Vol. 62, Issue 3, 433-438, September 2002

ACCELERATED COMMUNICATION
Inhibition of Tetrodotoxin (TTX)-Resistant and TTX-Sensitive Neuronal Na⁺ Channels by the Secretolytic Ambroxol

Thomas Weiser and Nicola Wilson

Department CNS Research, Boehringer Ingelheim Pharma KG, Ingelheim, Germany (T.W., N.W.); and University of Manchester, Manchester, Great Britain (N.W.)

Ambroxol has a long history for the treatment of airway diseases because of its beneficial effects on surfactant synthesis and mucus-modifying properties. Some findings, however, point to an additional effect on neuronal signal transduction: ambroxol can suppress reflexes such as the cough or the corneal reflex. The airways and the cornea are innervated by C-fibers, which express voltage-gated Na⁺ channels with and without sensitivity to tetrodotoxin (TTX). In this study, we performed voltage-clamp experiments to investigate whether ambroxol affects these channel types. In rat dorsal root ganglia, TTX-resistant Na⁺ currents were suppressed in a concentration-dependent manner with IC₅₀ values of 35.2 and 22.5 µM for tonic and phasic block, respectively. Depolarizing prepulses increased the potency of ambroxol, and steady-state inhibition curves were shifted to more negative values. The inhibition was not frequency-dependent. TTX-sensitive currents were inhibited with lower potency (~50% inhibition with 100 µM). Recombinant rat brain IIA channels in Chinese hamster ovary cells were blocked with IC₅₀ values of 111.5 and 57.6 µM for tonic and phasic block, respectively; in contrast to TTX-resistant channels the block was frequency-dependent. Thus, ambroxol indeed blocks neuronal voltage-gated Na⁺ channels, and TTX-resistant channels in sensory neurons were more sensitive than TTX-sensitive. Compared with known local anesthetics (e.g., lidocaine or benzocaine), the potency for Na⁺ channel block was relatively high. A recent clinical trial has further confirmed that ambroxol relieved pain and was beneficial in patients who suffered from sore throat.