Maria Madeira

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

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José Cunha‐Vaz

Association for Innovation and Biomedical Research on Light and Image

Ana Raquel Santiago

University of Coimbra

António Francisco Ambrósio

University of Coimbra

Inês Marques

University of Coimbra

Torcato Santos

Fundação Oswaldo Cruz

Ana Rita Santos

University of Coimbra

Conceição Lobo

University of Coimbra

João Figueira

University of Coimbra

Raquel Boia

University of Coimbra

Bindhu V. Karanam

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

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

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United States Military Academy

108

University of Coimbra

Association for Innovation and Biomedical Research on Light and Image

Merck (Japan)

Harvard University

Merck Institute for Science Education

Hospitais da Universidade de Coimbra

KU Leuven

Centro de Neurociências e Biologia Celular

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Controlling neuroinflammation in the retina through A2AR modulation: potential therapeutic implication in glaucoma

Maria Madeira

Tese de doutoramento em Ciencias da Saude, na especialidade de Ciencias Biomedicas apresentada a Faculdade de Medicina da Universidade de Coimbra

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Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects

Bioorganic & Medicinal Chemistry Letters (2016)

Matthew Lombardo Kate Bender Clare London Michael A. Plotkin Melissa Kirkland

Propanoic acid

Pharmacodynamics

GPR120

Lead compound

Benzofuran

10.1016/j.bmcl.2016.10.054

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Citations (24)

Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors

Journal of Medicinal Chemistry (2017)

Tim Cernak Nathan J. Gesmundo Kevin D. Dykstra Yang Yu Zhicai Wu

Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SNAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure–activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.

Microscale chemistry

High-Throughput Screening

Benzimidazole

10.1021/acs.jmedchem.6b01543

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Common and rare genetic risk variants for Age-related Macular Degeneration progression in the Coimbra Eye Study.

Cláudia Farinha Patrícia Barreto Rita Coimbra Maria Luz Cachulo Joana Barbosa Melo

Degeneration (medical)

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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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Citations (59)

Characterization of risk phenotypes of type 2 diabetes nonproliferative retinopathy

Investigative Ophthalmology & Visual Science (2021)

Conceição Lobo Luísa Ribeiro Rita Coimbra Maria Madeira Marta B. Lopes

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Association between visual acuity loss and disease pathways in the initial stages of nonproliferative retinopathy in type 2 diabetes

Investigative Ophthalmology & Visual Science (2021)

Diana Tavares Inês Marques Maria Madeira Ana Rita Santos Torcato Santos

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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)