2. Academic Validation
  3. Norepinephrine regulates epithelial-derived neurotrophins expression and sensory nerve regeneration through ADRB2 receptor

Norepinephrine regulates epithelial-derived neurotrophins expression and sensory nerve regeneration through ADRB2 receptor

  • Commun Biol. 2025 Mar 22;8(1):481. doi: 10.1038/s42003-025-07903-5.
Xingyue Yuan # 1 2 3,  Ya Li # 1 2,  Lin Cong 1 2,  Lingling Yang 1 2,  Yangyang Zhang 1 2,  Zhenzhen Zhang 1 2,  Ting Wang 1 4,  Muchen Dong 1 4,  Xianli Du 1 2,  Lixin Xie 1 2,  Qingjun Zhou 5 6
Affiliations

Affiliations

  • 1 State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266071, China.
  • 2 Qingdao Eye Hospital of Shandong First Medical University, Qingdao, 266071, China.
  • 3 Department of Pathology, Deyang People's Hospital, Deyang, 618000, China.
  • 4 Eye Hospital of Shandong First Medical University, Jinan, 250021, China.
  • 5 State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266071, China. qjzhou2000@hotmail.com.
  • 6 Qingdao Eye Hospital of Shandong First Medical University, Qingdao, 266071, China. qjzhou2000@hotmail.com.
  • # Contributed equally.
PMID: 40121310 DOI: 10.1038/s42003-025-07903-5
Abstract

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.

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