New natural agonists of the transient receptor potential Ankyrin 1 (TRPA1) channel.

The transient receptor potential (TRP) channels family are cationic channels involved in various physiological processes as pain, inflammation, metabolism, swallowing function, gut motility, thermoregulation or adipogenesis. In the oral cavity, TRP channels are involved in chemesthesis, the sensory chemical transduction of spicy ingredients. Among them, TRPA1 is activated by natural molecules producing pungent, tingling or irritating sensations during their consumption. TRPA1 can be activated by different chemicals found in plants or spices such as the electrophiles isothiocyanates, thiosulfinates or unsaturated aldehydes. TRPA1 has been as well associated to various physiological mechanisms like gut motility, inflammation or pain. Cinnamaldehyde, its well known potent agonist from cinnamon, is reported to impact metabolism and exert anti-obesity and anti-hyperglycemic effects. Recently, a structurally similar molecule to cinnamaldehyde, cuminaldehyde was shown to possess anti-obesity and anti-hyperglycemic effect as well. We hypothesized that both cinnamaldehyde and cuminaldehyde might exert this metabolic effects through TRPA1 activation and evaluated the impact of cuminaldehyde on TRPA1. The results presented here show that cuminaldehyde activates TRPA1 as well. Additionally, a new natural agonist of TRPA1, tiglic aldehyde, was identified and p-anisaldehyde confirmed.

A randomized clinical trial on the acute therapeutic effect of TRPA1 and TRPM8 agonists in patients with oropharyngeal dysphagia.

BACKGROUND: Oropharyngeal dysphagia (OD) treatment is moving away from compensatory strategies toward active treatments that improve swallowing function. The aim of this study was to assess the acute therapeutic effect of TRPA1/M8 agonists in improving swallowing function in OD patients. METHODS: Fifty-eight patients with OD caused by aging, stroke, or neurodegenerative disease were included in a three-arm, quadruple-blind, randomized clinical trial (NCT02193438). Swallowing safety and efficacy and the kinematics of the swallow response were assessed by videofluoroscopy (VFS) during the swallow of 182 ± 2 mPa·s viscosity (nectar) boluses of a xanthan gum thickener supplemented with (a) 756.6 µmol/L cinnamaldehyde and 70 µmol/L zinc (CIN-Zn) (TRPA1 agonists), (b) 1.6 mmol/L citral (CIT) (TRPA1 agonist), or (c) 1.6 mmol/L citral and 1.3 mmol/L isopulegol (CIT-ISO) (TRPA1 and TRPM8 agonists). The effects on pharyngeal event-related potentials (ERP) were assessed by electroencephalography. KEY RESULTS: TRPA1 stimulation with either CIN-Zn or CIT reduced time to laryngeal vestibule closure (CIN-Zn P = .002, CIT P = .023) and upper esophageal sphincter opening (CIN-Zn P = .007, CIT P = .035). In addition, CIN-Zn reduced the penetration-aspiration scale score (P = .009), increased the prevalence of safe swallows (P = .041), and reduced the latency of the P2 peak of the ERP. CIT-ISO had no positive effect on biomechanics or neurophysiology. No significant adverse events were observed. CONCLUSIONS AND INFERENCES: TRPA1 stimulation with CIN-Zn or CIT improves the swallow response which, in the case of CIN-Zn, is associated with a significant improvement in cortical activation and safety of swallow. These results provide the basis for the development of new active treatments for OD using TRPA1 agonists.

Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression.

There is growing evidence suggesting that antagonists of group II metabotropic glutamate receptors (mGluR2/3) exhibit antidepressant-like properties in several preclinical models of depression. However, all those studies have been performed using competitive group II non-selective orthosteric antagonists. In this study we extensively characterized a group II selective negative allosteric modulator (4-[3-(2,6-Dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one, namely RO4491533, Woltering et al., 2010) in several in vitro biochemical assays and in vivo models of depression. In vitro, RO4491533 completely blocked the glutamate-induced Ca(2+) mobilization and the glutamate-induced accumulation in [(35)S]GTP(γS) binding in cells expressing recombinant human or rat mGluR2 and in native tissues. Results from Schild plot experiments and reversibility test at the target on both cellular and membrane-based assays confirmed the negative allosteric modulator properties of the compound. RO4491533 was equipotent on mGluR2 and mGluR3 receptors but not active on any other mGluRs. RO4491533 has acceptable PK properties in mice and rats, is bioavailable following oral gavage (F = 30%) and brain-penetrant (CSF conc/total plasma conc ratio = 0.8%). RO4491533 appeared to engage the central mGluR2 and mGluR3 receptors since the compound reversed the hypolocomotor effect of an mGluR2/3 orthosteric agonist LY379268 in a target-specific manner, as did the group II orthosteric mGluR2/3 antagonist LY341495. RO4491533 and LY341495 dose-dependently reduced immobility time of C57Bl6/J mice in the forced swim test. Also, RO4491533 and LY341495 were active in the tail suspension test in a line of Helpless (H) mice, a putative genetic model of depression. These data suggest that mGluR2/3 receptors are viable targets for development of novel pharmacotherapies for depression.