Tear secretion by Diquafosol suppresses the excitability of trigeminal brainstem nuclear complex neurons by reducing excessive P2Y2 expression in the trigeminal ganglion in dry eye rats

Ayano Katagiri; Kazuo Tsubota; Lou Mikuzuki; Shigeru Nakamura; Akira Toyofuku; Takafumi Kato; David A. Bereiter; Koichi Iwata

doi:10.1016/j.neures.2023.01.003

Tear secretion by Diquafosol suppresses the excitability of trigeminal brainstem nuclear complex neurons by reducing excessive P2Y₂ expression in the trigeminal ganglion in dry eye rats

Ayano Katagiri, Kazuo Tsubota, Lou Mikuzuki, Shigeru Nakamura, Akira Toyofuku, Takafumi Kato, David A. Bereiter, Koichi Iwata

Basic Sciences

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

The P2Y₂ receptor agonist, diquafosol sodium, is commonly used to treat the signs and symptoms of dry eye disease (DE) patients. Although diquafosol improves tear film stability, the neural mechanisms underlying the reduction in ocular pain are not well defined. This study determined if repeated application of diquafosol reduces the sensitization of nociceptive neurons in the lower trigeminal brainstem nuclear complex (TBNC) via peripheral P2Y₂ mechanisms in a rat model for DE. Diquafosol was applied to the ocular surface daily for 28 days, starting at day 0 or day 14, after exorbital gland removal. The number of eyeblinks, P2Y₂-immunoreactive neurons in the trigeminal ganglion (TG), and correlates of TBNC neural excitability (i.e., cFos protein and phosphorylated extracellular signal-regulated kinase (pERK) expression) were assessed in male rats. Diquafosol increased spontaneous tear volume and reduced the number of ocular surface-evoked eyeblinks in DE rats. Fluorogold-labeled TG neurons that supply the cornea expressed P2Y₂. The number of P2Y₂-immunoreactive neurons was increased in DE rats and suppressed by diquafosol. Diquafosol also reduced the number of cFos- and pERK-immunoreactive neurons in the TBNC in DE rats. These findings suggest that diquafosol, regardless of late-phase treatment, relieves ocular nociception in DE by reducing peripheral P2Y₂ expression.

Original language	English (US)
Pages (from-to)	66-76
Number of pages	11
Journal	Neuroscience Research
Volume	191
DOIs	https://doi.org/10.1016/j.neures.2023.01.003
State	Published - Jun 2023

Bibliographical note

Funding Information:
This work was supported by a grant from Santen Pharmaceutical Co. The authors wish to thank Drs. S Sugawara, S Kishimoto, H Saito, S Okada for their early contributions to this project. We would like to thank Editage (www.editage.com) for English language editing. This work was supported by Santen Pharmaceutical Co. (to AK and KI), and diquafosol sodium was provided by Santen Pharmaceutical Co. Kazuo Tsubota acts as a consultant and receives research funding from Santen Pharmaceutical Co. Ltd. (outside of this study) and is the CEO of Tsubota Laboratory, a company that develops treatments, prophylaxis, and medical devices for dry eye.

Funding Information:
This work was supported by a grant from Santen Pharmaceutical Co. The authors wish to thank Drs. S Sugawara, S Kishimoto, H Saito, S Okada for their early contributions to this project. We would like to thank Editage (www.editage.com) for English language editing.

Publisher Copyright:
© 2023 Elsevier Ltd and Japan Neuroscience Society

Keywords

Central sensitization
Dry eye
Ocular pain
P2Y agonist
Peripheral sensitization
Trigeminal brainstem nuclear complex
Trigeminal ganglion

PubMed: MeSH publication types

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Katagiri, A., Tsubota, K., Mikuzuki, L., Nakamura, S., Toyofuku, A., Kato, T., Bereiter, D. A., & Iwata, K. (2023). Tear secretion by Diquafosol suppresses the excitability of trigeminal brainstem nuclear complex neurons by reducing excessive P2Y₂ expression in the trigeminal ganglion in dry eye rats. Neuroscience Research, 191, 66-76. https://doi.org/10.1016/j.neures.2023.01.003

Katagiri, A, Tsubota, K, Mikuzuki, L, Nakamura, S, Toyofuku, A, Kato, T, Bereiter, DA & Iwata, K 2023, 'Tear secretion by Diquafosol suppresses the excitability of trigeminal brainstem nuclear complex neurons by reducing excessive P2Y₂ expression in the trigeminal ganglion in dry eye rats', Neuroscience Research, vol. 191, pp. 66-76. https://doi.org/10.1016/j.neures.2023.01.003

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title = "Tear secretion by Diquafosol suppresses the excitability of trigeminal brainstem nuclear complex neurons by reducing excessive P2Y2 expression in the trigeminal ganglion in dry eye rats",

abstract = "The P2Y2 receptor agonist, diquafosol sodium, is commonly used to treat the signs and symptoms of dry eye disease (DE) patients. Although diquafosol improves tear film stability, the neural mechanisms underlying the reduction in ocular pain are not well defined. This study determined if repeated application of diquafosol reduces the sensitization of nociceptive neurons in the lower trigeminal brainstem nuclear complex (TBNC) via peripheral P2Y2 mechanisms in a rat model for DE. Diquafosol was applied to the ocular surface daily for 28 days, starting at day 0 or day 14, after exorbital gland removal. The number of eyeblinks, P2Y2-immunoreactive neurons in the trigeminal ganglion (TG), and correlates of TBNC neural excitability (i.e., cFos protein and phosphorylated extracellular signal-regulated kinase (pERK) expression) were assessed in male rats. Diquafosol increased spontaneous tear volume and reduced the number of ocular surface-evoked eyeblinks in DE rats. Fluorogold-labeled TG neurons that supply the cornea expressed P2Y2. The number of P2Y2-immunoreactive neurons was increased in DE rats and suppressed by diquafosol. Diquafosol also reduced the number of cFos- and pERK-immunoreactive neurons in the TBNC in DE rats. These findings suggest that diquafosol, regardless of late-phase treatment, relieves ocular nociception in DE by reducing peripheral P2Y2 expression.",

keywords = "Central sensitization, Dry eye, Ocular pain, P2Y agonist, Peripheral sensitization, Trigeminal brainstem nuclear complex, Trigeminal ganglion",

author = "Ayano Katagiri and Kazuo Tsubota and Lou Mikuzuki and Shigeru Nakamura and Akira Toyofuku and Takafumi Kato and Bereiter, {David A.} and Koichi Iwata",

note = "Funding Information: This work was supported by a grant from Santen Pharmaceutical Co. The authors wish to thank Drs. S Sugawara, S Kishimoto, H Saito, S Okada for their early contributions to this project. We would like to thank Editage (www.editage.com) for English language editing. This work was supported by Santen Pharmaceutical Co. (to AK and KI), and diquafosol sodium was provided by Santen Pharmaceutical Co. Kazuo Tsubota acts as a consultant and receives research funding from Santen Pharmaceutical Co. Ltd. (outside of this study) and is the CEO of Tsubota Laboratory, a company that develops treatments, prophylaxis, and medical devices for dry eye. Funding Information: This work was supported by a grant from Santen Pharmaceutical Co. The authors wish to thank Drs. S Sugawara, S Kishimoto, H Saito, S Okada for their early contributions to this project. We would like to thank Editage (www.editage.com) for English language editing. Publisher Copyright: {\textcopyright} 2023 Elsevier Ltd and Japan Neuroscience Society",

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AU - Mikuzuki, Lou

AU - Nakamura, Shigeru

AU - Toyofuku, Akira

AU - Kato, Takafumi

AU - Bereiter, David A.

AU - Iwata, Koichi

N1 - Funding Information: This work was supported by a grant from Santen Pharmaceutical Co. The authors wish to thank Drs. S Sugawara, S Kishimoto, H Saito, S Okada for their early contributions to this project. We would like to thank Editage (www.editage.com) for English language editing. This work was supported by Santen Pharmaceutical Co. (to AK and KI), and diquafosol sodium was provided by Santen Pharmaceutical Co. Kazuo Tsubota acts as a consultant and receives research funding from Santen Pharmaceutical Co. Ltd. (outside of this study) and is the CEO of Tsubota Laboratory, a company that develops treatments, prophylaxis, and medical devices for dry eye. Funding Information: This work was supported by a grant from Santen Pharmaceutical Co. The authors wish to thank Drs. S Sugawara, S Kishimoto, H Saito, S Okada for their early contributions to this project. We would like to thank Editage (www.editage.com) for English language editing. Publisher Copyright: © 2023 Elsevier Ltd and Japan Neuroscience Society

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N2 - The P2Y2 receptor agonist, diquafosol sodium, is commonly used to treat the signs and symptoms of dry eye disease (DE) patients. Although diquafosol improves tear film stability, the neural mechanisms underlying the reduction in ocular pain are not well defined. This study determined if repeated application of diquafosol reduces the sensitization of nociceptive neurons in the lower trigeminal brainstem nuclear complex (TBNC) via peripheral P2Y2 mechanisms in a rat model for DE. Diquafosol was applied to the ocular surface daily for 28 days, starting at day 0 or day 14, after exorbital gland removal. The number of eyeblinks, P2Y2-immunoreactive neurons in the trigeminal ganglion (TG), and correlates of TBNC neural excitability (i.e., cFos protein and phosphorylated extracellular signal-regulated kinase (pERK) expression) were assessed in male rats. Diquafosol increased spontaneous tear volume and reduced the number of ocular surface-evoked eyeblinks in DE rats. Fluorogold-labeled TG neurons that supply the cornea expressed P2Y2. The number of P2Y2-immunoreactive neurons was increased in DE rats and suppressed by diquafosol. Diquafosol also reduced the number of cFos- and pERK-immunoreactive neurons in the TBNC in DE rats. These findings suggest that diquafosol, regardless of late-phase treatment, relieves ocular nociception in DE by reducing peripheral P2Y2 expression.

AB - The P2Y2 receptor agonist, diquafosol sodium, is commonly used to treat the signs and symptoms of dry eye disease (DE) patients. Although diquafosol improves tear film stability, the neural mechanisms underlying the reduction in ocular pain are not well defined. This study determined if repeated application of diquafosol reduces the sensitization of nociceptive neurons in the lower trigeminal brainstem nuclear complex (TBNC) via peripheral P2Y2 mechanisms in a rat model for DE. Diquafosol was applied to the ocular surface daily for 28 days, starting at day 0 or day 14, after exorbital gland removal. The number of eyeblinks, P2Y2-immunoreactive neurons in the trigeminal ganglion (TG), and correlates of TBNC neural excitability (i.e., cFos protein and phosphorylated extracellular signal-regulated kinase (pERK) expression) were assessed in male rats. Diquafosol increased spontaneous tear volume and reduced the number of ocular surface-evoked eyeblinks in DE rats. Fluorogold-labeled TG neurons that supply the cornea expressed P2Y2. The number of P2Y2-immunoreactive neurons was increased in DE rats and suppressed by diquafosol. Diquafosol also reduced the number of cFos- and pERK-immunoreactive neurons in the TBNC in DE rats. These findings suggest that diquafosol, regardless of late-phase treatment, relieves ocular nociception in DE by reducing peripheral P2Y2 expression.

KW - Central sensitization

KW - Dry eye

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KW - Trigeminal ganglion

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