Li Lina, Patko Evelin, Szabo Edina, Molitor Dorottya, Meresz Balazs, Reglodi Dora, Varga Andras, Denes Diana, Dai Lei, Wang Hongjie, Vaczy Alexandra, Atlasz Tamas
Department of Anatomy, HUN-REN-PTE PACAP Research Team, Centre for Neuroscience, University of Pecs Medical School, Szigeti Str. 12, H-7624 Pecs, Hungary.
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Int J Mol Sci. 2025 Apr 16;26(8):3753. doi: 10.3390/ijms26083753.
The continuously growing diabetes population is a significant concern with type 2 diabetic retinal disease (T2DRD), which is a leading cause of permanent blindness. However, the underlying pathophysiological mechanism of T2DRD has not yet been fully understood. Pituitary adenylate cyclase-activating polypeptide (PACAP) was first isolated from the ovine hypothalamus based on its stimulating effect on the adenylate cyclase enzyme in anterior pituitary cells. PACAP38 (PACAP with 38 amino acids) activates anti-apoptotic pathways, inhibits pro-apoptotic signaling, and creates an anti-inflammatory environment in the retina. The aim of the present study was to test the possible retinoprotective effect of the topical administration of PACAP38 in a type 2 diabetic animal model induced by a high-fat diet and the intraperitoneally injected low-dose streptozotocin (STZ). Wistar rats were divided into four groups: the control, control + PACAP38, diabetes, and diabetes + PACAP38 groups randomly. Type 2 diabetes was induced with the combination of STZ (30 mg/kg) and a high-fat diet. All rats were treated topically two times a day for 16 weeks: the control + PACAP38 and diabetes + PACAP38 groups were applied with PACAP38 eye drops (1 µg/drop), while the control and diabetes groups were administered using vehicles (artificial tears). The diabetes model was validated by a fasting oral glucose tolerance test (OGTT) and C-peptide ELISA test. Animals were monitored during the whole experiment for the progression of the disease using electroretinography (ERG) and optical coherence tomography (OCT). Post-mortem immunohistochemistry and a vessel analysis were performed in the retina samples after 16 weeks. An OGTT, a C-peptide ELISA test, and the investigation of blood parameters proved the development of type 2 diabetes. Significant differences could be detected in visual function between the two diabetic groups at week 16 (in the a-wave, b-wave, and OP amplitudes), where the diabetes PACAP38-treated group was similar to the control ones. OCT measurements correlated with ERG data, where the total retinal thickness was preserved in the diabetes + PACAP38 group. PACAP38 also protected the microvascular structure in the retina. Topically administered PACAP38 has potent neuroprotective effects against type 2 diabetic retinal disease; therefore, it could be a promising therapeutic approach for the treatment of T2DRD.
不断增长的糖尿病患者群体是2型糖尿病视网膜疾病（T2DRD）的一个重大问题，该疾病是永久性失明的主要原因。然而，T2DRD潜在的病理生理机制尚未完全明确。垂体腺苷酸环化酶激活多肽（PACAP）最初是从羊下丘脑分离出来的，基于其对垂体前叶细胞中腺苷酸环化酶的刺激作用。PACAP38（含38个氨基酸的PACAP）激活抗凋亡途径，抑制促凋亡信号传导，并在视网膜中营造抗炎环境。本研究的目的是测试在高脂饮食和腹腔注射低剂量链脲佐菌素（STZ）诱导的2型糖尿病动物模型中局部应用PACAP38可能的视网膜保护作用。将Wistar大鼠随机分为四组：对照组、对照组 + PACAP38组、糖尿病组和糖尿病 + PACAP38组。通过STZ（30 mg/kg）与高脂饮食联合诱导2型糖尿病。所有大鼠每天局部给药两次，持续16周：对照组 + PACAP38组和糖尿病 + PACAP38组滴入PACAP38滴眼液（1 µg/滴），而对照组和糖尿病组给予赋形剂（人工泪液）。通过空腹口服葡萄糖耐量试验（OGTT）和C肽ELISA试验验证糖尿病模型。在整个实验过程中，使用视网膜电图（ERG）和光学相干断层扫描（OCT）监测动物疾病进展。16周后对视网膜样本进行死后免疫组织化学和血管分析。OGTT、C肽ELISA试验和血液参数检测证实了2型糖尿病的发展。在第16周时，两个糖尿病组之间的视觉功能（a波、b波和OP振幅）存在显著差异，其中糖尿病PACAP38治疗组与对照组相似。OCT测量结果与ERG数据相关，糖尿病 + PACAP38组的视网膜总厚度得以保留。PACAP38还保护了视网膜中的微血管结构。局部应用PACAP38对2型糖尿病视网膜疾病具有强大的神经保护作用；因此，它可能是治疗T2DRD的一种有前景的治疗方法。
