Non-Analgesic Symptomatic or Disease—Modifying Potential of TRPA1

Heber, Stefan; Fischer, Michael J.M.

doi:10.3390/medsci7100099

Cited by 10 publications

(14 citation statements)

References 98 publications

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“…In summary, we herein provide strong evidence that both TRPA1 and TRPV1 channels play a pivotal role in evoking indirect APP-dependent [Ca 2+ ] i responses. Since both TRPA1 and TRPV1 have received considerable attention as potential therapeutic targets for the treatment of several disorders including chronic pain, inflammation, respiratory diseases, and cancers [58][59][60] , further detailed mechanistic analyses of the APP-responsive activations of TRPA1 and TRPV1 channels is anticipated to provide new research insights for developing therapeutic interventions applicable to plasma medicine.…”

Section: Discussionmentioning

confidence: 99%

TRPA1 and TRPV1 channels participate in atmospheric-pressure plasma-induced [Ca2+]i response

Kawase

Chen

Kawaguchi

et al. 2020

Sci Rep

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Despite successful clinical application of non-equilibrium atmospheric pressure plasma (APP), the details of the molecular mechanisms underlying APP-inducible biological responses remain ill-defined. We previously reported that exposure of 3T3L1 cells to APP-irradiated buffer raised the cytoplasmic free Ca 2+ ([Ca 2+ ] i) concentration by eliciting Ca 2+ influx in a manner sensitive to transient receptor potential (TRP) channel inhibitors. However, the precise identity of the APP-responsive channel molecule(s) remains unclear. In the present study, we aimed to clarify channel molecule(s) responsible for indirect APP-responsive [Ca 2+ ] i rises. siRNA-mediated silencing experiments revealed that TRPA1 and TRPV1 serve as the major APP-responsive Ca 2+ channels in 3T3L1 cells. Conversely, ectopic expression of either TRPA1 or TRPV1 in APP-unresponsive C2C12 cells actually triggered [Ca 2+ ] i elevation in response to indirect APP exposure. Desensitization experiments using 3T3L1 cells revealed APP responsiveness to be markedly suppressed after pretreatment with allyl isothiocyanate or capsaicin, TRPA1 and TRPV1 agonists, respectively. APP exposure also desensitized the cells to these chemical agonists, indicating the existence of a bi-directional heterologous desensitization property of APP-responsive [Ca 2+ ] i transients mediated through these TRP channels. Mutational analyses of key cysteine residues in TRPA1 (Cys421, Cys621, Cys641, and Cys665) and in TRPV1 (Cys258, Cys363, and Cys742) have suggested that multiple reactive oxygen and nitrogen species are intricately involved in activation of the channels via a broad range of modifications involving these cysteine residues. Taken together, these observations allow us to conclude that both TRPA1 and TRPV1 channels play a pivotal role in evoking indirect APPdependent [Ca 2+ ] i responses. Recent innovative plasma technologies allow us to generate non-equilibrium atmospheric pressure plasma (APP), and have thus garnered a great deal of attention due to their biomedical and biotechnical applications. Indeed, direct or indirect application of APP to clinical targets has been successfully employed for wound healing, blood coagulation, the sterilization of surfaces, cancer therapy, and so on 1,2 , though the precise molecular mechanisms underlying these APP-mediated benefits have yet to be elucidated. While direct application of APP generates charged particles, ultraviolet radiation, electromagnetic fields, and shockwaves 3 , APP also has the capability to produce a variety of reactive oxygen and nitrogen species (RONS), including superoxide radical (O 2 •−), peroxynitrite anion (ONOO −) and nitric oxide radical (• NO) from oxygen (O 2), nitrogen (N 2), and water (H 2 O) in ambient air, which can be efficiently delivered into an aqueous biological medium 4. Given the physiological and pathophysiological importance of RONS in regulating a wide array of biological functions 5,6 , these reactive species generated in the medium via gas-liquid interfacial APPs are regarded a...

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Section: Discussionmentioning

confidence: 99%

TRPA1 and TRPV1 channels participate in atmospheric-pressure plasma-induced [Ca2+]i response

Kawase

Chen

Kawaguchi

et al. 2020

Sci Rep

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“…With the advent of potent TRPA1 agonists, a new human TRPA1 model can be used to test TRPA1 antagonists in humans [183]. Aside from pain, other diseases could benefit from TRPA1 inhibition [184]. However, similar to TRPV1, TRPA1 has been known for so long that the progress towards a usable analgesic is somewhat disappointing [185].…”

Section: Trp Channelsmentioning

confidence: 99%

Novel Analgesics with Peripheral Targets

Ciotu

Fischer

2020

Neurotherapeutics

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A limited number of peripheral targets generate pain. Inflammatory mediators can sensitize these. The review addresses targets acting exclusively or predominantly on sensory neurons, mediators involved in inflammation targeting sensory neurons, and mediators involved in a more general inflammatory process, of which an analgesic effect secondary to an anti-inflammatory effect can be expected. Different approaches to address these systems are discussed, including scavenging proinflammatory mediators, applying anti-inflammatory mediators, and inhibiting proinflammatory or facilitating anti-inflammatory receptors. New approaches are contrasted to established ones; the current stage of progress is mentioned, in particular considering whether there is data from a molecular and cellular level, from animals, or from human trials, including an early stage after a market release. An overview of publication activity is presented, considering a IuPhar/BPS-curated list of targets with restriction to pain-related publications, which was also used to identify topics.

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“…However, prolonged exposure of mouse and human DRG neurons to Ang II did not induce calcium overload or TRPA1 activation nor modulate action potential firing or other membrane potential properties of these neurons. These observations strongly suggest that the Ang II-induced mechanical and cold hypersensitivity that are indicators of neuropathic pain are not mediated by neuronally-located AT 2 R. Moreover, it is also noteworthy that TRPA1-mediated cold hypersensitivity is not observed in humans and therefore, this AT 2 R-effect in mice is not translatable ( Heber and Fischer, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…In invertebrates and ancestral vertebrates (fly, mosquito, frog, lizard and snakes) TRPA1 serves as a heat receptor that induces avoidance of heat and infrared detection ( Laursen et al, 2015 ) whereas in mammals it mediates cold hypersensitivity ( Obata et al, 2005 ; Sawada et al, 2007 ; del Camino et al, 2010 ; Chen et al, 2013 ). However, a study using four different mammalian species (mouse, rat, rhesus monkey and human) showed that TRPA1’s cold hypersensitivity is specific to rodents, but not primates, making the translational significance of cold hypersensitivity studies in rodents weak ( Heber and Fischer, 2019 ). Moreover, although TRPA1 antagonists (A–967079), show positive results in rodent neuropathic pain studies, they have not been validated for therapeutic use due to limited efficacy in the chosen models, or issues during development of the drug ( Heber and Fischer, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, a study using four different mammalian species (mouse, rat, rhesus monkey and human) showed that TRPA1’s cold hypersensitivity is specific to rodents, but not primates, making the translational significance of cold hypersensitivity studies in rodents weak ( Heber and Fischer, 2019 ). Moreover, although TRPA1 antagonists (A–967079), show positive results in rodent neuropathic pain studies, they have not been validated for therapeutic use due to limited efficacy in the chosen models, or issues during development of the drug ( Heber and Fischer, 2019 ). Recent studies have indicated TRPA1 plays a central role in Ang II-induced cold hypersensitivity in mice.…”

Section: Introductionmentioning

confidence: 99%

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Angiotensin Type 2 Receptors: Painful, or Not?

Pulakat

Sumners

2020

Front. Pharmacol.

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Pain in response to various types of acute injury can be a protective stimulus to prevent the organism from using the injured part and allow tissue repair and healing. On the other hand, neuropathic pain, defined as ‘pain caused by a lesion or disease of the somatosensory nervous system’, is a debilitating pathology. The TRPA1 neurons in the Dorsal Root Ganglion (DRG) respond to reactive oxygen species (ROS) and induce pain. In acute nerve injury and inflammation, macrophages infiltrating the site of injury undergo an oxidative burst, and generate ROS that promote tissue repair and induce pain via TRPA1. The latter discourages using the injured limb, with a lack of movement helping wound healing. In chronic inflammation caused by diabetes, cancer etc., ROS levels increase systemically and modulate TRPA1 neuronal functions and cause debilitating neuropathic pain. It is important to distinguish between drug targets that elicit protective vs. debilitating pain when developing effective drugs for neuropathic pain. In this context, the connection of the Angiotensin type 2 receptor (AT2R) to neuropathic pain presents an interesting dilemma. Several lines of evidence show that AT2R activation promotes anti-inflammatory and anti-nociceptive signaling, tissue repair, and suppresses ROS in chronic inflammatory models. Conversely, some studies suggest that AT2R antagonists are anti-nociceptive and therefore AT2R is a drug target for neuropathic pain. However, AT2R expression in nociceptive neurons is lacking, indicating that neuronal AT2R is not involved in neuropathic pain. It is also important to consider that Novartis terminated their phase II clinical trial (EMPHENE) to validate that AT2R antagonist EMA401 mitigates post-herpetic neuralgia. This trial, conducted in Australia, United Kingdom, and a number of European and Asian countries in 2019, was discontinued due to pre-clinical drug toxicity data. Moreover, early data from the trial did not show statistically significant positive outcomes. These facts suggest that may AT2R not be the proper drug target for neuropathic pain in humans and its inhibition can be harmful.

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Non-Analgesic Symptomatic or Disease—Modifying Potential of TRPA1

Cited by 10 publications

References 98 publications

TRPA1 and TRPV1 channels participate in atmospheric-pressure plasma-induced [Ca2+]i response

TRPA1 and TRPV1 channels participate in atmospheric-pressure plasma-induced [Ca2+]i response

Novel Analgesics with Peripheral Targets

Angiotensin Type 2 Receptors: Painful, or Not?

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