Salicylate, an aspirin metabolite, specifically inhibits the current mediated by glycine receptors containing α1‐subunits

Abstract

Background and purpose: Aspirin or its metabolite sodium salicylate is widely prescribed and has many side effects. Previous studies suggest that targeting neuronal receptors/ion channels is one of the pathways by which salicylate causes side effects in the nervous system. The present study aimed to investigate the functional action of salicylate on glycine receptors at a molecular level. Experimental approach: Whole-cell patch-clamp and site-directed mutagenesis were deployed to examine the effects of salicylate on the currents mediated by native glycine receptors in cultured neurones of rat inferior colliculus and by glycine receptors expressed in HEK293T cells. Key results: Salicylate effectively inhibited the maximal current mediated by native glycine receptors without altering the EC50 and the Hill coefficient, demonstrating a non-competitive action of salicylate. Only when applied simultaneously with glycine and extracellularly, could salicylate produce this antagonism. In HEK293T cells transfected with either a1-, a2-, a3-, a1b-, a2b-or a3b-glycine receptors, salicylate only inhibited the current mediated by those receptors that contained the a1-subunit. A single site mutation of I240V in the a1-subunit abolished inhibition by salicylate. Conclusions and implications:Salicylate is a non-competitive antagonist specifically on glycine receptors containing a1-subunits. This action critically involves the isoleucine-240 in the first transmembrane segment of the a1-subunit. Our findings may increase our understanding of the receptors involved in the side effects of salicylate on the central nervous system, such as seizures and tinnitus.

The protective action of tocopherol and acetylsalicylic acid on the behavior of rats treated with dioxins

“…[50][51][52] Administration of ASA in ASA (F) group also resulted in shorter response times, which confirms the positive effect of ASA on neurotransmission. Similar results are presented in the studies by Gong et al, Wang and Lu et al 40,53,54 This study confirms that ASA is an antagonist of the glycine receptor and it reduces the inhibitory effect of GABA, releases glutamate from presynaptic terminals, resulting in the facilitation effect, which induces the hyperreactivity. This can be beneficial both in subjects with delayed response times and depressive type disorders that occur in dioxin intoxication, as has been manifested in the swimming test with no attempts to swim or with extended immobility in swimming.…”

Effects of sodium salicylate on spontaneous and evoked spike rate in the dorsal cochlear nucleus

“…Fusiform cells receive strong glycinergic inhibitory inputs from cartwheel cells (Backoff et al, 1997; Juiz et al, 1996; Kaltenbach et al, 2005; Kaltenbach et al, 2002; Moore et al, 1996; Mugnaini, 1985; Rubio and Juiz, 2004), and recent evidence indicates that salicylate can inhibit glycine receptors containing alpha1-subunits (Lu et al, 2009). Therefore, we speculated that salicylate might increase the firing rate of fusiform cells by suppressing IPSC.…”

“…If tinnitus emerges from hyperactivity in DCN fusiform cells, then it would be important to determine exactly what effect salicylate has on fusiform cells and other major DCN cell types, especially cartwheel cells which make glycinergic inhibitory contacts on fusiform cells. Recent studies indicate that salicylate inhibits the current mediated by glycine receptors containing alpha1-subunits (Lu et al, 2009). These results suggest that salicylate might suppress glycinergic inhibitory inputs to fusiform cells thereby increasing the firing rate of fusiform cells and suppressing IPSC.…”

Orthogonal array design for the optimization of hollow fiber protected liquid-phase microextraction of salicylates from environmental waters

“…PAS is a traditional antituberculosis agent. These three salicylates have gastrointestinal toxicity, and high-level exposure to them may induce seizures, transient tinnitus and hearing lose [27,28]. In addition, PAS may induce skin rash, lymphadenopathy, joint pains and so on [29].…”