Adenosine A3 receptor activation is neuroprotective against retinal neurodegeneration. (November 2015)

• Record Type: Journal Article
• Authors: Galvao, Joana; Elvas, Filipe; Martins, Tiago; Cordeiro, M. Francesca; Ambrósio, António Francisco; Santiago, Ana Raquel
• Is Part Of: Experimental eye research. Volume 140(2015:Nov.)
• Page Start: 65
• Page End: 74
• Publication Date: 2015-11
• Subjects: A3 adenosine receptor -- Retinal ganglion cell -- Neuroprotection -- Excitotoxicity -- Ischemia-reperfusion -- Axon injury; A3R A3 receptor -- AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid -- CTZ cyclothiazide -- DARC Detection of Apoptosing Retinal Cells -- DIV days in vitro -- I-R Ischemia-reperfusion -- KA kainic acid -- pONT partial optic nerve transection -- RGC retinal ganglion cell -- TUNEL Terminal deoxynucleotidyl transferase dUTP nick end labeling; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2015.08.009
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: Death of retinal neural cells, namely retinal ganglion cells (RGCs), is a characteristic of several retinal neurodegenerative diseases. Although the role of adenosine A3 receptor (A3 R) in neuroprotection is controversial, A3 R activation has been reported to afford protection against several brain insults, with few studies in the retina. In vitro models (retinal neural and organotypic cultures) and animal models [ischemia-reperfusion (I-R) and partial optic nerve transection (pONT)] were used to study the neuroprotective properties of A3 R activation against retinal neurodegeneration. The A3 R selective agonist (2-Cl-IB-MECA, 1 μM) prevented apoptosis (TUNEL + -cells) induced by kainate and cyclothiazide (KA + CTZ) in retinal neural cultures (86.5 ± 7.4 and 37.2 ± 6.1 TUNEL + -cells/field, in KA + CTZ and KA + CTZ + 2-Cl-IB-MECA, respectively). In retinal organotypic cultures, 2-Cl-IB-MECA attenuated NMDA-induced cell death, assessed by TUNEL (17.3 ± 2.3 and 8.3 ± 1.2 TUNEL + -cells/mm 2 in NMDA and NMDA+2-Cl-IB-MECA, respectively) and PI incorporation (ratio DIV4/DIV2 3.3 ± 0.3 and 1.3 ± 0.1 in NMDA and NMDA+2-Cl-IB-MECA, respectively) assays. Intravitreal 2-Cl-IB-MECA administration afforded protection against I-R injury decreasing the number of TUNEL + cells by 72%, and increased RGC survival by 57%. Also, intravitreal administration of 2-Cl-IB-MECA inhibited apoptosis (from 449.4 ± 37.8 to 207.6 ± 48.9 annexin-V + -cells) and RGC loss (from 1.2 ± 0.6 to 8.1 ± 1.7 cells/mm) induced by pONT. This study demonstrates that 2-Cl-IB-MECA is neuroprotective to the retina, both in vitro and in vivo . Activation of A3 R may have great potential in the management of retinal neurodegenerative diseases characterized by RGC death, as glaucoma and diabetic retinopathy, and ischemic diseases. Highlights: A3 R activation protects retinal neural cells against glutamatergic excitotoxicity. A3 R activation protects against cell death induced by ischemia-reperfusion injury. A3 R activation protects against cell death induced by partial optic nerve transection.