Mechanisms of non‐steroid anti‐inflammatory drugs action on ASICs expressed in hippocampal interneurons

Abstract

The inhibitory action of non‐steroid anti‐inflammatory drugs was investigated on acid‐sensing ionic channels (ASIC) in isolated hippocampal interneurons and on recombinant ASICs expressed in Chinese hamster ovary (CHO) cells. Diclofenac and ibuprofen inhibited proton‐induced currents in hippocampal interneurons (IC50 were 622 ± 34 μM and 3.42 ± 0.50 mM, respectively). This non‐competitive effect was fast and fully reversible for both drugs. Aspirin and salicylic acid at 500 μM were ineffective. Diclofenac and ibuprofen decreased the amplitude of proton‐evoked currents and slowed the rates of current decay with a good correlation between these effects. Simultaneous application of acid solution and diclofenac was required for its inhibitory effect. Unlike amiloride, the action of diclofenac was voltage‐independent and no competition between two drugs was found. 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.

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

“…Inflammation induces a large increase in ASIC mRNA levels in DRGs, which is prevented by administration of the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin, diclofenac, and ibuprofen at therapeutic doses (Voilley et al, 2001). In addition, ASIC currents are inhibited by NSAIDs with IC 50 values in the order of hundreds of micromolars to several millimolars (Voilley et al, 2001;Dorofeeva et al, 2008), thus with 100-to 1000-fold lower potency than the inhibition of cyclooxygenases by these drugs (Warner et al, 1999). It is therefore likely that the inhibition of ASIC expression, but not the experimentally observed inhibition of ASIC currents, may contribute to the clinical effects of NSAIDs.…”

Acid-Sensing Ion Channels Contribute to the Effect of Acidosis on the Function of Dendritic Cells

“…Previous studies demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) significantly inhibited ASIC currents in hippocampus and sensory neurons (30,31). To investigate the effect of NSAIDs on ASICs in iDCs, the responses of ASIC currents to NSAIDs (ibuprofen or diclofenac) were tested.…”

High doses of salicylate and aspirin are inhibitory on acid‐sensing ion channels and protective against acidosis‐induced neuronal injury in the rat cortical neuron

“…However, the study by Dorofeeva et al (2008) showed that 0.5 mM aspirin and salicylate has no significant effect on the ASIC current in cultured hippocampal neurons. In this study, we found that high doses of salicylate and aspirin exerted partial inhibition on ASICs in the cultured cerebral cortical neuron.…”

“…In this study, we found that high doses of salicylate and aspirin exerted partial inhibition on ASICs in the cultured cerebral cortical neuron. We address the difference as follows: 1) the concentration of salicylate and aspirin used in the study by Dorofeeva et al was 0.5 mM (Dorofeeva et al, 2008), whereas in this study the concentration that produced significant inhibition was above 1 mM; 2) the regions we examined in this study are the cortex, for which no reports have described the effects of salicylate and aspirin on ASICs to date. In addition to ASIC1a, ASIC2a, and ASIC2b, our recent study has indicated that ASIC3 is present in the cortex of the rat (Biagini et al, 2001;Alvarez de la Rosa et al, 2003;Meng et al, 2009).…”