Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss

Dhukhwa, Asmita; Aameri, Raheem F. H. Al; Sheth, Sandeep; Mukherjea, Debashree; Rybak, Leonard P.; Ramkumar, Vickram

doi:10.1038/s41598-021-87387-5

Cited by 10 publications

(9 citation statements)

References 68 publications

(67 reference statements)

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“…Subsequent studies have shown that other members of the RGS family of proteins may be involved in cisplatin-induced ototoxicity. Cisplatin upregulates RGS17 expression in the cochlea, leading to increased oxidative stress, upregulation of inflammatory genes and enhanced apoptosis in the cochlea [ 102 ]. The silencing of RGS17 suppressed cisplatin-induced hearing loss in rats, while overexpression of RGS17 enhanced cisplatin-induced hearing loss.…”

Section: Regulators Of G Protein Signalling and Hearing Lossmentioning

confidence: 99%

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Purinergic Signalling in the Cochlea

Vlajkovic

Thorne

2022

IJMS

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The mammalian cochlea is the sensory organ of hearing with a delicate, highly organised structure that supports unique operating mechanisms. ATP release from the secretory tissues of the cochlear lateral wall (stria vascularis) triggers numerous physiological responses by activating P2 receptors in sensory, supporting and neural tissues. Two families of P2 receptors, ATP-gated ion channels (P2X receptors) and G protein-coupled P2Y receptors, activate intracellular signalling pathways that regulate cochlear development, homeostasis, sensory transduction, auditory neurotransmission and response to stress. Of particular interest is a purinergic hearing adaptation, which reflects the critical role of the P2X2 receptor in adaptive cochlear response to elevated sound levels. Other P2 receptors are involved in the maturation of neural processes and frequency selectivity refinement in the developing cochlea. Extracellular ATP signalling is regulated by a family of surface-located enzymes collectively known as “ectonucleotidases” that hydrolyse ATP to adenosine. Adenosine is a constitutive cell metabolite with an established role in tissue protection and regeneration. The differential activation of A1 and A2A adenosine receptors defines the cochlear response to injury caused by oxidative stress, inflammation, and activation of apoptotic pathways. A1 receptor agonism, A2A receptor antagonism, and increasing adenosine levels in cochlear fluids all represent promising therapeutic tools for cochlear rescue from injury and prevention of hearing loss.

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Section: Regulators Of G Protein Signalling and Hearing Lossmentioning

confidence: 99%

“…The silencing of RGS17 suppressed cisplatin-induced hearing loss in rats, while overexpression of RGS17 enhanced cisplatin-induced hearing loss. RGS17 represents a novel mediator of cisplatin ototoxicity and a potential therapeutic target for cisplatin-induced hearing loss [ 102 ].…”

Section: Regulators Of G Protein Signalling and Hearing Lossmentioning

confidence: 99%

Purinergic Signalling in the Cochlea

Vlajkovic

Thorne

2022

IJMS

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“…CB2Rs are mainly distributed in OC, spiral ligament and SGN cells in the cochlea of rats and mice ( Kim et al, 2014 ; Kaur et al, 2016 ; Ghosh et al, 2018 ). CB2Rs can protect the cochlea and reduce ototoxicity, inflammation and oxidative stress with cisplatin treatment in rats ( Vlajkovic et al, 2006 ; Dhukhwa et al, 2021 ). The effect of CB2Rs on preventing cisplatin induced hearing loss was blocked by injection of the antagonist AM630, but HC loss was reduced by injection of JWH105 (one agonist of CB2R).…”

Section: Roles Of Class a G Protein-coupled Receptors In Cochleamentioning

confidence: 99%

“…In cochlear research and treatment, GPCR-targeted drugs have also been used to some extent. For example, S1PR2 agonist (CYM-5478) ( Wang et al, 2020 ), CaSR inhibitors (NPS2143 and Calhex231) ( Minakata et al, 2019 ), V2R antagonist (OPC-41061/Tolvaptan) ( Egami et al, 2016 ), CB2R agonist (JWH105) ( Vlajkovic et al, 2006 ; Dhukhwa et al, 2021 ), AA1R agonists (R-PIA and ADAC) ( Vlajkovic et al, 2010 ; Kaur et al, 2016 ), AA2AR antagonist (istradefylline) ( Han et al, 2019 ; Manalo et al, 2020 ; Shin et al, 2021 ) all have a therapeutic and protective effect on the cochlea. Among these GPCR-targeted drugs, V2R antagonist (OPC-41061/Tolvaptan) and AA2AR antagonist (istradefylline) have been approved by the US Food and Drug Administration (FDA) (NDA022075, NDA022275).…”

Section: Emerging G Protein-coupled Receptor-based Treatmentmentioning

confidence: 99%

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss

Guo²,

Fu³

et al. 2022

Front. Mol. Neurosci.

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The prevalence of hearing loss-related diseases caused by different factors is increasing worldwide year by year. Currently, however, the patient’s hearing loss has not been effectively improved. Therefore, there is an urgent need to adopt new treatment measures and treatment techniques to help improve the therapeutic effect of hearing loss. G protein-coupled receptors (GPCRs), as crucial cell surface receptors, can widely participate in different physiological and pathological processes, particularly play an essential role in many disease occurrences and be served as promising therapeutic targets. However, no specific drugs on the market have been found to target the GPCRs of the cochlea. Interestingly, many recent studies have demonstrated that GPCRs can participate in various pathogenic process related to hearing loss in the cochlea including heredity, noise, ototoxic drugs, cochlear structure, and so on. In this review, we comprehensively summarize the functions of 53 GPCRs known in the cochlea and their relationships with hearing loss, and highlight the recent advances of new techniques used in cochlear study including cryo-EM, AI, GPCR drug screening, gene therapy vectors, and CRISPR editing technology, as well as discuss in depth the future direction of novel GPCR-based drug development and gene therapy for cochlear hearing loss. Collectively, this review is to facilitate basic and (pre-) clinical research in this area, and provide beneficial help for emerging GPCR-based cochlear therapies.

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“…RGS 17 appears to contribute to cisplatin ototoxicity by uncoupling protective GPCRs, such as CB2, from their normal protective actions. RGS17 inhibitors could provide novel agents for ameliorating cisplatin induced hearing loss [ 71 ] by extending the period of activation of GPCR activation.…”

Section: G-proteinsmentioning

confidence: 99%

Oxidative Stress and Inflammation Caused by Cisplatin Ototoxicity

et al. 2021

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Hearing loss is a significant health problem that can result from a variety of exogenous insults that generate oxidative stress and inflammation. This can produce cellular damage and impairment of hearing. Radiation damage, ageing, damage produced by cochlear implantation, acoustic trauma and ototoxic drug exposure can all generate reactive oxygen species in the inner ear with loss of sensory cells and hearing loss. Cisplatin ototoxicity is one of the major causes of hearing loss in children and adults. This review will address cisplatin ototoxicity. It includes discussion of the mechanisms associated with cisplatin-induced hearing loss including uptake pathways for cisplatin entry, oxidative stress due to overpowering antioxidant defense mechanisms, and the recently described toxic pathways that are activated by cisplatin, including necroptosis and ferroptosis. The cochlea contains G-protein coupled receptors that can be activated to provide protection. These include adenosine A1 receptors, cannabinoid 2 receptors (CB2) and the Sphingosine 1-Phosphate Receptor 2 (S1PR2). A variety of heat shock proteins (HSPs) can be up-regulated in the cochlea. The use of exosomes offers a novel method of delivery of HSPs to provide protection. A reversible MET channel blocker that can be administered orally may block cisplatin uptake into the cochlear cells. Several protective agents in preclinical studies have been shown to not interfere with cisplatin efficacy. Statins have shown efficacy in reducing cisplatin ototoxicity without compromising patient response to treatment. Additional clinical trials could provide exciting findings in the prevention of cisplatin ototoxicity.

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Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss

Cited by 10 publications

References 68 publications

Purinergic Signalling in the Cochlea

Purinergic Signalling in the Cochlea

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss

Oxidative Stress and Inflammation Caused by Cisplatin Ototoxicity

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