鼻腔黏膜-三叉神经节-角膜神经通路在药物防治糖尿病性角膜病变中的作用及其机制研究

The standard clinical treatment of diabetic keratopathy may be ineffective, and the outcome is often severe impairment or loss of vision. The cornea displays the highest nerve fiber density in the whole human body, comprising innervating nerves that originate from the ophthalmic division of the trigeminal nerve. The nasal mucosa also contains innervating nerves that originate from the ophthalmic and maxillary division of the trigeminal nerve. In our previous experimental work, we found pathological changes in both cornea and trigeminal ganglia in diabetic mice, such as oxidative stress imbalances and ultrastructural destruction. Curcumin can be transported to both the trigeminal ganglia and the corneal tissue when it was encapsulated into the nanomicelle and delivered via intranasal administration in diabetic mice, and it was also found that the nanomicellar curcumin could significantly enhance recovery of corneal epithelium/nerve after injury when delivered via intranasal administration. Based on these points, we propose the following two theories: (1) Trigeminal neuropathy occurs with diabetic keratopathy, and successful treatment of the trigeminal neuropathy is benificial to the treatment of diabetic keratopathy. (2) The nasal mucosa epithelium - trigeminal ganglion - corneal nerve transporting pathway is realized as a route to transport drugs to the trigeminal ganglion during the treatment of diabetic keratopathy. Based on these two theories, an innovative intranasal administration of nanomicellar curcumin is designed to treat the eye diseases such as diabetic keratopathy through the nasal mucosa epithelium - trigeminal ganglion - corneal nerve transporting pathway. The purpose of this study is to enrich the knowledge of the pathway and provide novel targets for the therapy of diabetic keratopathy.

糖尿病性角膜病变表现为反复的上皮糜烂、持续性上皮缺损等，可最终导致角膜溃疡甚至穿孔，而临床无有效手术或药物等治疗措施。我们前期研究发现：糖尿病小鼠不仅发生角膜上皮和角膜神经病变，还可发生三叉神经节病理性改变，但现眼科临床常规药物等治疗对三叉神经节干预作用弱；鼻腔给药显著促进糖尿病小鼠角膜上皮/神经损伤后修复且疗效优于滴眼给药；鼻腔给药可吸收至三叉神经节并进一步吸收至角膜。基于上述发现，本课题首次提出并实验验证如下理论：①糖尿病可引起三叉神经节病变，且该病变与糖尿病性角膜病变有密切联系，干预三叉神经节病变有助于治疗糖尿病性角膜病变；②提出存在鼻腔黏膜-三叉神经节-角膜神经通路，通过该通路药物有效吸收至三叉神经节，干预三叉神经节病变，并协助实现有效治疗糖尿病性角膜病变。以上述理论为基础，本课题创新性设计鼻腔给药以鼻治眼，提高糖尿病性角膜病变治疗效果，为糖尿病性角膜病变治疗提供新思路和理论基础。

糖尿病性角膜病变表现为反复的上皮糜烂、持续性上皮缺损等，可最终导致角膜溃疡甚至穿孔，而临床无有效手术或药物等治疗措施。因此，研究糖尿病性角膜病变新的治疗靶标和有效防治措施具有重要的临床意义。经过4年的研究，本课题取得如下相应的研究进展：1基于三叉神经解剖学分布特点(即三叉神经广泛分布于眼部角膜、鼻腔黏膜等组织)和课题组前期研究发现，本课题首次提出并确证存在“鼻腔黏膜-三叉神经节-角膜神经通路”，即药物经鼻腔给药后，可主要由鼻黏膜中广泛分布的三叉神经吸收后转运至三叉神经节，进一步递送至眼部角膜神经末梢；创新性地设计鼻腔给药“以鼻治眼”，通过鼻腔黏膜-三叉神经节-角膜神经通路治疗糖尿病性三叉神经节病变和角膜病变，从而提高糖尿病性角膜病变治疗效果，为糖尿病性角膜病变治疗研究开拓新的研究领域和干预策略；2糖尿病性角膜病变干预新靶点研究方面，首次发现HMGB1可能是糖尿病性角膜病变发生发展中起重要作用的关键分子，靶向调控HMGB1有望用于防治糖尿病性角膜病变。但是糖尿病病理状态下角膜HMGB1信号通路及其关键调控分子尚未明确，尚需进一步研究。研究结果有望揭示糖尿病性角膜病变新的发病机制，为临床防治提供新思路和理论依据；3基于糖尿病性角膜病变新发现的靶点及其特异性抑制剂的特性，本课题首次将HMGB1抑制剂甘草酸为药物载体，计载药纳米滴眼液，达到了调控HMGB1而发挥干预糖尿病性角膜病变作用，并依据此思路构建了一系列的眼科纳米药物并对其体内外特性进行了实验研究。通过本课题资助研究，目前已发表论文22篇，在连续四届（2018-2021）的全国眼科学术大会等全国性学术会议作会议发言10人次；获授权国家发明专利2项；本项目培养副高职称1名，培养研究生5名。