Targeting Stress Activated Protein Kinases, JNK and p38, as New Therapeutic Approach for Neurodegenerative Diseases

Caterina      Bendotti; Massimo      Tortarolo; Tiziana      Borsello

doi:10.2174/187152406777441880

Abstract

Signal transduction pathways involving the activation of c-Jun N-terminal kinases (JNK) and p38 mitogenactivated protein kinase (p38MAPK), also called stress-activated protein kinases, have been implicated in many cellular processes such as proliferation, differentiation and death of a variety of cell populations. Growing evidence indicates that these pathways can strongly contribute to the neuronal death associated to neurodegenerative diseases such as Alzheimers, Parkinsons, amyotrophic lateral sclerosis and cerebral ischemia . These kinases can be activated by a variety of toxic stimuli such as oxidative stress, excitotoxicity, inflammatory cytokines through different signalling cascades. Once activated these kinase cascades may induce alterations in the cellular function through transcriptional activity, alterations of cytoskeletal proteins and production and release of inflammatory molecules, all factors highly implicated in the neurodegenerative processes. Thus considerable effort is being addressed to the manipulation of these signal transduction pathways as a potential strategy for therapeutic interventions in neurodegenerative disorders. In this review we will examine the role of JNK and p38MAPK in neurodegeneration and we will illustrate the progresses in the development of inhibitors targeting these stress activated protein kinase pathways as therapeutic approach to neurodegenerative disorders.

Keywords: Stress activated protein kinases, c-Jun N terminal kinase (JNK), p38 mitogen activated protein kinase (p38MAPK), neurodegeneration, Stroke, Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease(PD)