3 (CA3c) was observed; therefore, this dose was used in our subsequent studies. Later, we established that PFD reduces neuronal degeneration using Fluoro-Jade B stain in the CA3c but not in the CA1, and PFD reduces the presence of 4-hydroxynonenal, a lipid peroxidation product, in the CA3 by tissue immunohistochemistry. We concluded that only a single 325 mg/kg PFD dose had a neuroprotective effect after KA brain injury. This treatment may be advantageous because adequate pharmacological therapy with PFD can be developed to protect the neuron even after an acute neuronal disorder such as seizures or hypoxic/ischemic damage.

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Abbreviations

4-HNE:

4-Hydroxynonenal

KA:

Kainic Acid

PFD:

Pirfenidone

CA1:

Cornu Ammonis Field 1

CA3:

Cornu Ammonis Field 3

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Acknowledgments

The present work was supported by grants from Consejo Nacional de la Ciencia y Tecnología (CONACYT No. 0177594 to Carlos Beas-Zárate and No. 298337 to Rubén Darío Castro-Torres).

Conflict of Interest

The authors have declared that no conflict of interest exists.

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Authors and Affiliations

  1. Laboratorio de Neurobiología Celular y Molecular, Centro de Investigación Biomédica de Occidente (CIBO), Guadalajara, Jalisco, 44421, Mexico

    Rubén Darío Castro-Torres, Verónica Chaparro-Huerta, Mario Eduardo Flores-Soto & Carlos Beas-Zárate

  2. Lab. Neuromorfología, Depto. de Medicina Veterinaria, CUCBA, Universidad de Guadalajara, Guadalajara, Mexico

    Jacinto Bañuelos-Pineda

  3. Unitat de Farcalogia i Farmacognosia, Facultat de Farmacia, Centros de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Instituto de Biomedicina (IBUB), Universitat de Barcelona, Nuclei Universtari de Pedralbes, 08028, Barcelona, Spain

    Antoni Camins

  4. Unidad de Investigación Médica en Enfermedades Neurológicas, Centro Médico Nacional “XXII” IMSS, México DF, Mexico, Mexico

    Sandra A. Orozco-Suárez

  5. Instituto de Biología Molecular en Medicina y Terapia Génica, CUCS, Departamento de Biología Molecular y Genómica, CUCS, Universidad de Guadalajara, Guadalajara, Mexico

    Juan Armendáriz-Borunda

  6. INNOVARE, Guadalajara, Jalisco, Mexico

    Juan Armendáriz-Borunda

  7. Carlos Beas Zárate, Departamento de Biología Celular y Molecular, CUCBA, Universidad de Guadalajara, Km. 15.5 Carr GDL-Nogales, Nextipac, Zapopan, Jalisco, 45110, Mexico

    Carlos Beas-Zárate

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  1. Rubén Darío Castro-Torres
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  2. Verónica Chaparro-Huerta
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  3. Mario Eduardo Flores-Soto
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  8. Carlos Beas-Zárate
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Correspondence to Carlos Beas-Zárate.

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Castro-Torres, R.D., Chaparro-Huerta, V., Flores-Soto, M.E. et al. A Single Dose of Pirfenidone Attenuates Neuronal Loss and Reduces Lipid Peroxidation after Kainic Acid-Induced Excitotoxicity in the Pubescent Rat Hippocampus. J Mol Neurosci 52, 193–201 (2014). https://doi.org/10.1007/s12031-013-0121-6

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  • DOI: https://doi.org/10.1007/s12031-013-0121-6

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