Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Avda Diagonal 641, E-08028, Barcelona, Spain.
Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156, Oeiras, Portugal.
Mol Neurobiol. 2018 May;55(5):4437-4452. doi: 10.1007/s12035-017-0669-1. Epub 2017 Jun 29.
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.
c-Jun-N 末端激酶（JNK）通路的激活与神经退行性疾病中的发病机制和神经元死亡有很大关系。总的来说，这证明了 JNK 成为新治疗策略筛选的焦点是有道理的。本研究的目的是确定不同 JNK 同工型（JNK1、JNK2 和 JNK3）在脑损伤诱导后的细胞凋亡和炎症中的作用。为了达到这个目的，我们通过腹腔内注射红藻氨酸（一种谷氨酸 - 红藻氨酸受体激动剂）诱导野生型和 JNK 敲除小鼠（jnk1 、jnk2 和 jnk3 ）产生兴奋性毒性，从而诱导癫痫发作。每组动物分为两种处理方式：腹腔内单次注射生理盐水作为对照，腹腔内单次注射 30mg/kg 的红藻氨酸。我们的结果报告说，在红藻氨酸处理后，jnk1 和 jnk3 小鼠的海马神经元变性明显减少，与 WT 处理的小鼠相比，几种凋亡基因的表达减少或不变。此外，jnk1 和 jnk3 小鼠的神经胶质反应也减少，表现为炎症基因表达降低和 JNK 磷酸化减少。此外，jnk3 小鼠的 c-Jun 磷酸化也减少。综上所述，这些发现提供了令人信服的证据，证明 JNK1 或 JNK3 同工型的缺失对 KA 诱导的神经元损伤具有神经保护作用，并首次证明了 JNK1 在兴奋性毒性中的作用。因此，JNK1 和/或 JNK3 是预防癫痫发生过程中细胞死亡和炎症的有前途的靶点。
