Vinpocetine Is a Potent Blocker of Rat Na_V1.8 Tetrodotoxin-Resistant Sodium Channels

Abstract

Vinpocetine is a clinically used synthetic vincamine derivative with a diverse pharmacological profile that includes action at several ion channels, principally "generic" populations of sodium channels that give rise to tetrodotoxin-sensitive conductances. A number of cell types are known to express tetrodotoxin-resistant (TTXr) sodium conductances, the molecular bases of which have remained elusive until recently. One such TTXr channel, termed Na V 1.8, is of particular interest because of its prominent and selective expression in peripheral afferent nerves. The effects of vinpocetine on TTXr channels specifically, are unknown. We have assessed the effects of the drug on cloned rat Na V 1.8 channels expressed in a dorsal root ganglion-derived cell line, ND7/23. Vinpocetine produced a concentration-and state-dependent inhibition of Na V 1.8 sodium channel activity. Voltage-clamp experiments revealed an ϳ3-fold increase in vinpocetine potency when whole-cell Na V 1.8 conductances were elicited from relatively depolarized potentials (Ϫ35 mV; IC 50 ϭ 3.5 M) compared with hyperpolarized holding potentials (Ϫ90 mV; IC 50 ϭ 10.4 M). Vinpocetine also produced an ϳ22 mV leftward shift in the voltage dependence of Na V 1.8 channel inactivation but did not affect the voltage range of channel activation. These properties are reminiscent of several other known sodium channel blockers and suggested that vinpocetine may exhibit frequency-dependent block. Accordingly, tonic block of Na V 1.8 channels by vinpocetine (3 M) increased proportionally with increasing depolarizing commands over the frequency range 0.1 to 1Hz. In summary, the present data demonstrate that vinpocetine is capable of blocking Na V 1.8 sodium channel activity and suggest a potential additional utility in various sensory abnormalities arising from abnormal peripheral nerve activity. Vinpocetine (Fig.

Fibroblast Growth Factor Homologous Factor 2B: Association with Nav1.6 and Selective Colocalization at Nodes of Ranvier of Dorsal Root Axons

“…The ND7/23 cell line produces a TTX-S, but not a TTX-resistant (TTX-R), current (Zhou et al, 2003;John et al, 2004). The lack of a TTX-R current is consistent with the absence of TTX-R channel transcripts from these cells (data not shown).…”

“…The lack of a TTX-R current is consistent with the absence of TTX-R channel transcripts from these cells (data not shown). However, the ND7/23 cell line has been used successfully to express recombinant, TTX-R Na v 1.8 channels (Zhou et al, 2003;John et al, 2004). The human embryonic kidney 293 (HEK 293) cell line was used for coimmunoprecipitation experiments of FHF2B and Na v 1.6 because it produces very low levels of endogenous sodium channels.…”

Restoration of Neuronal Plasticity by a Phosphodiesterase Type 1 Inhibitor in a Model of Fetal Alcohol Exposure

“…In addition to PDE1 inhibition, VINP treatment may also affect voltagedependent sodium channels (Molnar and Erdo, 1995). However, recent findings suggest that VINP affects more potently a subset of sodium channels resistant to tetrodotoxin (Zhou et al, 2003). Nevertheless, if VINP substantially affects sodium channel function in the neocortex, one may expect a reduction of cortical activity.…”

Altered Ion Channels in an Animal Model of Charcot-Marie-Tooth Disease Type IA

“…TTX treatment, however, failed to provide evidence for a role of Nav1.8 in AP regeneration. In addition, vinpocetine, which blocks Nav1.8 channels without any known effects on the other Nav subunits (Zhou et al, 2003), did not have much effect on Trembler-J nerves (100 M; data not shown). Thus, whether Nav1.8 functions at Trembler-J nodes remains to be proven.…”