A hypothermia mimetic molecule (zr17-2) reduces ganglion cell death and electroretinogram distortion in a rat model of intraorbital optic nerve crush (IONC)
Introduction: Ocular and periocular traumatisms may result in loss of vision. Our previous work showed that therapeutic hypothermia prevents retinal damage caused by traumatic neuropathy. We also generated and characterized small molecules that elicit the beneficial effects of hypothermia at normal...
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1112318/full |
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| author | Daniela S. Contartese Manuel Rey-Funes Rafael Peláez Manuel Soliño Juan C. Fernández Ronan Nakamura Nicolás S. Ciranna Aníbal Sarotto Verónica B. Dorfman Juan J. López-Costa José M. Zapico Ana Ramos Beatriz de Pascual-Teresa Ignacio M. Larrayoz César F. Loidl Alfredo Martínez |
| author_facet | Daniela S. Contartese Manuel Rey-Funes Rafael Peláez Manuel Soliño Juan C. Fernández Ronan Nakamura Nicolás S. Ciranna Aníbal Sarotto Verónica B. Dorfman Juan J. López-Costa José M. Zapico Ana Ramos Beatriz de Pascual-Teresa Ignacio M. Larrayoz César F. Loidl Alfredo Martínez |
| author_sort | Daniela S. Contartese |
| collection | DOAJ |
| description | Introduction: Ocular and periocular traumatisms may result in loss of vision. Our previous work showed that therapeutic hypothermia prevents retinal damage caused by traumatic neuropathy. We also generated and characterized small molecules that elicit the beneficial effects of hypothermia at normal body temperature. Here we investigate whether one of these mimetic molecules, zr17-2, is able to preserve the function of eyes exposed to trauma.Methods: Intraorbital optic nerve crush (IONC) or sham manipulation was applied to Sprague-Dawley rats. One hour after surgery, 5.0 µl of 330 nmol/L zr17-2 or PBS, as vehicle, were injected in the vitreum of treated animals. Electroretinograms were performed 21 days after surgery and a- and b-wave amplitude, as well as oscillatory potentials (OP), were calculated. Some animals were sacrificed 6 days after surgery for TUNEL analysis. All animal experiments were approved by the local ethics board.Results: Our previous studies showed that zr17-2 does not cross the blood-ocular barrier, thus preventing systemic treatment. Here we show that intravitreal injection of zr17-2 results in a very significant prevention of retinal damage, providing preclinical support for its pharmacological use in ocular conditions. As previously reported, IONC resulted in a drastic reduction in the amplitude of the b-wave (p < 0.0001) and OPs (p < 0.05), a large decrease in the number of RGCs (p < 0.0001), and a large increase in the number of apoptotic cells in the GCL and the INL (p < 0.0001). Interestingly, injection of zr17-2 largely prevented all these parameters, in a very similar pattern to that elicited by therapeutic hypothermia. The small molecule was also able to reduce oxidative stress-induced retinal cell death in vitro.Discussion: In summary, we have shown that intravitreal injection of the hypothermia mimetic, zr17-2, significantly reduces the morphological and electrophysiological consequences of ocular traumatism and may represent a new treatment option for this cause of visual loss. |
| first_indexed | 2024-04-10T20:55:59Z |
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| language | English |
| last_indexed | 2024-04-10T20:55:59Z |
| publishDate | 2023-01-01 |
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| spelling | doaj.art-c3692b7a46e34c249641c84f1b254f082023-01-23T05:07:08ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-01-011410.3389/fphar.2023.11123181112318A hypothermia mimetic molecule (zr17-2) reduces ganglion cell death and electroretinogram distortion in a rat model of intraorbital optic nerve crush (IONC)Daniela S. Contartese0Manuel Rey-Funes1Rafael Peláez2Manuel Soliño3Juan C. Fernández4Ronan Nakamura5Nicolás S. Ciranna6Aníbal Sarotto7Verónica B. Dorfman8Juan J. López-Costa9José M. Zapico10Ana Ramos11Beatriz de Pascual-Teresa12Ignacio M. Larrayoz13César F. Loidl14Alfredo Martínez15Departamento de Biología Celular, Histología, Embriología y Genética, Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” (IBCN), UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartamento de Biología Celular, Histología, Embriología y Genética, Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” (IBCN), UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaBiomarkers and Molecular Signaling, Neurodegenerative Diseases Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, SpainDepartamento de Biología Celular, Histología, Embriología y Genética, Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” (IBCN), UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartamento de Biología Celular, Histología, Embriología y Genética, Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” (IBCN), UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartamento de Biología Celular, Histología, Embriología y Genética, Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” (IBCN), UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartamento de Biología Celular, Histología, Embriología y Genética, Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” (IBCN), UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartamento de Biología Celular, Histología, Embriología y Genética, Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” (IBCN), UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaCentro de Estudios Biomédicos Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimónides, Buenos Aires, ArgentinaDepartamento de Biología Celular, Histología, Embriología y Genética, Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” (IBCN), UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartment of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, SpainDepartment of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, SpainDepartment of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, SpainBiomarkers and Molecular Signaling, Neurodegenerative Diseases Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, SpainDepartamento de Biología Celular, Histología, Embriología y Genética, Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” (IBCN), UBA-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaAngiogenesis Group, Center for Biomedical Research of La Rioja, Logroño, SpainIntroduction: Ocular and periocular traumatisms may result in loss of vision. Our previous work showed that therapeutic hypothermia prevents retinal damage caused by traumatic neuropathy. We also generated and characterized small molecules that elicit the beneficial effects of hypothermia at normal body temperature. Here we investigate whether one of these mimetic molecules, zr17-2, is able to preserve the function of eyes exposed to trauma.Methods: Intraorbital optic nerve crush (IONC) or sham manipulation was applied to Sprague-Dawley rats. One hour after surgery, 5.0 µl of 330 nmol/L zr17-2 or PBS, as vehicle, were injected in the vitreum of treated animals. Electroretinograms were performed 21 days after surgery and a- and b-wave amplitude, as well as oscillatory potentials (OP), were calculated. Some animals were sacrificed 6 days after surgery for TUNEL analysis. All animal experiments were approved by the local ethics board.Results: Our previous studies showed that zr17-2 does not cross the blood-ocular barrier, thus preventing systemic treatment. Here we show that intravitreal injection of zr17-2 results in a very significant prevention of retinal damage, providing preclinical support for its pharmacological use in ocular conditions. As previously reported, IONC resulted in a drastic reduction in the amplitude of the b-wave (p < 0.0001) and OPs (p < 0.05), a large decrease in the number of RGCs (p < 0.0001), and a large increase in the number of apoptotic cells in the GCL and the INL (p < 0.0001). Interestingly, injection of zr17-2 largely prevented all these parameters, in a very similar pattern to that elicited by therapeutic hypothermia. The small molecule was also able to reduce oxidative stress-induced retinal cell death in vitro.Discussion: In summary, we have shown that intravitreal injection of the hypothermia mimetic, zr17-2, significantly reduces the morphological and electrophysiological consequences of ocular traumatism and may represent a new treatment option for this cause of visual loss.https://www.frontiersin.org/articles/10.3389/fphar.2023.1112318/fulltraumatic optic neuropathytherapeutic hypothermiahypothermia mimeticsintravitreal injectionelectroretinogramapoptosis |
| spellingShingle | Daniela S. Contartese Manuel Rey-Funes Rafael Peláez Manuel Soliño Juan C. Fernández Ronan Nakamura Nicolás S. Ciranna Aníbal Sarotto Verónica B. Dorfman Juan J. López-Costa José M. Zapico Ana Ramos Beatriz de Pascual-Teresa Ignacio M. Larrayoz César F. Loidl Alfredo Martínez A hypothermia mimetic molecule (zr17-2) reduces ganglion cell death and electroretinogram distortion in a rat model of intraorbital optic nerve crush (IONC) Frontiers in Pharmacology traumatic optic neuropathy therapeutic hypothermia hypothermia mimetics intravitreal injection electroretinogram apoptosis |
| title | A hypothermia mimetic molecule (zr17-2) reduces ganglion cell death and electroretinogram distortion in a rat model of intraorbital optic nerve crush (IONC) |
| title_full | A hypothermia mimetic molecule (zr17-2) reduces ganglion cell death and electroretinogram distortion in a rat model of intraorbital optic nerve crush (IONC) |
| title_fullStr | A hypothermia mimetic molecule (zr17-2) reduces ganglion cell death and electroretinogram distortion in a rat model of intraorbital optic nerve crush (IONC) |
| title_full_unstemmed | A hypothermia mimetic molecule (zr17-2) reduces ganglion cell death and electroretinogram distortion in a rat model of intraorbital optic nerve crush (IONC) |
| title_short | A hypothermia mimetic molecule (zr17-2) reduces ganglion cell death and electroretinogram distortion in a rat model of intraorbital optic nerve crush (IONC) |
| title_sort | hypothermia mimetic molecule zr17 2 reduces ganglion cell death and electroretinogram distortion in a rat model of intraorbital optic nerve crush ionc |
| topic | traumatic optic neuropathy therapeutic hypothermia hypothermia mimetics intravitreal injection electroretinogram apoptosis |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1112318/full |
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