Therapeutically relevant concentrations of neomycin selectively inhibit P-type Ca2+ channels in rat striatum

The effects of neomycin on voltage-activated Ca2+ channels (VACCs) were studied by Ca2+-dependent K+- and veratridine-evoked [H-3]dopamine release from rat striatal slices. Neomycin (0.01 - 1 mM) concentration dependently reduced K+-evoked [H-3]dopamine release (IC50 similar to 25 muM), producing similar to 98% inhibition at 1 mM. Contribution of N-, P- and Q-type Ca2+ channels to this neomycin-sensitive [H-3]dopamine release was tested by the combined application of 100 muM neomycin and selective Ca2+ channel blockers. The effects of neomycin combined with 1 muM of omega-conotoxin GVIA (N-type Ca2+ channels) or with 100 nM of omega-conotoxin MVIIC (Q-type Ca2+ channels) were additive, excluding involvement of N- and Q-type Ca2+ channels. However, the combined effects of neomycin with 30 nM of omega-agatoxin-IVA (P-type Ca2+ channels) were not additive, suggesting involvement of P-type Ca2+ channels in neomycin-induced inhibition of [H-3]dopamme release. On the other hand, veratridine-evoked [H-3]dopamine release was shown to be mediated by Q-type Ca2+ channels only. In addition, neither the inhibitor of sarcoplasmic reticulum Ca2 + -ATPase thapsigargin (500 nM) nor the blocker of sarcoplasmic reticulum ryanodine Ca2+ channels ryanodine (30 muM) modulate veratridine-evoked [H-3]dopamine release, suggesting no contribution of intracellular Ca2+ stores. Neomycin (up to 100 muM) did not affect veratridine-evoked [H-3]dopamine release, suggesting that intracellular Ca2+ stores are not a prerequisite for the action of neomycin. Lack of inhibitory effect of neomycin is taken as additional indirect evidence for the involvement of P-type Ca2+ channels. In conclusion, therapeutically relevant concentrations of neomycin preferentially block P-type Ca2+ channels which regulate dopamine release in rat striatum. This block could be responsible for aminoglycoside-induced toxicity. (C) 2003 Elsevier Science B.V. All rights reserved.