Kansai Medical University Team Discovers Odor Molecules that Induce Artificial Hibernation/Life Protection and Elucidation of Their Sensory Transmission Principles

Dr. Ko Kobayakawa’s team from Kansai Medical University has discovered a group of odor molecules termed "thiazoline-related fear odors (tFOs)" that induce latent life-protective effects and enable mice to survive in a lethal hypoxic environment for a long time. The team elucidated that these odor molecules bind to TRPA1 channels expressed in the sensory nerves and activate the central crisis pathway from the brainstem to the midbrain, inducing life-protective effects. Additionally, prolonged exposure to high concentrations of tFOs can induce artificial hibernation in mice. The TRPA1 gene and its sensory pathway are also conserved in humans, and investigators expect this finding to be applied to “sensory medicine” to induce potential life-protective effects by odor stimulation.

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Humans and animals possess latent life-protective abilities, acquired through evolution, that allow them to survive in crises. However, what kind of protective effects exist, what kind of stimuli can be used to induce these protective effects, and whether such induction methods can be applied to medical treatment are issues that have remained unexplored. Innate fear is an emotion that is thought to be a function of the brain that integrates and induces biological responses, increasing the probability of survival in a crisis. Therefore, potential life-protective effects could be induced by intervening in the brain's innate fear-emotion system by using appropriate sensory stimuli. tFOs developed by Dr. Kobayakawa’s team are odor molecules that induce extreme innate fear in rodents and investigated their effects.

Their investigation showed that tFOs-stimulation can induce hypothermia/hypometabolism in mice, and continuous stimulation for several hours with these odorants can safely induce artificial hibernation. However, the characteristics of tFO-induced hypothermia/hypometabolism were clearly different from those of natural hibernation in terms of metabolism, physiological responses, and the induction systems triggered in the brain. In contrast to natural hibernation, which aims to conserve energy, the artificial hibernation/life-protective state induced by tFOs maximized the life-protective effects.

Further, in a 4% oxygen environment, control mice can survive for an average of only 11.7 minutes. Surprisingly, mice pre-stimulated with a type of tFO survived in 4% oxygen for an average of 231.8 minutes. Moreover, stimulation by tFOs also had powerful therapeutic effects in brain and cutaneous ischemia-reperfusion animal models. Therefore, tFO stimulation may have a role as a therapeutic agent for hypoxia and ischemia-reperfusion disorders such as cerebral infarctions in the field of emergency medicine.

Additionally, hypothermia, hypometabolism and hypoxic resistance induced by tFOs were found to be regulated by three pathways: olfactory, vagal, and trigeminal pathways. The team also elucidated that tFOs activate TRPA1 in the vagus and trigeminal nerves, and this information is transmitted to the central crisis pathway from the brainstem to the midbrain, inducing these latent life-protective effects.

Most pharmaceuticals exert their therapeutic effects by acting directly on cells and tissues that have become abnormal due to disease or trauma, or on pathogens. In contrast, tFOs exert their therapeutic effects through an indirect mechanism, activating sensory receptors to induce latent life-protective effects orchestrated by the brain. Thus, the current study proposes the new technological concept of “sensory medicine,” artificially inducing the latent life-protective effects that organisms have acquired through evolution. The TRPA1 receptor to which tFOs bind, the trigeminal/vagal pathways that transmit this information to the brain, and the central crisis pathways from the brainstem to the midbrain are similarly conserved in humans. Therefore, if the type of tFOs that appropriately activate the human TRPA1 can be identified, they may be used as therapeutic agents for emergency patients.

This research is published in Communications Biology and will be published in Nature Communications.

The article, “Artificial hibernation/life-protective state induced by thiazoline-related innate fear odors,” was published in Communications Biology at DIO: 10.1038/s42003-020-01629-2

The article, “Thiazoline-related innate fear stimuli orchestrate hypothermia and anti-hypoxia via sensory TRPA1 activation,” will be published in Nature Communications at DIO: 10.1038/s41467-021-22205-0

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