Adenosine A(3) receptor activation is neuroprotective against retinal neurodegeneration

作者：Galvao Joana; Elvas Filipe; Martins Tiago; Cordeiro M Francesca; Ambrosio Antonio Francisco; Santiago Ana Raquel^*

来源：Experimental Eye Research, 2015, 140: 65-74.

DOI：10.1016/j.exer.2015.08.009

• A(3) adenosine receptor
• Retinal ganglion cell
• Neuroprotection
• Excitotoxicity
• Ischemia-reperfusion
• Axon injury

Death of retinal neural cells, namely retinal ganglion cells (RGCs), is a characteristic of several retinal neurodegenerative diseases. Although the role of adenosine A(3) receptor (A(3)R) in neuroprotection is controversial, A(3)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 A(3)R activation against retinal neurodegeneration. The A(3)R selective agonist (2-Cl-IB-MECA, 1 mu M) 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 13 +/- 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 A(3)R may have great potential in the management of retinal neurodegenerative diseases characterized by RGC death, as glaucoma and diabetic retinopathy, and ischemic diseases.

• 出版日期2015-11