Abstract
Our lab has previously demonstrated that multiple sclerosis-induced spinal cord white matter damage and motor deficits are mediated by the pathological disruption of zinc homeostasis. Abnormal vesicular zinc release and intracellular zinc accumulation may mediate several steps in the pathophysiological processes of multiple sclerosis (MS), such as matrix metallopeptidase 9 (MMP-9) activation, blood-brain barrier (BBB) disruption, and subsequent immune cell infiltration from peripheral systems. Oral administration of a zinc chelator decreased BBB disruption, immune cell infiltration, and spinal white matter myelin destruction. Therefore, we hypothesized that zinc released into the extracellular space during MS progression is involved in destruction of the myelin sheath in spinal cord white mater and in generation of motor deficits. To confirm our previous study, we employed zinc transporter 3 (ZnT3) knockout mice to test whether vesicular zinc depletion shows protective effects on multiple sclerosis-induced white matter damage and motor deficits. ZnT3 gene deletion profoundly reduced the daily clinical score of experimental autoimmune encephalomyelitis (EAE) by suppression of inflammation and demyelination in the spinal cord. ZnT3 gene deletion also remarkably inhibited formation of multiple sclerosis-associated aberrant synaptic zinc patches, MMP-9 activation, and BBB disruption. These two studies strongly support our hypothesis that zinc release from presynaptic terminals may be involved in multiple sclerosis pathogenesis. Further studies will no doubt continue to add mechanistic detail to this process and with luck, clarify how these observations may lead to development of novel therapeutic approaches for the treatment of multiple sclerosis.
Highlights
Multiple sclerosis (MS) is characterized by numerous maladaptive or abnormal responses of the immune system, which result in the erroneous and progressive destruction of central nervous system (CNS) structures, including those of the brain and spinal cord
These results demonstrate that zinc transporter 3 (ZnT3) gene deletion inhibits the clinical features and neuropathological changes associated with EAE
The idea of zinc playing a significant role in MS pathogenesis may arise from its high concentration in the CNS and involvement in brain physiology
Summary
Multiple sclerosis (MS) is characterized by numerous maladaptive or abnormal responses of the immune system, which result in the erroneous and progressive destruction of central nervous system (CNS) structures, including those of the brain and spinal cord. MS is an autoimmune disease characterized by damage to the myelin sheath that entwines and insulates the naked nerve fibers, allowing efficient conduction of neural impulses This demyelinating process is initiated when T cells become sensitized to endogenous myelin proteins and begin to erroneously attack myelinated structures in the central and peripheral nervous system. Excretory products of Trichruis suis have been shown to reduce disease severity in experimental autoimmune encephalomyelitis (EAE), a well-known animal model for MS [10]. These findings hypothesize that immunomodulation by parasite infection is protective with respect to MS, but the precise mechanism in terms of how these organisms modulate the immune system is elusive. The typical susceptible rodent will debut with clinical symptoms in a prodromal period of 10–15 days after immunization, followed by ascending paralysis beginning in the tail and hind limbs with progress to the forelimbs, concurrent with weight loss
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