Pharmacologic intervention in axonal excitability: in vivo assessment of nodal p

[Guest guest]

Curr Mol Pharmacol. 2008 Jan;1(1):61-7.

Pharmacologic intervention in axonal excitability: in vivo assessment of nodal

persistent sodium currents in human neuropathies.

Kuwabara S, Misawa S.

Department of Neurology, Chiba University School of Medicine, Japan.

Axonal excitability testing can provide new insights into the ionic mechanisms

underlying the pathophysiology of hyperexcitability of motor and sensory axons

in human neuropathies. Threshold tracking was developed in the 1990's to

non-invasively measure a number of axonal excitability indices that depend on

sodium and potassium channel function, and this makes it possible to monitor the

effects of pharmacologic intervention with ion channel modulators. This paper

reviews recent advances in ionic-pathophysiological studies in humans.

(1) Neuropathic pain or muscle cramp/fasciculation is partly caused by

hyperexcitability of the injured axons. The enhanced excitability can result

from altered ion channel function; such as an increase in persistent sodium

currents. Persistent sodium currents can be reliably estimated using threshold

tracking. In peripheral neuropathy, persistent sodium currents usually increase

possibly due to over-expression of sodium channels associated with axonal

regeneration, and could be responsible for ectopic firings. Administration of

sodium channel blockers such as mexiletine, results in marked alleviation of

muscle cramping in parallel with a decrease in nodal persistent sodium currents.

(2) In diabetic neuropathy, the activation of the polyol pathway mediated by an

enzyme, aldose reductase, leads to reduced Na(+)/K(+) pump activity, and

intra-axonal sodium accumulation; sodium currents are reduced presumably due to

decreased trans-axonal sodium gradient. Aldose reductase inhibitiors improve

nodal sodium currents, as well as nerve conduction, and this can be objectively

assessed by threshold tracking. Studies of ion-channel pathophysiology in human

subjects have recently begun. Investigating ionic mechanisms by monitoring the

corresponding ionic currents is of clinical relevance, because once a specific

ionic conductance is identified, pharmacologic blocking or modulation could

provide a new therapeutic option.