Abstract
Multiple sclerosis (MS), the most common chronic autoimmune inflammatory disease of the central nervous system (CNS), is characterized by demyelination and neurodegeneration. In particular, neurodegeneration is a major factor in disease progression with neuronal death and irreversible axonal damage leading to disability. MS is manageable with current therapies that are directed towards immunomodulation but there are no available therapies for neuroprotection. The complex pathophysiology and heterogeneity of MS indicate that therapeutic agents should be directed to both the inflammatory and neurodegenerative arms of the disease. Activity of the Ca 2+ activated protease calpain has been previously implicated in progression of MS and its primary animal model, experimental autoimmune encephalomyelitis (EAE). The effects of calpain inhibitors in EAE involve downregulation of Th1/Th17 inflammatory responses and promotion of regulatory T cells, overall leading to decreased inflammatory cell infiltration in CNS tissues. Furthermore, analysis of brains, spinal cords and optic nerves from EAE animals revealed decreases in axon degeneration, motor neuron and retinal ganglion cell death. This resulted in improved severity of paralysis and preservation of visual function. Taken together, the studies presented in this brief review suggest that use of calpain inhibitors in combination with an immunomodulatory agent may be a potential therapeutic strategy for MS and optic neuritis.
Highlights
Epidemiology of Multiple sclerosis (MS)Multiple Sclerosis (MS) is an autoimmune inflammatory and neurodegenerative disease of the central nervous system (CNS) that is the leading cause of neurologic disability in young adulthood, and there is no cure for the disease [1]
There is increasing evidence that the central nervous system (CNS) is continuously surveyed by virus-specific T cells, which protect against reactivating neurotropic viruses
An increased activation of ubiquitous calpain has been associated with processes integral to demyelination and neurodegeneration [31,39,40]
Summary
Multiple Sclerosis (MS) is an autoimmune inflammatory and neurodegenerative disease of the central nervous system (CNS) that is the leading cause of neurologic disability in young adulthood, and there is no cure for the disease [1]. The worldwide disease burden of MS is upwards of 2.5 million individuals, with an incidence of approximately 7 new cases per 100,000 people per year and a lifetime risk of 1 in 400. As many as 26% of MS patients live without impaired mobility in their lifetime, but a minority (15%) become rapidly disabled [2,3]. The reduction in life expectancy due to MS is small, so most patients live at least 25 years after diagnosis, and the majority experience increasing neurologic disability for the duration of their lives. Therapies need to be developed that are directed towards this aspect of the disease, especially since damage to axons and neurons appears to predict long term disability in MS [4,6,7,8]
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