Intersections in Neuropsychiatric and Metabolic Disorders: Possible Role of TRPA1 Channels

Abstract

Neuropsychiatric disorders (NPDs) are a huge burden to the patient, their family, and society. NPDs have been greatly associated with cardio-metabolic comorbidities such as obesity, type-2 diabetes mellitus, dysglycaemia, insulin resistance, dyslipidemia, atherosclerosis, and other cardiovascular disorders. Antipsychotics, which are frontline drugs in the treatment of schizophrenia and off-label use in other NPDs, also add to this burden by causing severe metabolic perturbations. Despite decades of research, the mechanism deciphering the link between neuropsychiatric and metabolic disorders is still unclear. In recent years, transient receptor potential Ankyrin 1 (TRPA1) channel has emerged as a potential therapeutic target for modulators. TRPA1 agonists/antagonists have shown efficacy in both neuropsychiatric disorders and appetite regulation and thus provide a crucial link between both. TRPA1 channels are activated by compounds such as cinnamaldehyde, allyl isothiocyanate, allicin and methyl syringate, which are present naturally in food items such as cinnamon, wasabi, mustard, garlic, etc. As these are present in many daily food items, it could also improve patient compliance and reduce the patients’ monetary burden. In this review, we have tried to present evidence of the possible involvement of TRPA1 channels in neuropsychiatric and metabolic disorders and a possible hint towards using TRPA1 modulators to target appetite, lipid metabolism, glucose and insulin homeostasis and inflammation associated with NPDs.

Diisocyanates influence models of atopic dermatitis through direct activation of TRPA1

“…We have previously shown that this model correlated with our therapeutic outcomes in both clinical trials of AD and the MC903 mouse model [16]. Activation with the TRPA1 agonist cinnamaldehyde [24] reduced modeled healing in both the HaCaT keratinocyte (KC) and Schwann (neuronal) cell lines (Fig 5E and 5F). Blockade of TRPA1 improved healing times in Schwann cells but not in KC (Fig 5E and 5F).…”

Dual role of transient receptor potential ankyrin 1 in respiratory and gastrointestinal physiology: From molecular mechanisms to therapeutic targets

“…TRPA1, positioned strategically in epithelial cells throughout the gastrointestinal tract, plays a pivotal role in sensory transduction of dietary components. Its responsiveness to a diverse array of chemicals, including those found in spicy foods (e.g., isothiocyanates) ( Wu et al, 2017 ; Radhakrishnan et al, 2023 ) and pungent substances (e.g., allicin in garlic) ( Sodhi et al, 2021 ), underscores its significance in translating the chemical landscape of ingested nutrients into cellular signals. Considering its physiological function in the gastrointestinal tract, TRPA1 agonists, such as allicin and AITC, might exert a regulatory influence on gastrointestinal motility ( Tsuchiya and Kawamata, 2019 ).…”

“…Agonists and antagonists targeting TRPA1 have demonstrated effectiveness in treating neuropsychiatric disorders and appetite regulation, establishing a vital connection between the two. TRPA1 channels play a role in regulating appetite, lipid metabolism, glucose and insulin homeostasis, and the inflammation associated with neuropsychiatric and metabolic disorders ( Sodhi et al, 2021 ). Non-electrophilic TRPA1 activators, including menthol, carvacrol, and clotrimazole, induce an increase in the permeability of fluorescein isothiocyanate-conjugated dextran (4 kDa) and a decrease in transepithelial electrical resistance in epithelial MDCK II monolayers.…”

A Comprehensive Review on the Regulatory Action of TRP Channels: A Potential Therapeutic Target for Nociceptive Pain

“…These channels are reported to be stimulated by a wide range of irritants namely allyl isothiocyanate, allicin, and cinnamaldehyde. 64 , 65 Furthermore, an array of endogenous molecules released during inflammation and oxidative stress have been found to be involved in TRPA1 activation, evidently highlighting a potential role of this channel in pain and nociception. A growing body of evidence employing animal models suggests the therapeutic potency of TRPA1 antagonists namely HC-030031, A-967079, and AMG0902 in human subjects undergoing neuropathic pain.…”