Neuroprotective Effects of the Absence of JNK1 or JNK3 Isoforms on Kainic Acid-Induced Temporal Lobe Epilepsy-Like Symptoms

Abstract

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.

JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

“…Instead, JNK3 is mainly involved in neurodegenerative processes like Alzheimer’s disease (AD) [ 27 , 28 ], Parkinson’s disease (PD) [ 29 ], cerebral ischemia [ 30 ] and other CNS disorders [ 31 , 32 ].…”

“…Different studies have also proved that JNK3 is associated with kainic acid (KA)-induced temporal lobe epilepsy; in fact, JNK3 knockout mice show decreased neuronal degeneration after KA injection [ 32 ], and pharmacological blockage of JNK3 has a neuroprotective effect against the neurotoxicity induced by KA [ 111 ], pointing to JNK3 as a key mediator of cell death during epileptogenesis.…”

Sex differences in gene expression with galactosylceramide treatment in Cln3Δex7/8 mice

“…Also, the ErbB signaling pathway and the Mapk8 gene itself were significantly modulated by exogenous GalCer (S3 Table). The c-Jun N-terminal kinases (JNKs), a subfamily of MAP kinases (MAPK), are central signal transducers in the mammalian brain, mostly associated with pathogenesis and neuronal death in neurodegenerative diseases [44]. De Lemos et al…”

Role of c-Jun N-Terminal Kinases (JNKs) in Epilepsy and Metabolic Cognitive Impairment

“…Specifically, combining TLE preclinical models with isoform-specific JNK KOs has revealed that the absence of JNK1 and JNK3 renders neuroprotection in mice [11,[70][71][72][73][74]. Furthermore, it has been demonstrated that the absence of these isoforms also reduces the occurrence and severity of seizures, glial reactivity, and the expression of proinflammatory genes [66,71]. Finally, our research group has recently demonstrated that it also prevents the alteration of subpopulations of neurogenic cells after KA insults [72].…”

“…For instance, whole body absence of JNK1 in KO models increases sensitivity to insulin and reduces body weight, even when animals are chronically exposed to a high-fat diet (HFD) [9,17,109,110]. Furthermore, these animals show reduced oxidative damage and inflammatory responses, as well as lower anxiety levels and increased neurogenesis [71,72,111]. Importantly, when conditional KO for JNK1 were produced in neurons, these animals showed even higher insulin sensitivity, as well as protection against the damage associated with chronic HFD feeding [112,113].…”