Abstract
Objective: This research aimed to validate the therapeutic effect of losmapimod and explore the underlying mechanism in its treatment of epilepsy. Methods: A rat model of epilepsy was constructed with an injection of pilocarpine. Microarray analysis was performed to screen aberrantly expressed mRNAs and activated signaling pathways between epileptic rats and normal controls. A TdT-mediated dUTP nick-end labeling (TUNEL) assay was used to identify cell apoptosis. Hippocampal cytoarchitecture was visualized with Nissl staining. The secretion of inflammatory factors as well as the marker proteins in the mitogen-activated protein kinase (MAPK) pathway were detected by Western blot. A Morris water maze navigation test evaluated the rats’ cognitive functions. Results: Activation of the MAPK signaling pathway was observed in epilepsy rats. A decrease in the MAPK phosphorylation level by application of losmapimod protected against epilepsy by reducing neuron loss. Losmapimod effectively improved memory, reduced the frequency of seizures, protected the neuron from damage, and limited the apoptosis of neurons in epilepsy rats. Conclusion: The application of losmapimod could partly reverse the development of epilepsy.
Highlights
Epilepsy is a common neurological disorder, featuring an enduring predisposition to epileptic seizures due to hyperexcitability and hypersynchrony in brain neurons (Devinsky et al, 2013; Fisher et al, 2014) and affecting approximately 50 million people approximately worldwide, with a heavy burden brought on by individual complications, medical costs, related disability, and mortality (Moshe et al, 2015; Rana and Musto, 2018)
Mitogen-activated protein kinases (MAPKs) consist of a family of protein–serine/protein–threonine kinases followed by proline, prevalent in mammals (Pearson et al, 2001), which can be activated by tyrosine kinase activity upstream through signal transduction (Oldenhof et al, 2002)
The losmapimod-interacted proteins were predicted by STITCH, among which MAPK14, MAPK11, and CPB showed the strongest association with losmapimod (Figure 1C)
Summary
Epilepsy is a common neurological disorder, featuring an enduring predisposition to epileptic seizures due to hyperexcitability and hypersynchrony in brain neurons (Devinsky et al, 2013; Fisher et al, 2014) and affecting approximately 50 million people approximately worldwide, with a heavy burden brought on by individual complications, medical costs, related disability, and mortality (Moshe et al, 2015; Rana and Musto, 2018). As a pivotal biochemical cascade, the MAPK signaling pathway is involved in diverse fundamental events in cells and signal transduction pathways, namely, differentiation, proliferation, apoptosis, activation of other specific regulatory factors, acute responses to hormones, and developmental alteration of organisms (Pearson et al, 2001; Bandyopadhyay et al, 2010; Gorter et al, 2014) Abnormalities in this pathway are disastrous, inducing various carcinomas such as colorectal cancer as well as neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and motor neuron diseases (Corcoran et al, 2012; Gorter et al, 2014), making the MAPK pathway a target for drug development (Kim and Choi, 2010). Inhibition of p38 MAPK suppressed the elevation of high-sensitivity C-reactive protein (hsCRP) concentrations after percutaneous coronary intervention (PCI) (Sarov-Blat et al, 2010)
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