Stimulation of the adenosine A3 receptor, not the A1 or A2 receptors, promote neurite outgrowth of retinal ganglion cells

被引:18
|
作者
Nakashima, Kei-Ichi [1 ]
Iwao, Keiichiro [1 ,2 ]
Inoue, Toshihiro [1 ]
Haga, Akira [1 ]
Tsutsumi, Takayuki [1 ]
Mochita, Miyuki Inoue [1 ]
Fujimoto, Tomokazu [1 ]
Tanihara, Hidenobu [1 ]
机构
[1] Kumamoto Univ, Fac Life Sci, Dept Ophthalmol, Kumamoto, Japan
[2] Kengun Sakuragi Eye Clin, Kumamoto, Japan
关键词
Adenosine receptors; Neuroregeneration; Glaucoma; Akt; 2-Cl-IB-MECA; TRAUMATIC OPTIC NEUROPATHY; OPEN-ANGLE GLAUCOMA; CYCLIC-AMP; AXON REGENERATION; INTRAOCULAR-PRESSURE; TENSION GLAUCOMA; MESSENGER-RNAS; POTENTIAL ROLE; NERVE HEAD; IN-VIVO;
D O I
10.1016/j.exer.2018.02.019
中图分类号
R77 [眼科学];
学科分类号
100212 ;
摘要
Among candidate neuroprotective agents, adenosine is thought to be a possible treatment for central nervous system disorders. Adenosine elicits biological effects through four G protein-coupled receptors (A;, A(2A), A(2B,) and A(3)). The A(2A) and A(2B) receptors stimulate adenylyl cyclase (AC) and increase cyclic adenosine monophosphate (cAMP) levels, whereas A(1) and A(3) receptors inhibit AC and decrease cAMP levels. Several studies have investigated the effects of adenosine receptors (AdoRs) in glaucoma, because modulation of A(1),A(2A,) or A(3) receptor regulates intraocular pressure. In addition, AdoR-related phenomena may induce neuroprotective effects in retinal neurons. Notably, A(1,) A(2A,) and A(3) receptor agonists reportedly inhibit retinal ganglion cell (RGC) death in m vitro and in vivo glaucoma models. However, there is limited knowledge of the effects of AdoR activation on neurite outgrowth or the regeneration of RGCs. In this report, we described the role of an AdoR subtype in neurite outgrowth and RGC axonal regeneration. The distribution of AdoRs in the retina was evaluated by lmmunohistochemical analysis. Using primary cultured rat RGCs in vitro and an optic nerve crush model m vivo, neurite elongation was evaluated after stimulation by the following AdoR agonists: CHA, an A(1) receptor agonist; CGS21680, an A(2A) receptor agonist; BAY60-6583, an A(2B) receptor agonist; and 2-C1-IB-MECA, an A(3) receptor agonist. To determine the mechanism of neunte promotion, the candidate molecules of signal transduction associated with the neurite elongation of AdoRs were evaluated by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, respectively. All four AdoRs (A(1), A(2A) A(2B), and A(3)) were present in the inner retinal layers. Among the agonists for AdoR, only 2-C1-IB-MECA significantly promoted neurite outgrowth m primary cultured RGCs. Signaling pathway analyses showed that 2-C1-IB-MECA caused upregulated phosphorylation of Akt in cultured RGCs. Additionally, LY294002, an inhibitor of Akt, suppressed the neunte-promoting effects of the A(3) receptor agonist in RGCs. Moreover, 2-C1-IB-MECA increased the number of regenerating axons in the optic nerve crush model. Taken together, these data indicate that activation of the A(3) receptor, not the A(3) or A(2) receptors, promotes in vitro and in vivo neurite outgrowth during the regeneration of rat RGCs, which is caused by the activation of an Akt-dependent signaling pathway. Therefore, AdoR activation may be a promising candidate for the development of novel regenerative modalities for glaucoma and other optic neuropathies.
引用
收藏
页码:160 / 168
页数:9
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