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Nonclassical Ion Channels and Ischemia
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
TRP channels are involved in various physiological processes, including sensory transduction. The TRP channel TRPV6 mediates calcium uptake in epithelia and its expression is dramatically increased in numerous types of cancer [43]. In ischemia, myelin is damaged in Ca2+ involved pathway which is devoted to glutamate release activating NMDA receptors. The H+-gated [Ca2+]i elevation is mediated by channels with characteristics of TRPA1, which could be inhibited by ruthenium red, isopentenyl pyrophosphate, HC-030031, A967079 or TRPA1 knockout, suggesting that TRPA1-containing ion channels performs a potential value in white matter ischemia [44]. In edema, ischemic stroke can be prevented by TRPV4, because TRPV4 is activated by body temperature and is enhanced by heating through glutamate receptors [45]. TRPV4 is a calcium-permeable cation channel that is also sensitive to cell swelling, modulating the mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathways that regulate cell apoptosis when activated [46]. Up-regulation of TRPV4 is mediated through NR2B-NMDAR down-regulating the Akt signaling pathway for neurotoxicity [47]. In the penumbra, peri-infarct depolarizations (PIDs) are accompanied by strong intracellular calcium elevations in astrocytes and neurons, thereby negatively affecting infarct size and clinical outcome. TRPV4 channels contribute to calcium influx into astrocytes and neurons and subsequent extracellular glutamate accumulation ameliorate the PID-induced calcium overload during acute stroke [48]. TRPM2 has a high sensitivity to oxidative damage, so the oxidative stress and the release of extracellular Ca2+, hydrogen peroxide, adenosine diphosphate ribose, and nicotinic acid adenine dinucleotide phosphate can change the activity of TRPM2 in the central nervous system and the immune system [49]. As a result, N-acetyl-l-cysteine (NAC) treatment can provide neuroprotection via regulation of TRPM2 [50]. Besides, the suppression of TRPM7 channels reduce delayed neuronal cell death and preserved neuronal functions in global cerebral ischemia [13]. And the TRPA1 is expressed by primary afferent nerve fibers, which is also a ‘receptor-operated’ channel whose activation downstream of metabotropic receptors elicits inflammatory pain or itch. It functions as a low-threshold sensor for structurally diverse electrophilic irritants, which may act as an attractive target for novel analgesic therapies [51]. Zn2+ is transferred from endolysosomal vesicles to the cytosol through the TRPML1 channel, and its sensitivity of Ca2+ play critical roles in neuronal function [52]. The TRPC5 ion channel is involved in ischemia which is related to endothelial cell sprouting and angiogenesis. Riluzole, the TRPC5 activator, are tested on ischemic injury regulating nuclear factor of activated T cell isoform c3 and angiopoietin-1 which could provide the mechanism for the angiogenic function of TRPC5 [53].
TRPA1 as a therapeutic target for nociceptive pain
Published in Expert Opinion on Therapeutic Targets, 2020
Daniel Souza Monteiro de Araujo, Romina Nassini, Pierangelo Geppetti, Francesco De Logu
The search for more selective TRPA1 channel antagonists has led to the development of molecules with optimization of existing scaffolds. Xanthine derivatives, including HC-030031, were the first identified as TRPA1 antagonists [71]. HC-030031 has proven effective in vivo at 100 and 300 mg/kg [71]. Later, other xanthinic derivatives were recognized as TRPA1 selective antagonists, including Chembridge-5861528, which is about 10 times more potent than HC-030031 [94,95]. Another antagonist is the oxime derivative, A-967079 (WO/2009/089082) [96]. A wide range of trichloro(sulfanyl)ethyl benzamides has also been produced and made available as potent TRPA1 antagonists, showing activity in human, but not in rat, TRPA1 [97]. More recently, additional TRPA1 antagonists have been reported. These include GRC 17536 [98], and in 2010, a series of heterocyclic amides revealed properties of TRPA1 inhibition (2010/141805 A1) [99]. However, the promising compounds in this series suffer from poor solubility.
Transient receptor potential ankyrin 1 (TRPA1)-mediated toxicity: friend or foe?
Published in Toxicology Mechanisms and Methods, 2020
Mohaddeseh Sadat Alavi, Ali Shamsizadeh, Gholamreza Karimi, Ali Roohbakhsh
Aromatase inhibitors or estrogen synthetase inhibitors (AIs) including exemestane, anastrozole, and letrozole are recommended for breast cancer therapy (Gibson et al. 2009). Clinical use of AIs has been described by severe musculoskeletal and neuropathic pain symptoms (Laroche et al. 2014). AIs stimulate TRPA1-mediated calcium flux and current in rodent DRG neurons and human cells expressing the recombinant TRPA1 (Fusi et al. 2014). In mice, AIs were able to produce acute nociception and neurogenic inflammation in the peripheral tissues, which was exacerbated by pre-exposure to proalgesic stimuli and releasing of sensory neuropeptides (Fusi et al. 2014). AIs also evoked mechanical allodynia and decreased grip strength that did not undergo desensitization on prolonged AI administration. These effects were markedly attenuated by TRPA1 blockade by HC-030031 or in TRPA1 KO mice. The researchers proposed TRPA1 as a major mediator of the proinflammatory/proalgesic actions of AIs (Fusi et al. 2014). Accordingly, TRPA1 antagonists have the potential to be used for the treatment of allodynia and/or hyperalgesia associated with AIs use (Fusi et al. 2014). Interestingly, Logu et al. showed that androstenedione, an aromatase substrate, promoted AIs-induced painful musculoskeletal symptoms by TRPA1 activation in rats (De Logu et al. 2016).
Redox-sensitive TRP channels: a promising pharmacological target in chemotherapy-induced peripheral neuropathy
Published in Expert Opinion on Therapeutic Targets, 2021
Ramandeep Singh, Pratik Adhya, Shyam Sunder Sharma
TRPA1 is a cold-sensitive, Ca2+permeable cation channel with 14 ankyrin repeats, present in both neuronal and non-neuronal cells [118]. TRPA1 is most sensitive to ROS as reported by Yamamoto and colleagues [111]. TRPA1 gets activated through the S-nitrosylation of cysteine by nitric oxide (NO) [119]. Apart from oxidative stress, TRPA1 is also activated through pro-inflammatory cytokines such as TNF-α and IL-6 [120,121]. TRPA1 has been linked to the development of CIPN in different studies. Nassini et al. elucidated that a single dose of oxaliplatin causes mechanical and cold hyperalgesia in rats and mice by increasing TRPA1 activation [122]. On treatment with HC-030031, a TRPA1 antagonist, the pain was found to be reduced. A similar increase in TRPA1 induction was shown by Yamamoto and colleagues in DRGs of rats using oxaliplatin [123]. Moreover, Zhao et al. also documented cold hypersensitivity with a single oxaliplatin dose and a decrease in cold hypersensitivity after HC-030031 treatment [16]. Not only HC-030031 other TRPA1 antagonist like ADM09 was also described to be effective in ameliorating oxaliplatin-induced hyperalgesia [124]. The inhibitory action of oxaliplatin on prolyl hydroxylase, which contributes to TRPA1 sensitization to ROS, was found to be the underlying mechanism of oxaliplatin-induced TRPA1 sensitization [125]. Cisplatin, which is also a platinum compound was also reported to enhance expression of TRPA1 channel and subsequent neuropathic pain in mice [126]. Further, in an investigation conducted by Materazzi and colleagues, Paclitaxel was also reported to cause cold allodynia in mice through activation of the TRPA1 channel. Treatment with HC-030031 effectively minimized such cold allodynia. In another study, mechanical hypersensitivity to paclitaxel was ameliorated by A-967,079 in mice (another TRPA1 antagonist) [34]. Docetaxel treatment also increased TRPA1 expression in rat DRGs, resulting in neuropathic pain that was alleviated by the TRPA1 antagonist AP-18 [39]. Apart from platinum compounds and taxanes, vincristine also leads to neuropathic pain by causing an increase in the expression of TRPA1 in DRG’s of rats [118]. In the case of bortezomib, although the expression of TRPA1 does not change but mechanical, chemical, and cold hyperalgesia occurs in an animal model of neuropathic pain [44]. TRPA1 channel was also shown to mediate the mechanical allodynia in mice model of letrozole and exemestane induced neuropathy [69]. Bruscoet al. reported that in preclinical study, dacarbazine induced neuropathic pain is mediated by the TRPA1 channel which was effectively ameliorated by HC-030031 and antisense oligonucleotide treatment [74]. Table 3 highlights various redox-sensing TRP channels that are involved in CIPN.