Understanding Abnormal c-JNK/p38MAPK Signaling in Amyotrophic Lateral Sclerosis: Potential Drug Targets and Influences on Neurological Disorders

Abstract

: c-JNK (c-Jun N-terminal kinase) and p38 mitogen-activated protein kinase (MAPK) family members work in a cell-specific manner to incorporate neuronal signals that cause glutamate excitotoxicity, impaired protein homeostasis, defective axonal transport, and synaptic dysfunctions. Consistent with the importance of these cellular events in the up-regulation of c-JNK/p38MAPK signaling is associated with neurodegenerative diseases in various clinical and pre-clinical studies. Exceptionally, a large number of experimental evidence has recently shown that c-JNK/p38MAPK has also been involved in the development of the central nervous system in a variety of neuropathological conditions, including amyotrophic lateral sclerosis (ALS). Overall, the currently available information has shown that c-JNK/p38MAPK signaling inhibitors can be a promising therapeutic solution for modifying histopathological, functional, and demyelination defects associated with motor neuron disabilities. Understanding the correlation between c-JNK/p38MAPK signaling and prediction of motor neuron degradation can help identify significant therapeutic measures that may avoid neuro complications. Therefore, in the current study, we explore the manifestations of disease utilizing the c-JNK/p38MAPK upregulation that could potentially cause ALS and other neurodegenerative diseases, as well as providing data on pre-clinical trials, accessible and successful drug treatment, and disease management strategies.

Immunomodulatory activities and biomedical applications of melittin and its recent advances

“…The initiation of this pathway followed by the activation of microglia cells and onset of the MAPK signaling cascade results in inflammation of the neurons. [ 114 ] p38 kinase activity is firmly linked to motor neuron degeneration in animal models of ALS. The results have shown that MLT can effectively reduce the phosphorylation of p38.…”

5Z‐7‐Oxozaenol attenuates cuprizone‐induced demyelination in mice through microglia polarization regulation

“…Overactivation of JNK/p38 signaling has been observed in demyelination and neuroinflammation (Singh et al, 2021). Downregulation of c-JNK/p38MAPK can promote oligodendrocyte regeneration and prevent mitochondrial dysfunction, microglia survival, and neurotransmitter recovery (Yadav et al, 2021b). Activation of p65 in astrocytes and microglia appears to favor demyelination, while its inhibition supports remyelination (Blank & Prinz, 2014).…”

Editorial: Protein kinase inhibitors in neurodegeneration and cancer targeted therapies

“…Protein kinases are the modulators of various signaling cascades and govern major functions of cellular homeostasis. Kinase overexpression is associated with various human diseases ( Borgo et al, 2021 ; Lee and Paull, 2021 ), including cancers and neurodegenerative disorders ( Yadav et al, 2021 ). Recent findings have unravelled kinases as therapeutic markers and urged the development of potent and selective inhibitors against kinases.…”