The Aminoglycosides Modulate the Acid-Sensing Ionic Channel Currents in Dorsal Root Ganglion Neurons from the Rat

Abstract

Acid-sensing ionic channels (ASICs) have been shown to have a significant role in a growing number of physiological and pathological processes, such as nociception, synaptic transmission and plasticity, mechanosensation, and acidosis-induced neuronal injury. The discovery of pharmacological agents targeting ASICs has significant therapeutic potential and use as a research tool. In our work, we studied the action of transient perfusion (5-15 s) of aminoglycosides (AGs) (streptomycin and neomycin) on the proton-gated ionic currents in dorsal root ganglion (DRG) neurons of the rat and in human embryonic kidney (HEK)-293 cells. In DRG neurons, streptomycin and neomycin (30 M) produced a significant, concentration-dependent, and reversible reduction in the amplitude of the proton-gated current, and a slowing of the desensitization rate of the ASIC current. Gentamycin (30 M) also showed a significant reversible action on the ASIC currents. The curves of the pH effect for streptomycin and neomycin indicated that their effect was not significantly affected by pH. In HEK-293 cells, streptomycin (30 M) produced a significant reduction in the amplitude of the proton-gated current. Neomycin and gentamycin had no significant action. Reduction of extracellular Ca 2ϩ concentration produced a significant increase in the action of streptomycin and neomycin on the desensitization time course of ASIC currents. These results indicate that ASICs are molecular targets for AGs, which may contribute to the understanding of their actions on excitable cells. Moreover, AGs may constitute a source to develop novel molecules with a greater affinity, specificity, and selectivity for the different ASIC subunits.

Inhibition of Peripheral Nociceptors by Aminoglycosides Produces Analgesia in Inflammatory Pain Models in the Rat

“…Our results are in agreement with reports that document the blockade of ASICs and the reduction of phase II but not phase I pain-like behaviour in different animal models [4,18]. The AGs ST and NEO have a similar pharmacological effect to AMI in the formalin test and have a welldocumented inhibitory effect on ASICs [6]. Both of the AGs significantly reduced the phase II pain-like behaviour without affecting phase I.…”

“…In both cases, AGs significantly reduce the channel current in rat sensory neurons [5,6]. In rat DRG neurons, the highvoltage activation Ca 2+ and TTX-resistant Na + currents are inhibited by NEO at micromolar and millimolar concentrations.…”

ENaCs and ASICs as therapeutic targets

“…Acidinduced pain in humans was attenuated by treatment with amiloride (392), suggesting that inhibitors of ASICs, potentially including peptide toxins and aminoglycoside antibiotics (145), in addition to the more conventional amiloride and NSAID analogs (128), could play a role in the treatment of pain, while avoiding the behavioral issues associated with opiates (272). A more detailed account of the literature surrounding the role of ASICs in pain is provided in an excellent recent review (98).…”

Acid-Sensing Ion Channels in Neurodegenerative Diseases: Potential Therapeutic Target

“…Recently, Garza et al determined the effect of AGs on proton-gated ionic currents in DRG neurons of the rat, and in human embryonic kidney (HEK)-293 cells (Garza et al, 2010). In DRG neurons, streptomycin and neomycin produced a significant, reversible reduction in the amplitude of proton-gated currents in a concentration-dependent manner.…”