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Targeting calpain‐mediated proteolysis and peptide signaling as a strategy to reduce injury in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory and demyelinating disease (Stadelmann et al. 2011) that affects over 2.3 million people worldwide. The etiology of MS remains unknown but is thought to be the result of multiple genetic, environmental, and immunological factors (Ascherio and Munger 2007; Milo and Kahana 2010). The disease targets the CNS resulting in the loss of myelin and the formation of demyelinating plaques (Compston and Coles 2002). The loss of myelin within the plaque results in a decrease in synapse density and an increase in neuronal cell loss (Noseworthy et al. 2000). All of which, can have a profound effect on motor function and can induce deficits in learning, memory, and cognitive function (Noseworthy et al. 2000). Therefore, developing new orally available therapeutic strategies to reduce or slow the progression of demyelination in MS is of great importance to people who suffer from this disease. While the etiology of the disease remains unknown, demyelinating lesions based on plaque morphology, myelin protein expression, oligodendrocyte pathology, and the presence of complex deposition have provided valuable information regarding the pathology of the disease (Lucchinetti et al. 1996). Types I and II, based on the presence of T-cell and macrophage infiltration or Ig deposition and complement activation, respectively, suggests that the demyelination is secondary to an autoimmune reaction against the host’s myelin. Interestingly, plaque Types III and IV do not show hallmarks of immune system activation but rather are classified by mature oligodendrocyte cell death or oligodendrocyte degeneration. All of which suggests that MS pathology may be secondary to an autoimmune reaction or consist of a more complex sequelae of events that disrupts oligodendrocyte health and function (Kornek and Lassmann 2003). Despite the understanding of the pathological differences in MS, only a handful of FDA-approved drugs are available to treat people suffering from the disease. Available therapies focus on reducing CNS inflammation or involve the use of disease modifying agents that act to slow disease progression (Rice 1999; Menge et al. 2008) all of which treat the physical symptoms associated with the disease (Palumbo and Bosetti 2013). These include corticosteroids and nonsteroidal anti-inflammatory drugs used to reduce CNS inflammation and ease the severity of demyelinating attacks or the use of disease modifying drugs that work by suppressing or altering the body’s immune response. The later drug therapies are based on the premise that MS is in large part secondary to an autoimmune-mediated disorder. It is without argument both strategies have increased the quality of life for those who suffer from MS by reducing symptoms of the disease and disease severity. Trager et al. (2014) on the other hand, have adapted a strategy using an orally available inhibitor of calpain (SNJ-1945) in which they demonstrate the reduction of the development of clinical signs in a rodent model of MS, experimental autoimmune encephalomyelitis (EAE). In this manuscript, the authors show that the oral administration of SNJ-1945 inhibits both the consolidation of the peripheral immune response and reduces central gliosis and neuronal damage. Inhibiting cellular proteolysis and attenuating peptide signaling represents an interesting and novel approach to reduce injury progression in this model. Furthermore, targeting calpainmediated proteolysis and the subsequent downstream peptide signaling inhibited by this orally available compound may offer alternative therapies to help reduce plaque formation and disease severity in patients suffering from MS.