Ana Raquel Santiago

University of Coimbra

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António Francisco Ambrósio

University of Coimbra

Raquel Boia

University of Coimbra

Inês Aires

Hospital Curry Cabral

Maria Madeira

Merck & Co., Inc., Rahway, NJ, USA (United States)

Paulo F. Santos

University of Coimbra

Marta Agudo‐Barriuso

Instituto Murciano de Investigación Biosanitaria

Manuel Vidal‐Sanz

Universidad de Murcia

Armando J. Cristóvão

University of Coimbra

Caridad Galindo‐Romero

Universidad de Murcia

João Martins

University of Coimbra

Cooperative Institutions

University of Coimbra

111

Association for Innovation and Biomedical Research on Light and Image

Centro de Neurociências e Biologia Celular

Inserm

Hospitais da Universidade de Coimbra

Universidade do Porto

Université de Montpellier

Centre Hospitalier Universitaire de Montpellier

University College London

Centre National de la Recherche Scientifique

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Course of retinal ganglion cell loss and microglial activation in two models of neuronal degeneration

Acta Ophthalmologica (2022)

María Josefa González Riquelme Fernando Lucas‐Ruiz Raquel Boia Ana Raquel Santiago Manuel Vidal‐Sanz

Abstract Purpose Organotypic retinal cultures (COR) are inherently a model of retinal axotomy and detachment. In vivo, optic nerve axotomy causes degeneration of retinal ganglion cells (RGCs). Our objective is to evaluate and compare the time course of RGC death and the activation of microglial cells (MCs) in vivo and in vitro . Methods C57/Bl6 mice were used. For the in vitro model, retinas were dissected and cultured in supplemented medium, and axotomy in vivo was done to the left optic nerve. In both models, retinas were analyzed from 24 hours to 9 days. RGCs were immunodetected with Brn3a, MCs with Iba1 and the density in the medial retinal area was quantified for both populations. Results The loss of RGCs was similar in vivo and in vitro during the first days, but from 5 days onwards RGC loss is quicker and more abrupt in vitro than in vivo . MC morphology differs between both models and their density is smaller in vitro than in vivo at all time points. Conclusions RGCs loss in vitro and in vivo follows the same kinetics at early time points. Morphologically, MCs seem to be differently activated in both models, and because their density is lower in vitro than in vivo , it is possible that in vivo either MCs or circulating macrophages invade the retina to cope with RGC degeneration.

Axotomy

10.1111/j.1755-3768.2022.211

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Metabolite profiling of the effects of diabetes in rat retina by 1H NMR spectroscopy

Investigative Ophthalmology & Visual Science (2004)

A. F. Ambrósio Rui A. Carvalho Armando J. Cristóvão Ana Raquel Santiago M. Garrido

Metabolite profiling

Profiling (computer programming)

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In Vivo Characterization of Corneal Changes in a Type 1 Diabetic Animal Model

Ultrasound in Medicine & Biology (2018)

Miguel Caixinha Pedro Oliveira Inês Aires António Francisco Ambrósio Ana Raquel Santiago

High frequency ultrasound

10.1016/j.ultrasmedbio.2018.11.002

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Caffeine administration prevents retinal neuroinflammation and loss of retinal ganglion cells in an animal model of glaucoma

Scientific Reports (2016)

Maria Madeira Arturo Ortín-Martínez Francisco M. Nadal‐Nicolás António Francisco Ambrósio Manuel Vidal‐Sanz

Abstract Glaucoma is the second leading cause of blindness worldwide, being characterized by progressive optic nerve damage and loss of retinal ganglion cells (RGCs), accompanied by increased inflammatory response involving retinal microglial cells. The etiology of glaucoma is still unknown and despite elevated intraocular pressure (IOP) being a major risk factor, the exact mechanisms responsible for RGC degeneration remain unknown. Caffeine, which is an antagonist of adenosine receptors, is the most widely consumed psychoactive drug in the world. Several evidences suggest that caffeine can attenuate the neuroinflammatory responses and afford protection upon central nervous system (CNS) injury. We took advantage of a well characterized animal model of glaucoma to investigate whether caffeine administration controls neuroinflammation and elicits neuroprotection. Caffeine or water were administered ad libitum and ocular hypertension (OHT) was induced by laser photocoagulation of the limbal veins in Sprague Dawley rats. Herein, we show that caffeine is able to partially decrease the IOP in ocular hypertensive animals. More importantly, we found that drinking caffeine prevented retinal microglia-mediated neuroinflammatory response and attenuated the loss of RGCs in animals with ocular hypertension (OHT). This study opens the possibility that caffeine or adenosine receptor antagonists might be a therapeutic option to manage RGC loss in glaucoma.

Intravitreal administration

Adenosine receptor antagonist

10.1038/srep27532

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Intraocular implants loaded with A3R agonist rescue retinal ganglion cells from ischemic damage

Journal of Controlled Release (2022)

Raquel Boia Paulo A.N. Dias Caridad Galindo‐Romero Hugo Ferreira Inês Aires

Retinal ganglion cell (RGC) loss underlies several conditions which give rise to significant visual compromise, including glaucoma and ischaemic optic neuropathies. Neuroprotection of RGCs is a clinical well-defined unmet need in these diseases, and adenosine A3 receptor (A3R) activation emerges as a therapeutic pharmacological approach to protect RGCs. A porous biodegradable intraocular implant loaded with 2-Cl-IB-MECA (selective A3R agonist) was used as a strategy to protect RGCs. Drug-loaded PCL implants released 2-Cl-IB-MECA for an extended period and the released 2-Cl-IB-MECA limited glutamate-evoked calcium (Ca2+) rise in RGCs. Retinal thinning due to transient ischemia was not prevented by 2-Cl-IB-MECA-PCL implant. However, 2-Cl-IB-MECA-PCL implants decreased retinal cell death, promoted the survival of RGCs, preserved optic nerve structure and anterograde axonal transport. We further demonstrated that 2-Cl-IB-MECA-loaded PCL implants were able to enhance RGC function that was compromised by transient ischemia. Taking into consideration the beneficial effects afforded by 2-Cl-IB-MECA released from the PCL implant, this can be envisaged a good therapeutic strategy to protect RGCs.

10.1016/j.jconrel.2022.02.001

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Editorial: Molecular and cellular players of axonal regeneration in injured CNS

Frontiers in Neuroscience (2023)

Ana Raquel Santiago Inês Aires Marta Agudo‐Barriuso Raquel Boia

EDITORIAL article Front. Neurosci., 01 November 2023Sec. Neurodegeneration Volume 17 - 2023 | https://doi.org/10.3389/fnins.2023.1315632

10.3389/fnins.2023.1315632

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Comparative Analysis of Retinal Organotypic Cultures and In Vivo Axotomized Retinas

International Journal of Molecular Sciences (2023)

María José González‐Riquelme Fernando Lucas‐Ruiz Caridad Galindo‐Romero Raquel Boia António Francisco Ambrósio

Retinal organotypic cultures (ROCs) are used as an in vivo surrogate to study retinal ganglion cell (RGC) loss and neuroprotection. In vivo, the gold standard to study RGC degeneration and neuroprotection is optic nerve lesion. We propose here to compare the course of RGC death and glial activation between both models. The left optic nerve of C57BL/6 male mice was crushed, and retinas analyzed from 1 to 9 days after the injury. ROCs were analyzed at the same time points. As a control, intact retinas were used. Retinas were studied anatomically to assess RGC survival, microglial, and macroglial activation. Macroglial and microglial cells showed different morphological activation between models and were activated earlier in ROCs. Furthermore, microglial cell density in the ganglion cell layer was always lower in ROCs than in vivo. RGC loss after axotomy and in vitro followed the same trend up to 5 days. Thereafter, there was an abrupt decrease in viable RGCs in ROCs. However, RGC somas were still immuno-identified by several molecular markers. ROCs are useful for proof-of-concept studies on neuroprotection, but long-term experiments should be carried out in vivo. Importantly, the differential glial activation observed between models and the concomitant death of photoreceptors that occurs in vitro may alter the efficacy of RGC neuroprotective therapies when tested in in vivo models of optic nerve injury.

Axotomy

10.3390/ijms24043481

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Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro

Scientific Reports (2018)

Maria Madeira Khalid Rashid António Francisco Ambrósio Ana Raquel Santiago Thomas Langmann

Age-related macular degeneration (AMD) is characterized by pathological changes in the retinal pigment epithelium (RPE) and loss of photoreceptors. Growing evidence has demonstrated that reactive microglial cells trigger RPE dysfunction and loss of photoreceptors, and inflammasome pathways and complement activation contribute to AMD pathogenesis. We and others have previously shown that adenosine A2A receptor (A2AR) blockade prevents microglia-mediated neuroinflammatory processes and mediates protection to the retina. However, it is still unknown whether blocking A2AR in microglia protects against the pathological features of AMD. Herein, we show that an A2AR antagonist, SCH58261, prevents the upregulation of the expression of pro-inflammatory mediators and the alterations in the complement system triggered by an inflammatory challenge in human microglial cells. Furthermore, blockade of A2AR in microglia decreases the inflammatory response, as well as complement and inflammasome activation, in ARPE-19 cells exposed to conditioned medium of activated microglia. Finally, we also show that blocking A2AR in human microglia increases the clearance of apoptotic photoreceptors. This study opens the possibility of using selective A2AR antagonists in therapy for AMD, by modulating the interplay between microglia, RPE and photoreceptors.

Adenosine A2A receptor

10.1038/s41598-018-20733-2

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Citations (48)

Selective A2A receptor antagonist prevents microglia-mediated neuroinflammation and protects retinal ganglion cells from high intraocular pressure–induced transient ischemic injury

Translational research (2015)

Maria Madeira Raquel Boia Filipe Elvas Tiago Martins Rodrigo A. Cunha

Proinflammatory cytokine

Adenosine A2A receptor

10.1016/j.trsl.2015.11.005

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Citations (76)