Mechanisms of non-steroid anti-inflammatory drugs action on ASICs expressed in hippocampal interneurons.
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 (IC(50) were 622 +/- 34 muM 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 muM 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.
Dorofeeva
Natalia A
NA
Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, St Petersburg, Russia.
Barygin
Oleg I
OI
Staruschenko
Alexander
A
Bolshakov
Konstantin V
KV
Magazanik
Lev G
LG
D062565:Acid Sensing Ion Channels; D000143:Acids / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004008:Diclofenac / Q000494:pharmacology; D004347:Drug Interactions / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007052:Ibuprofen / Q000494:pharmacology; D007395:Interneurons / Q000187:drug effects* / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009924:Organ Culture Techniques; D011522:Protons; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism
D062565:Acid Sensing Ion Channels; D000143:Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011522:Protons; D015222:Sodium Channels; D004008:Diclofenac; D007052:Ibuprofen