Mechanisms of non-steroid anti-inflammatory drugs action on acid-sensing ion channels of hippocampal interneurons

306 The inhibitiory action of non-steroid anti-inflammatory drugs (diclofenac, ibuprofen, aspirin and salicylic acid) was investigated on acid-sensing ion channels (ASIC) in isolated hippocampal interneurons and on recombinant homoand heteromeric ASICs expressed in CHO cells. Diclofenac and ibuprofen inhibited proton-induced currents in a range of concentrations from 100 μ M to 3 mM (IC 50 were 622 ± 34 μ M and 3.42 ± 0.50 mM respectively). The non-competitive inhibition was fast and fully reversible for both drugs. Aspirin and salicylic acid were ineffective up to 500 μ M. Diclofenac and ibuprofen decreased the amplitude of proton-evoked currents and slowed the rate of currents decay with a good correlation between these two effects ( r = 0.99, p < 0.05 for both drugs). Simultaneous application of acid solution (pH = 5.5) and diclofenac was required for its inhibitory action. Unlike amiloride, nonselective inhibitor of ENaC/Deg family of sodium channels, the action of diclofenac was voltage-independent. No competition was found between diclofenac and amiloride. Analysis of the action of diclofenac and ibuprofen on activation and desensitization of ASICs showed that diclofenac but not ibuprofen shifted the steady-state desensitization curve to more alkaline pH values. The reason for this shift was slowing down the recovery from desensitization of ASICs. Thus, diclofenac may serve as a neuroprotective agent during pathological conditions associated with acidification of extracellular environment.