**The Herbal Combination CPA4-1 Inhibits Changes in Retinal Capillaries and Reduction of Retinal Occludin in db**/**db Mice**

**Young Sook Kim 1,**†**, Junghyun Kim 2,3,**†**, Chan-Sik Kim 4, Ik Soo Lee 1, Kyuhyung Jo 1, Dong Ho Jung 2, Yun Mi Lee 2 and Jin Sook Kim 2,\***


Received: 24 June 2020; Accepted: 14 July 2020; Published: 16 July 2020

**Abstract:** Increased formation of advanced glycation end products (AGEs) plays an important role in the development of diabetic retinopathy (DR) via blood-retinal barrier (BRB) dysfunction, and reduction of AGEs has been suggested as a therapeutic target for DR. In this study, we examined whether CPA4-1, a herbal combination of Cinnamomi Ramulus and Paeoniae Radix, inhibits AGE formation. CPA4-1 and fenofibrate were tested to ameliorate changes in retinal capillaries and retinal occludin expression in db/db mice, a mouse model of obesity-induced type 2 diabetes. CPA4-1 (100 mg/kg) or fenofibrate (100 mg/kg) were orally administered once a day for 12 weeks. CPA4-1 (the half maximal inhibitory concentration, IC50 = 6.84 ± 0.08 μg/mL) showed approximately 11.44-fold higher inhibitory e ffect on AGE formation than that of aminoguanidine (AG, the inhibitor of AGEs, IC50 = 78.28±4.24 μg/mL), as well as breaking e ffect on AGE-bovine serum albumin crosslinking with collagen (IC50 = 1.30 ± 0.37 μg/mL). CPA4-1 treatment ameliorated BRB leakage and tended to increase retinal occludin expression in db/db mice. CPA4-1 or fenofibrate treatment significantly reduced retinal acellular capillary formation in db/db mice. These findings suggested the potential of CPA4-1 as a therapeutic supplement for protection against retinal vascular permeability diseases.

**Keywords:** diabetic retinopathy; db/db mice; Cinnamomi Ramulus; Paeoniae Radix; CPA4-1; blood-retinal barrier; occludin
