p38 MAP Kinase Inhibitors as Potential Therapeutic Drugs for Neural Diseases

Abstract

Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by various cellular stresses, as well as in response to inflammatory cytokines. In the central nervous systems (CNS), activation of the p38 MAPK pathway constitutes a key step in the development of several diseases, and the molecular mechanisms mediated by p38 MAPK signaling have been defined. Activation of this cascade releases pro-inflammatory cytokines that are known to be involved in cerebral ischemia, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), neuropathic pain and depression. In AD, stimulated p38 MAPK may trigger the hyperphosphorylation of a neural microtubule-associated protein, tau. In addition, we have recently revealed that activation of p38 MAPK signaling decreases dendritic spine number, which may be associated with memory impairment after epileptic seizures. Thus, p38 MAPK can serve as a target for novel drug development for neural diseases. p38 MAPK inhibitors have been studied extensively in both preclinical experiments and clinical trials for inflammatory diseases. New p38 MAPK inhibitors are now being tested in phase II clinical trials for neuropathic pain and depression. Here, we review current and possible future applications of p38 MAPK inhibitors as therapeutic agents in neural diseases.

Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma

“…57 As a result, p38 inhibitors have recently been claimed as novel and potential therapeutics for neurodegenerative diseases. 58,59 These findings suggest that inhibition of p38 may be therapeutically effective in protecting degenerating RGCs from various pathological conditions, including glaucoma.…”

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease

“…The means by which p38 α kinase have been theorized to impact AD disease progression broadly fall into three categories1, 2, 3, 4, 5: (1) as an anti‐inflammatory through reducing proinflammatory cytokine production from immune cells, (2) promoting amyloid plaque clearance through modulating microglial phenotype, and (3) reversing inflammation and/or amyloid‐beta induced synaptic dysfunction, particularly impaired synaptic plasticity in the hippocampus. The first mechanism (i.e., inhibition of proinflammatory cytokine production) is the classical drug effect of p38 α kinase inhibitors that formed the basis for evaluating this class of inhibitors for rheumatoid arthritis and other peripheral inflammatory disorders.…”

“…A broad range of preclinical studies indicates that the alpha isoform of p38 mitogen‐activated protein kinase (p38 α kinase) is a robust therapeutic target for Alzheimer's disease (AD) 1, 2, 3, 4, 5. Traditionally p38 α kinase is considered to be an inflammation‐related target as microglial p38 α promotes production of proinflammatory cytokines6 and modulates microglial activation state,7, 8 and in the healthy state p38 α expression within neurons is low 9.…”

CNI-1493 Attenuates Neuroinflammation and Dopaminergic Neurodegeneration in the Acute MPTP Mouse Model of Parkinson's Disease

“…Considering the wide range of pathophysiological states in which p38 MAPK is aberrantly activated, its signaling pathway is a candidate target for investigation of novel therapeutic strategies aimed at the amelioration of p38 activation in a variety of neural diseases [34]. …”