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

Madeira, Maria; Boia, Raquel; Elvas, Filipe; Martins, Tiago; Cunha, Rodrigo A.; Ambrósio, António Francisco; Santiago, Ana Raquel

doi:10.1016/j.trsl.2015.11.005

Cited by 77 publications

(116 citation statements)

References 79 publications

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“…43 Furthermore, a selective A 2A AR antagonist (SCH58261, 33) prevented ischemia-reperfusion death of retinal ganglion cells arising from transient elevation of IOP. 60 The neuroprotection was thought to have been mediated by attenuating the microglial-mediated neuroinflammatory response. 55,60 Another caveat is that the effect of A 2A AR agonists on IOP is expected to be unfavorable since the A 2A AR antagonist ZM241385 31 lowered pressure in the mouse, 33 while activation of A 2A ARs transiently increased pressure in rabbit and cynomolgus monkey eyes.…”

mentioning

confidence: 99%

“…60 The neuroprotection was thought to have been mediated by attenuating the microglial-mediated neuroinflammatory response. 55,60 Another caveat is that the effect of A 2A AR agonists on IOP is expected to be unfavorable since the A 2A AR antagonist ZM241385 31 lowered pressure in the mouse, 33 while activation of A 2A ARs transiently increased pressure in rabbit and cynomolgus monkey eyes. 61 In short, A 2A AR agonists and antagonists have multiple effects, and current published evidence that A 2A AR agonists would be helpful in glaucoma is not yet compelling.…”

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confidence: 99%

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Ocular Purine Receptors as Drug Targets in the Eye

Civan

2016

Journal of Ocular Pharmacology and Therapeutics

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Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are under consideration as agents for the treatment of ocular diseases, including glaucoma and dry eye. Numerous nucleoside and nonnucleoside modulators of the receptors are available as research tools and potential therapeutic molecules. Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A 1 , A 2A , and A 3 . An A 1 AR agonist is in clinical trials for glaucoma, A 2A AR reduces neuroinflammation, A 3 AR protects retinal ganglion cells from apoptosis, and both A 3 AR agonists and antagonists had been reported to lower intraocular pressure (IOP). Extracellular concentrations of endogenous nucleotides, including dinucleoside polyphosphates, are increased in pathological states, activating P2Y and P2XRs throughout the eye. P2YR agonists, including P2Y 2 and P2Y 6 , lower IOP. Antagonists of the P2X7R prevent the ATP-induced neuronal apoptosis in the retina. Thus, modulators of the purinome in the eye might be a source of new therapies for ocular diseases.

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confidence: 99%

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confidence: 99%

Ocular Purine Receptors as Drug Targets in the Eye

Civan

2016

Journal of Ocular Pharmacology and Therapeutics

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“…Further studies have demonstrated that the release of IL-6 by microglial cells elicited by EHP is able to reduce the pressure-induced apoptotic cascade triggered by glial cells [33] . A recent study reported microglia activation and upregulation of adenosine A 2A receptors in retinal microglial cell cultures following exposure to 70 mm Hg for 4 or 24 h [54] . Microglia activation and RGC death were also reported in retinal organotypic cultures exposed to the same conditions [24] .…”

Section: Pressurized Chambermentioning

confidence: 96%

“…These systems provide a constant hydrostatic pressure within ±1 mm Hg and allow stable control of the pressure influx to the chamber [24][25][26][33][34][35][36][37] , while control cells are usually kept at atmospheric pressure (760 mm Hg) in standard cell incubators [22,25,[33][34][35][37][38][39][40][41][42] or in some cases exposed to 15 mm Hg to mimic normotensive conditions [27,[43][44][45][46] . Cell lines (RGC-5, B35, and PC12) [25-27, 35, 39, 40, 47] , primary cultures of RGC and astrocytes [41,[48][49][50] , Müller cell cultures [38,51,52] , or microglial cell cultures [24,48,53,54] , and more complex preparations like organotypic retinal cultures [24] and eye cup preparations [44,45,55,56] have been exposed to EHP. In addition, human retinal cells, human organotypic retinal cultures [37] , and human optic nerve head (ONH) astrocytes [41,49,…”

Section: The Ehp Modelmentioning

confidence: 99%

Modeling Human Glaucoma: Lessons from the in vitro Models

Aires

Ambrósio²,

Santiago³

2016

Ophthalmic Res

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Glaucoma, a leading cause of blindness worldwide, is a degenerative disease characterized by retinal ganglion cell (RGC) loss and optic nerve atrophy. Elevated intraocular pressure (IOP) is a main risk factor for onset and progression of the disease. Since increased IOP is the only modifiable risk factor, relevant models for glaucoma would comprise RGC and optic nerve damage triggered by ocular hypertension. Animal models of glaucoma have greatly contributed to the understanding of the molecular mechanisms of this pathology, and they have also facilitated the development of new pharmacological interventions. Although animal models of glaucoma have provided valuable information about the disease, there is still no ideal model for studying glaucoma due to its complexity. There is a recognized demand for in vitro models that can replace or reduce the need for animal experiments. Several in vitro models have emerged as a great opportunity in the field of glaucoma research, helping to clarify the mechanisms involved in disease progression. Several types of equipment have been developed to expose cells and tissue cultures to elevated pressures. Herein, we discuss the methodology used to increase pressure, the main findings, and the relevance of in vitro models for the study of the pathophysiology of glaucoma.

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“…In fact, the blockade of A 2A R also has neuroprotective effects, protecting retinal function and structure in a model of retinal ischemia [102]. Moreover, we have recently demonstrated that the blockade of A 2A R affords protection to the retina by controlling microglia-mediated neuroinflammation [103,104]. …”

Section: A2ar Blockade: Potential Therapeutic Strategy For Neuroprotementioning

confidence: 99%

Therapeutic Opportunities for Caffeine and A<sub>2A</sub> Receptor Antagonists in Retinal Diseases

Boia

Ambrósio²,

Santiago³

2016

Ophthalmic Res

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Caffeine, the major component of coffee, is the most consumed psychostimulant in the world. Caffeine is an adenosine analog and acts as a nonselective adenosine receptor antagonist. The majority of the effects of caffeine are mainly mediated by the blockade of adenosine receptors, and the proved neuroprotective effects of caffeine in brain disorders have been mimicked by the blockade of adenosine A_2A receptor (A_2AR). A growing body of evidence demonstrates that microglia-mediated neuroinflammation plays a key role in the pathophysiology of brain and retinal diseases. Moreover, the control of microglia reactivity by blocking A_2AR has been proposed to be the mechanism underlying the observed protective effects of caffeine. Hence, it is conceivable that caffeine and A_2AR antagonists offer therapeutic value for the treatment of retinal diseases, mainly those involving microglia-mediated neuroinflammation.

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

Cited by 77 publications

References 79 publications

Ocular Purine Receptors as Drug Targets in the Eye

Ocular Purine Receptors as Drug Targets in the Eye

Modeling Human Glaucoma: Lessons from the in vitro Models

Therapeutic Opportunities for Caffeine and A<sub>2A</sub> Receptor Antagonists in Retinal Diseases

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