Thiazoline-related innate fear stimuli orchestrate hypothermia and anti-hypoxia via sensory TRPA1 activation

Abstract

Thiazoline-related innate fear-eliciting compounds (tFOs) orchestrate hypothermia, hypometabolism, and anti-hypoxia, which enable survival in lethal hypoxic conditions. Here, we show that most of these effects are severely attenuated in transient receptor potential ankyrin 1 (Trpa1) knockout mice. TFO-induced hypothermia involves the Trpa1-mediated trigeminal/vagal pathways and non-Trpa1 olfactory pathway. TFOs activate Trpa1-positive sensory pathways projecting from trigeminal and vagal ganglia to the spinal trigeminal nucleus (Sp5) and nucleus of the solitary tract (NTS), and their artificial activation induces hypothermia. TFO presentation activates the NTS-Parabrachial nucleus pathway to induce hypothermia and hypometabolism; this activation was suppressed in Trpa1 knockout mice. TRPA1 activation is insufficient to trigger tFO-mediated anti-hypoxic effects; Sp5/NTS activation is also necessary. Accordingly, we find a novel molecule that enables mice to survive in a lethal hypoxic condition ten times longer than known tFOs. Combinations of appropriate tFOs and TRPA1 command intrinsic physiological responses relevant to survival fate.

Energy‐sparing by 2‐methyl‐2‐thiazoline protects heart from ischaemia/reperfusion injury

“…Previous data strongly suggest an association with 2MT and TRPA1, but the role of TRPA1 during ischaemic damage has not been well established. Although our previous reports indicate that in trigeminal/vagus nerves TRPA1 acts as a chemosensor and affects systemic energy metabolism via peripheral sensory nerves, 37 the present data suggest that 2MT may have a direct effect on cardiomyocytes. TRPA1 deficiency reportedly ameliorates myocardial I/R injury and mediates enhanced Ca 2+ levels in cardiomyocytes 38,39 .…”

“…Even if 2MT itself is not available, other thiazoline compounds may have similar effects. In fact, some thiazoline analogues other than 2MT induce hypothermia and hypoxia resistance 37 . Furthermore, human and mouse TRPA1 differ in ligand responsiveness 42 .…”

“…In fact, some thiazoline analogues other than 2MT induce hypothermia and hypoxia resistance. 37 Furthermore, human and mouse TRPA1 differ in ligand responsiveness. 42 To establish the cardioprotective effect of 2MT or similar thiazoline compounds in human, it is necessary to evaluate the effect of 2MT or similar thiazoline compounds in large mammals by comparing the drug‐treated group with the conventional hypothermic group.…”

The Hypothermic Effect of Hydrogen Sulfide Is Mediated by the Transient Receptor Potential Ankyrin-1 Channel in Mice

“…The involvement of TRPA1 was shown in the development of hypothermia in response to diverse stimuli, such as acetaminophen [ 71 ], relative hypoxia [ 72 ], and thiazoline-related innate fear-eliciting compounds [ 73 ]. Although these agents should not be considered as selective activators of TRPA1, the hypothermic response to them was markedly attenuated or completely absent after the pharmacological or genetic blockade of TRPA1 channels yielding to the conclusion that activation of the TRPA1 channel by the applied stimuli mediates the hypothermia [ 71 , 72 , 73 ]. In one of these studies, the TRPA1 agonist cinnamaldehyde induced a marked hypothermia in Trpa1 +/+ mice, which was significantly reduced in Trpa1 −/− mice [ 71 ].…”

The Anterior Piriform Cortex and Predator Odor Responses: Modulation by Inhibitory Circuits

“…TRPA1, a chemoreceptor for noxious stimuli, such as formaldehyde ( McNamara et al, 2007 ), has an important role in nociception ( Story et al, 2003 ). In addition, a recent study suggests that innate fear stimuli orchestrate hypothermia and anti-hypoxia via TRPA1 activation ( Matsuo et al, 2021 ). Elucidation of stress-related neural circuits, their selective inhibitory systems, and related chemoreceptors is necessary for the future development of effective therapeutic interventions.…”