Yuan Xingyue, Li Ya, Cong Lin, Yang Lingling, Zhang Yangyang, Zhang Zhenzhen, Wang Ting, Dong Muchen, Du Xianli, Xie Lixin, Zhou Qingjun
State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266071, China.
Qingdao Eye Hospital of Shandong First Medical University, Qingdao, 266071, China.
Commun Biol. 2025 Mar 22;8(1):481. doi: 10.1038/s42003-025-07903-5.
Norepinephrine (NE) is mainly released by sympathetic nerve terminals to act on organs and tissues. After corneal epithelial debridement, we found that the sympathetic nerve fibers penetrated the limbus and regenerated toward the cornea within 24 h post-wounding. Topical NE application recapitulated the characteristics of delayed corneal epithelial wound healing and nerve regeneration in healthy mice, accompanied by the partial depletion of multiple neurotrophins, such as nerve growth factor and glial cell-derived nerve growth factor. Moreover, the diabetes mellitus (DM) mice exhibited corneal sensory nerve dysfunction and increased plasma and corneal NE contents, which were rescued by 6-hydroxydopamine (6-OHDA) and bretylium. In the cell culture model, the conditioned medium of NE-treated corneal epithelial cells inhibited trigeminal ganglion (TG) neurite outgrowth, which was reversed by the β2 adrenergic receptor (ADRB2) antagonist, but not by the β1 adrenergic receptor (ADRB1) antagonist. Topical application of the ADRB2 antagonist recovered the expression of corneal neurotrophins, and promoted corneal epithelial and nerve regeneration in DM mice. Taken together, the NE-ADRB2 axis regulates corneal neurotrophin expression and nerve regeneration in mice. Topical application of the ADRB2 antagonist may represent a promising therapeutic strategy for diabetic corneal sensory nerve dysfunction.
去甲肾上腺素（NE）主要由交感神经末梢释放，作用于器官和组织。角膜上皮清创术后，我们发现交感神经纤维在受伤后24小时内穿过角膜缘并向角膜再生。局部应用NE可重现健康小鼠角膜上皮伤口愈合延迟和神经再生的特征，同时伴有多种神经营养因子的部分消耗，如神经生长因子和胶质细胞源性神经生长因子。此外，糖尿病（DM）小鼠表现出角膜感觉神经功能障碍，血浆和角膜NE含量增加，而6-羟基多巴胺（6-OHDA）和溴苄铵可使其恢复。在细胞培养模型中，NE处理的角膜上皮细胞的条件培养基抑制三叉神经节（TG）神经突生长，β2肾上腺素能受体（ADRB2）拮抗剂可逆转这种抑制作用，而β1肾上腺素能受体（ADRB1）拮抗剂则不能。局部应用ADRB2拮抗剂可恢复DM小鼠角膜神经营养因子的表达，并促进角膜上皮和神经再生。综上所述，NE-ADRB2轴调节小鼠角膜神经营养因子的表达和神经再生。局部应用ADRB2拮抗剂可能是治疗糖尿病角膜感觉神经功能障碍的一种有前景的治疗策略。
