p38 MAP Kinase Inhibitors as Potential Therapeutic Drugs for Neural Diseases

S.      Yasuda; H.      Sugiura; H.      Tanaka; S.      Takigami; K.      Yamagata

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, Alzheimers disease (AD), Parkinsons 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.

Keywords: p38 MAP kinase inhibitor, synaptic plasticity, epilepsy, ischemia, cytokine, Alzheimer's disease, neuropathic pain, depression, p38 MAPK, neural disease, p38 MAPK inhibitor, SB203580, learning and memory impairment, IEG, dendritic spine, arcadlin, TAO kinase, Mek3, tau hyperphospohrylation, parkinson disease, MPP, major depressive disorder, Structure-Activity Relationships (SAR), multiple sclerosis, b-amyroid, microglia, cytoskeletal protein