Voltage-Gated Potassium Channels in Multiple Sclerosis: Overview and New Implications for Treatment of Central Nervous System Inflammation and Degeneration

Article excerpt

Abstract--Inflammatory tissue damage and the presence of reactive immunocompetent T lymphocytes, macrophages, microglia, and dendritic cells (DCs) are characteristic features in the human chronic inflammatory demyelinating disease, multiple sclerosis (MS). Together, these cells orchestrate the inflammation and immunopathogenesis underlying the MS autoimmune disease processes and all up-regulate the same voltage-gated potassium ([K.sub.v]) channel, [K.sub.v]1.3, when fully activated. Only microglia, which mediate central nervous system (CNS) inflammatory processes (possibly playing a dual role of CNS protection and mediation of neuroinflammation/ neurodegeneration), and DC, which are pivotal to the induction of T cell responses, express the distinct [K.sub.v]1.5 prior to [K.sub.v]1.3 upregulation. Although the precise functional roles of first [K.sub.v]1.5 and then [K.sub.v]1.3 channels are unclear, their differential expression is likely a common mechanism used by both microglia and DC, revealing [K.sub.v]1.5 (in addition to [K.sub.v]1.3) as a potentially important target for the development of new immunomodulatory therapies in MS.

Key words: 3,4 diaminopyridine, 4-aminopyridine, bloodbrain barrier, central nervous system, dendritic cells, experimental allergic encephalomyelitis, multiple sclerosis, murine leukemia virus, voltage-gated potassium channels.

INTRODUCTION

Multiple sclerosis (MS) is a chronic and progressive neurodegenerative disease for which no cure exists. Considered a primary inflammatory disease of central nervous system (CNS) white matter, pathological lesions in MS are characterized by inflammatory demyelination with relative sparing of axons [1], perivascular/parenchymal infiltration of T lymphocytes (T cells) and macrophages [1-3], and proliferation and activation of resident microglia and astrocytes [4], as well as peripheral dendritic cells (DCs) [5]. In addition to inflammation and demyelination (white and gray matter), axonal damage and loss are now recognized as contributing to irreversible deficits in MS [6]. Clinical symptoms include blurred vision, unstable balance, poor coordination, tremors, numbness, and slurred speech, for which the underlying physiological impairment is believed to be conduction block arising from demyelination and inflammation.

Current approaches to treating MS patients include symptomatic treatment of neurological deficits and immunomodulatory therapy to treat neuroinflammation and possibly limit neurodegeneration. Voltage-gated potassium ([K.sub.v]) channels are potential targets for both types of therapies. As symptomatic therapies, only two relatively nonspecific blockers of [K.sub.v] channels, 4-aminopyridine (4-AP) and 3,4 diaminopyridine (3,4-DAP), have been tested clinically for their efficacy in the treatment of patients with MS [7-15]. To date, in vivo immunosuppressive treatments that use nonspecific (4-AP and quinidine) and various highly selective [K.sub.v] channel blockers (margatoxin, correolide, kaliotoxin, ShK, and Sh-Dap22) have been restricted to miniswine [16-17] and rodent experimental allergic encephalomyelitis (EAE) [18-20] animal models for MS.

The first study implicating a [K.sub.v] blocker (quinidine) as a successful therapeutic treatment in an inflammatory demyelinating disease was an animal model performed in rats with experimental allergic neuritis (EAN), an accepted animal model for the human Guillain-Barre syndrome that is the peripheral nervous system (PNS) counterpart of EAE in the CNS. Mix and colleagues demonstrated that injecting EAN rats with quinidine ameliorated symptoms of clinical EAN [21]. These neurological benefits were accompanied with reduced inflammatory infiltrates in target tissue but not improved peripheral nerve conduction, thus foreshadowing the emerging view that [K.sub.v] blockers may primarily exert their neurological benefits in MS through immunomodulatory effects.

TARGETING [K. …