Neural Diseases: Inhibitors of p38 MAP Kinase as Potential Therapeutic Agents

Various cellular stressors, as well as inflammatory cytokines, activate mammalian p38 Mitogen-Activated Protein Kinases (MAPKs). Activation of the p38 MAPK pathway is a critical stage in the development of various disorders in the Central Nervous System (CNS), and the molecular processes mediated by p38 MAPK signaling have been identified. When this cascade is activated, pro-inflammatory cytokines are released, which have been linked to cerebral ischemia, Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Multiple Sclerosis (MS), neuropathic pain, and depression. In Alzheimer’s disease, activated p38 MAPK may cause hyperphosphorylation of tau, a brain microtubule-associated protein. Furthermore, we recently discovered that activating p38 MAPK signaling reduces dendritic spine quantity, which may be related to memory impairment following epileptic episodes. As a result, p38 MAPK can be used as a target for new medication development for neurological disorders. p38 MAPK inhibitors have been widely investigated in both preclinical and clinical studies for inflammatory disorders. In phase II clinical studies for neuropathic pain and depression, new p38 MAPK inhibitors are being explored. In this paper, we look at the present and potential future uses of p38 MAPK inhibitors as therapeutic agents in neurological disorders.