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Letters   |    
Voltage-Gated Sodium Channel Gating Modifiers: Valuable Targets for Multiple Sclerosis Treatment
Somayeh Mahdavi, M.Sc.; Shahriar Gharibzadeh, M.D., Ph.D.; Bijan Ranjbar; Mohammad Javan
The Journal of Neuropsychiatry and Clinical Neurosciences 2011;23:E17-E17.
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Department of Biophysics, Tarbiat Modares University, Tehran, Iran

Biomedical Engineering, Amirkabir University of Technology, Somayyeh, Hafez, Tehran

Department of Biophysics, Tarbiat Modares University, Tehran

Department of Physiology, Tarbiat Modares University, Tehran

To the Editor: Most symptoms of multiple sclerosis, such as paresis, ataxia, and hypoesthesia, are derived from conduction block at the demyelinated portion of nerve fibers.1 Conduction block is generated because of an initial lack of sodium channels in the newly exposed axolemma. The axolemma under the normal myelin sheet has a relatively low voltage-gated sodium channel density, which may be insufficient for action-potential propagation.2 Demyelination decreases the safety factor of action-potential propagation for at least two different reasons: 1) the electrical capacity of the demyelinated membranes increases and, consequently, more current is needed for a constant potential change; and 2) the local potential may be insufficient to depolarize the subsequent node because of leakage across the neuron. In the normal axon, the safety factor for saltatory conduction is 3 to 5. In the demyelinated axon, the safety factor is typically reduced to near 1. This is a critical level; small improvement in the safety factor may cause a successful conduction and, conversely, a small decrease will result in conduction block.

Enhancement of the sodium current or facilitation of action-potential propagation can retrieve the leakage of sodium current in the demyelinated region. We propose voltage-gated sodium channel (VGSC) gating modifiers as a novel strategy for multiple sclerosis symptom treatment.

Since different VGSC toxins are available, we can change the VGSC function in an arbitrary way. Some well-recognized VGSC modifiers can shift the voltage dependence of the activation gate to more hyperpolarized potentials and inhibit the channel inactivation gate. On the other hand, some VGSCs stabilize the open state of the channel. For example, Alpha-scorpion toxin, sea anemone toxins, and some spider toxins postpone sodium channel inactivation. Experimental data show that the effect of these toxins facilitates the stimulation of VGSC and can increase the flow of sodium during each action potential.3,4

The most important point in using these toxins is that they target specific molecules. They are able to find and interact with their own target, usually at low concentrations. This property is very useful for drug candidates because of the reduction of side effects. There are different types of VGSCs in different neurons. This helps us to target specific channels in relevant neurons using special drugs.

Because of disease complexity and heterogeneity, multiple sclerosis pathogenesis remains unknown, and, despite extensive research efforts, specific and effective treatments have not yet been developed. Efforts for finding suitable effective treatments are being made. We suggest paying attention to VGSCs gating modifiers as a novel and potent strategy for reducing the symptoms of multiple sclerosis disease. Surely, it is necessary to carry out drug design studies in order to find more efficient biocompatible compounds and to do animal studies before using these drugs in humans.

Kesselring  J;  Beer  S:  Symptomatic therapy and neurorehabilitation in multiple sclerosis.  Lancet Neurol 2005; 4:643–652
[PubMed]
[CrossRef]
 
Smith  KJ;  McDonald  WI:  The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease.  Philos Trans R Soc Lond B Biol Sci 1999; 354:1649–1673
[PubMed]
[CrossRef]
 
Blumenthal  KM;  Seibert  AL:  Voltage-gated sodium channel toxins: poisons, probes, and future promise.  Cell Biochem Biophys 2003; 38:215–238
[PubMed]
[CrossRef]
 
Cestèle  S;  Catterall  WA:  Molecular mechanisms of neurotoxin action on voltage-gated sodium channels.  Biochimie 2000; 82(9–10):883–892
[PubMed]
[CrossRef]
 
References Container
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References

Kesselring  J;  Beer  S:  Symptomatic therapy and neurorehabilitation in multiple sclerosis.  Lancet Neurol 2005; 4:643–652
[PubMed]
[CrossRef]
 
Smith  KJ;  McDonald  WI:  The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease.  Philos Trans R Soc Lond B Biol Sci 1999; 354:1649–1673
[PubMed]
[CrossRef]
 
Blumenthal  KM;  Seibert  AL:  Voltage-gated sodium channel toxins: poisons, probes, and future promise.  Cell Biochem Biophys 2003; 38:215–238
[PubMed]
[CrossRef]
 
Cestèle  S;  Catterall  WA:  Molecular mechanisms of neurotoxin action on voltage-gated sodium channels.  Biochimie 2000; 82(9–10):883–892
[PubMed]
[CrossRef]
 
References Container
+
+

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