a-317567 and Disease-Models--Animal

Acid sensing ion channels (ASICs) are proton-gated ion channels located in the central and peripheral nervous systems. Of particular interest is ASIC1a, which is located in areas associated with fear and anxiety behaviors. Recent reports suggest a role for ASIC1a in preclinical models of fear conditioning and anxiety.. The present experiments evaluated various ASIC inhibitors in preclinical models of autonomic and behavioral parameters of anxiety. In addition, neurochemical studies evaluated the effects of an ASIC inhibitor (A-317567) on neurotransmitter levels in the amygdala.. In electrophysiological studies using hippocampal primary neuronal cultures, three ASIC inhibitors (PcTX-1, A-317567, and amiloride) produced concentration-dependent inhibition of acid-evoked currents. In the stress-induced hyperthermia model, acute administration of psalmotoxin 1 (PcTX-1; 10-56 ng, i.c.v.), A-317567 (0.1-1.0 mg/kg, i.p.), and amiloride (10-100 mg/kg, i.p.) prevented stress-induced elevations in core body temperature. In the four-plate test, acute treatment with PcTX-1 (10-56 ng, i.c.v.) and A-317567 (0.01-0.1 mg/kg, i.p.), but not amiloride (3-100 mg/kg, i.p.), produced dose-dependent and significant increases in the number of punished crossings relative to vehicle-treated animals. Additionally, PcTX-1 (56-178 ng, i.c.v.), A-317567 (0.1-10 mg/kg, i.p.), and amiloride (10-100 mg/kg, i.p.) lacked significant anxiolytic-like activity in the elevated zero maze. In neurochemical studies, an infusion of A-317567 (100 microM) into the amygdala significantly elevated the extracellular levels of GABA, but not glutamate, in this brain region.. These findings demonstrate that ASIC inhibition produces anxiolytic-like effects in some behavioral models and indicate a potential role for GABAergic mechanisms to underlie these anxiolytic-like effects.

Topics: Acid Sensing Ion Channels; Amiloride; Amygdala; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Exploratory Behavior; Fever; gamma-Aminobutyric Acid; Glutamic Acid; Hippocampus; Isoquinolines; Male; Membrane Potentials; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microdialysis; Naphthalenes; Nerve Tissue Proteins; Neurons; Peptides; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Sodium Channels; Spider Venoms; Stress, Psychological

Acid Sensing Ion Channels (ASICs) are a group of sodium-selective ion channels that are activated by low extracellular pH. The role of ASIC in disease states remains unclear partly due to the lack of selective pharmacological agents. In this report, we describe the effects of A-317567, a novel non-amiloride blocker, on three distinct types of native ASIC currents evoked in acutely dissociated adult rat dorsal root ganglion (DRG) neurons. A-317567 produced concentration-dependent inhibition of all pH 4.5-evoked ASIC currents with an IC50 ranging between 2 and 30muM, depending upon the type of ASIC current activated. Unlike amiloride, A-317567 equipotently blocked the sustained phase of ASIC3-like current, a biphasic current akin to cloned ASIC3, which is predominant in DRG. When evaluated in the rat Complete Freud's Adjuvant (CFA)-induced inflammatory thermal hyperalgesia model, A-317567 was fully efficacious at a dose 10-fold lower than amiloride. A-317567 was also potent and fully efficacious when tested in the skin incision model of post-operative pain. A-317567 was entirely devoid of any diuresis or natriuresis activity and showed minimal brain penetration. In summary, A-317567 is the first reported small molecule non-amiloride blocker of ASIC that is peripherally active and is more potent than amiloride in vitro and in vivo pain models. The discovery of A-317567 will greatly help to enhance our understanding of the physiological and pathophysiological role of ASICs.

Topics: Acid Sensing Ion Channels; Acids; Amiloride; Animals; Cell Count; Cell Size; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Freund's Adjuvant; Ganglia, Spinal; Hydrogen-Ion Concentration; Hyperalgesia; Isoquinolines; Membrane Potentials; Membrane Proteins; Naphthalenes; Nerve Tissue Proteins; Neurons; Pain Measurement; Pain Threshold; Pain, Postoperative; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Sodium Channels