Neuroprotective Effects of the Absence of JNK1 or JNK3 Isoforms on Kainic Acid-Induced Temporal Lobe Epilepsy-Like Symptoms
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The activation of c-Jun-N-terminal kinases (JNK) pathway has been largely associated with the pathogenesis and the neuronal death that occur in neurodegenerative diseases. Altogether, this justifies why JNKs have become a focus of screens for new therapeutic strategies. The aim of the present study was to identify the role of the different JNK isoforms (JNK1, JNK2, and JNK3) in apoptosis and inflammation after induction of brain damage. To address this aim, we induced excitotoxicity in wild-type and JNK knockout mice (jnk1 −/− , jnk2 −/− , and jnk3 −/− ) via an intraperitoneal injection of kainic acid, an agonist of glutamic-kainate-receptors, that induce status epilepticus.
Each group of animals was divided into two treatments: a single intraperitoneal dose of saline solution, used as a control, and a single intraperitoneal dose (30 mg/kg) of kainic acid. Our results reported a significant decrease in neuronal degeneration in the hippocampus of jnk1 −/− and jnk3 −/− mice after kainic acid treatment, together with reduced or unaltered expression of several apoptotic genes compared to WT treated mice. In addition, both jnk1 −/− and jnk3 −/− mice exhibited a reduction in glial reactivity, as shown by the lower expression of inflammatory genes and a reduction of JNK phosphorylation. In addition, in jnk3 −/− mice, the c-Jun phosphorylation was also diminished.
Collectively, these findings provide compelling evidence that the absence of JNK1 or JNK3 isoforms confers neuroprotection against neuronal damage induced by KA and evidence, for the first time, the implication of JNK1 in excitotoxicity. Accordingly, JNK1 and/or JNK3 are promising targets for the prevention of cell death and inflammation during epileptogenesis.
Keywordsc-Jun N-terminal kinase Excitotoxicity Hippocampus Inflammation Kainic acid Knockout mice Neurodegeneration Neuroprotection
We thank Richard A. Flavell, Ph.D, a Howard Hughes Medical Institute (“HHMI”) Investigator at Yale University School of Medicine, Department of Immunobiology, for providing knockout mice.
This research was supported by the following:
• Ministerio Español de Ciéncia y Innovación (PI2016/01)
• Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) CB06/05/0024
• Consejo Nacional de Ciencia y Tecnología (CONACYT). Project No. 177594 (CBZ)
• Postdoctoral Fellowship CONACYT. No. 298337 and Doctoral Program in Sciences in Molecular Biology in Medicine, LGAC Molecular Bases of Chronic Diseases-Degenerative and its Applications (000091, PNPC, CONACYT)
• Research team from UB and URV belongs to 2014SGR-525 from Generalitat de Catalunya
CA and EV designed the experiments. CA wrote the manuscript. LL, FJ, and EV performed the kainic acid treatment and sample preparation. LL and FJ performed RNA extraction, quantitative real-time PCR, and western blots. FJ and JO performed Fluoro-Jade staining. LL, FJ, RD, and EV performed immunochemistry and immunofluorescence experiments. JF, AC, and CB assisted with the development of experimental procedures, data processing, and statistical analyses. All authors read and approved the final manuscript.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
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