Role of calpain in immunobiology of neurodegenerative diseases

Abstract

Calpain is a Ca2+-dependent protease that significantly contributes to the pathogenesis of demyelinative and neurodegenerative diseases and injuries of the central nervous system (CNS). Studies from our laboratory and other laboratories clearly indicate that calpain plays crucial roles in pro-inflammatory immune responses to perpetuate inflammation in multiple sclerosis (MS), which is a demy- elinative and neurodegenerative disease of the CNS, and experimental autoimmune encephalomyelitis (EAE), the animal model of MS. Calpain mediates its proinflammatory roles with activation of nuclear factor-kappa B (NF-kB), promotion of synthesis of cytokines and chemokines, maintenance of Th1/Th2 imbalances, and reactive astrogliosis and microgliosis in MS and EAE. Besides, calpain is known to take part in promoting activation of caspases for neurodegeneration in a wide range of diseases and injuries of the CNS. Recently, there is a great interest in developing water-soluble and cell-permeable small molecule inhibitors of calpain for treatment of MS and other neurodegenerative diseases. Although exciting results are being reported showing efficacy of experimental calpain inhibitors in preclinical models, these inhibitors have not yet been successfully used for treatment of MS and other neurodegenerative diseases in humans.