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New, potent, small molecule agonists of tyrosine kinase receptors attenuate dry eye disease

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin3 (NT-3) bind to tyrosine kinase (Trk) receptors, TrkA, TrkB, and TrkC, respectively. This study investigated the efficacy of novel molecule agonists of Trk receptors in an in vivo model of dry eye disease (DED). Sm...

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Autores principales: Yu, Zhiyuan, Joy, Shaon, Mi, Tianxiong, Yazdanpanah, Ghasem, Burgess, Kevin, de Paiva, Cintia S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9453230/
https://www.ncbi.nlm.nih.gov/pubmed/36091713
http://dx.doi.org/10.3389/fmed.2022.937142
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author Yu, Zhiyuan
Joy, Shaon
Mi, Tianxiong
Yazdanpanah, Ghasem
Burgess, Kevin
de Paiva, Cintia S.
author_facet Yu, Zhiyuan
Joy, Shaon
Mi, Tianxiong
Yazdanpanah, Ghasem
Burgess, Kevin
de Paiva, Cintia S.
author_sort Yu, Zhiyuan
collection PubMed
description Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin3 (NT-3) bind to tyrosine kinase (Trk) receptors, TrkA, TrkB, and TrkC, respectively. This study investigated the efficacy of novel molecule agonists of Trk receptors in an in vivo model of dry eye disease (DED). Small molecule TrkC agonist (C1) and a pan-Trk agonist (pan) were synthesized for this. C57BL/6J mice were subjected to desiccating stress (DS) and received bilateral eye drops of C1, pan, or vehicle (2x/day). Dry eye signs, inflammation and expression of corneal barrier function, and conjunctival goblet cell (GC) densities were measured as part of the DED phenotype. Corneal epithelial lysates were collected for either western blot or RNA extraction. Extracted total RNAs were used for NanoString analyses. Immunofluorescent staining was performed on whole-mount corneas using anti-TNFAIP3 and anti-EP4 antibodies. Compared to vehicle, mice subjected to desiccating stress and treated with agonists pan and C1 showed improved corneal barrier function, while C1 also increased GC density. NanoString analyses revealed upregulation of specific mRNA transcripts (Ptger4, Tnfaip3, Il1a and Ptger4, Tlr3, Osal1) in pan- and C1-treated corneas compared to vehicle-treated corneas. Western blots showed that pan and C1 decreased vehicle-induced NFkB nuclear translocation after DS for one day and increased EP4 and TNFAIP3 protein levels after 5 days of DS in corneal epithelium lysates. We conclude that small-molecule agonists of Trk receptors improve DED by decreasing NFkB activation and increasing protein expression of anti-inflammatory molecules TNFAIP3 and EP4. Surprisingly, the most efficacious small molecule agonists were not TrkA selective but TrkC and panTrk, suggesting that wider exploration of TrkB and C and pan Trk agonists are warranted in efforts to treat DED.
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spelling pubmed-94532302022-09-09 New, potent, small molecule agonists of tyrosine kinase receptors attenuate dry eye disease Yu, Zhiyuan Joy, Shaon Mi, Tianxiong Yazdanpanah, Ghasem Burgess, Kevin de Paiva, Cintia S. Front Med (Lausanne) Medicine Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin3 (NT-3) bind to tyrosine kinase (Trk) receptors, TrkA, TrkB, and TrkC, respectively. This study investigated the efficacy of novel molecule agonists of Trk receptors in an in vivo model of dry eye disease (DED). Small molecule TrkC agonist (C1) and a pan-Trk agonist (pan) were synthesized for this. C57BL/6J mice were subjected to desiccating stress (DS) and received bilateral eye drops of C1, pan, or vehicle (2x/day). Dry eye signs, inflammation and expression of corneal barrier function, and conjunctival goblet cell (GC) densities were measured as part of the DED phenotype. Corneal epithelial lysates were collected for either western blot or RNA extraction. Extracted total RNAs were used for NanoString analyses. Immunofluorescent staining was performed on whole-mount corneas using anti-TNFAIP3 and anti-EP4 antibodies. Compared to vehicle, mice subjected to desiccating stress and treated with agonists pan and C1 showed improved corneal barrier function, while C1 also increased GC density. NanoString analyses revealed upregulation of specific mRNA transcripts (Ptger4, Tnfaip3, Il1a and Ptger4, Tlr3, Osal1) in pan- and C1-treated corneas compared to vehicle-treated corneas. Western blots showed that pan and C1 decreased vehicle-induced NFkB nuclear translocation after DS for one day and increased EP4 and TNFAIP3 protein levels after 5 days of DS in corneal epithelium lysates. We conclude that small-molecule agonists of Trk receptors improve DED by decreasing NFkB activation and increasing protein expression of anti-inflammatory molecules TNFAIP3 and EP4. Surprisingly, the most efficacious small molecule agonists were not TrkA selective but TrkC and panTrk, suggesting that wider exploration of TrkB and C and pan Trk agonists are warranted in efforts to treat DED. Frontiers Media S.A. 2022-08-25 /pmc/articles/PMC9453230/ /pubmed/36091713 http://dx.doi.org/10.3389/fmed.2022.937142 Text en Copyright © 2022 Yu, Joy, Mi, Yazdanpanah, Burgess and de Paiva. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Yu, Zhiyuan
Joy, Shaon
Mi, Tianxiong
Yazdanpanah, Ghasem
Burgess, Kevin
de Paiva, Cintia S.
New, potent, small molecule agonists of tyrosine kinase receptors attenuate dry eye disease
title New, potent, small molecule agonists of tyrosine kinase receptors attenuate dry eye disease
title_full New, potent, small molecule agonists of tyrosine kinase receptors attenuate dry eye disease
title_fullStr New, potent, small molecule agonists of tyrosine kinase receptors attenuate dry eye disease
title_full_unstemmed New, potent, small molecule agonists of tyrosine kinase receptors attenuate dry eye disease
title_short New, potent, small molecule agonists of tyrosine kinase receptors attenuate dry eye disease
title_sort new, potent, small molecule agonists of tyrosine kinase receptors attenuate dry eye disease
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9453230/
https://www.ncbi.nlm.nih.gov/pubmed/36091713
http://dx.doi.org/10.3389/fmed.2022.937142
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