Acid sensing ion channel (ASIC) inhibitors exhibit anxiolytic-like activity in preclinical pharmacological models

Abstract

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.

ENaCs and ASICs as therapeutic targets

“…However, a case-control twin study showed no association between polymorphisms of ASIC1 and anxiety spectrum disorders (175). Still, functional tests with ASIC inhibitors in animal models found that ASIC inhibition was able to produce antidepressive, sedative, and anxiolytic effects (88,112,234). For example, amiloride, PcTx1, and A317567 all exhibited anxiolytic activity, with PcTx1 and A317567 being most effective, most likely reflecting the lower potency of amiloride in ASIC inhibition (112).…”

“…Still, functional tests with ASIC inhibitors in animal models found that ASIC inhibition was able to produce antidepressive, sedative, and anxiolytic effects (88,112,234). For example, amiloride, PcTx1, and A317567 all exhibited anxiolytic activity, with PcTx1 and A317567 being most effective, most likely reflecting the lower potency of amiloride in ASIC inhibition (112). The exact role and mechanism of ASIC in anxiety and fear learning remains to be elucidated, but the data suggest that inhibition of ASICs can play a role in the treatment of anxiety or depression states.…”

Inhibition of acid-sensing ion channels in articular chondrocytes by amiloride attenuates articular cartilage destruction in rats with adjuvant arthritis

“…The choice of drug concentrations of amiloride was based on a previous study in vivo [14,15], which showed that at the doses of 100 and 200 mg/kg, amiloride suppressed limbic seizures in 33% of pilocarpine-treated animals, and reduced the seizure severity score in 67% of the remaining animals. These findings suggest that amiloride may modulate seizure generation and propagation, probably via mechanisms involving ASICs in the pilocarpine model of temporal lobe epilepsy.…”

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

“…Thus, it is necessary to develop a new generation of effective and better-tolerated anxiolytic agents. In this regard, Dwyer et al have shown that ASIC1a inhibitors have an effect in preclinical rodent models of autonomic and behavioral parameters of anxiety (Dwyer et al, 2009). In the stress-induced hyperthermia model, acute administration of ASIC inhibitors PcTX1, A-317567, and amiloride prevented stress-induced elevations in core body temperature.…”