**4. Potential inflammation-targeting in diabetic retinopathy**

Over the years, significant effort has been made to develop new strategies for the treatment of DR by targeting inflammation. Clinical and pre-clinical trials have tested a variety of anti-inflammatory therapeutics.

#### **4.1 Steroids**

Intravitreal injection of crystalline cortisone was first reported in 2001 by Jonas et al. [88]. Their mechanism of action consist in repressing pro-inflammatory transcription factors. Several routes of administration were tried but the oral steroids were avoided because of the high risk of DM exacerbation and systemic complications [89]. Tamura et al. found that intravitreal injection of dexamethasone suppresses the leukostasis, the up-regulation of ICAM-1 and also prevents retinal vascular leakage [90]. Since it seems to target different pathways than those targeted by anti-VEGF agents, corticosteroids may improve DME [91]. Especially DME with SRD, no HRF and a continuous ellipsoid zone at the fovea seems to have a better response to injectable dexamethasone implant, as shown by previous studies [92], explained by the increased concentrations of inflammatory cytokines and IL-6 found in the AH and VH of eyes with SRD. In a similar manner, intravitreal triamcinolone has proved to be effective in the resolution of cyst in the CME type of DME [93]. The source of intraretinal cyst is the liquefaction and necrosis of Müller cells which subsequently induces the production of prostaglandins and inflammatory cytokines. The better outcome of steroid might be explained by the reduction of Müller cells' swelling [94]. One study found better results for intravitreal injection of triamcinolone than with anti-VEGF therapy in reducing macular thickness and improving BCVA in patients with SRD but the authors requested

*Local Inflammatory Biomarkers and Potential Inflammation-Targeting Therapies in Diabetic… DOI: http://dx.doi.org/10.5772/intechopen.99807*

cautious interpretation of the results because of the short follow-up (24 weeks) and the increased risk of associated long-term complications like cataract and elevated intraocular pressure [95].

#### **4.2 NSAIDs**

Their anti-inflammatory activity is characterized by inhibiting the production of the two isoforms of cyclooxygenase enzyme-mediated eicosanoid (COX): COX-1 and COX-2. While COX-1 is involved in homeostatic processes, COX-2 produces pro-inflammatory Prostaglandins (PGE), like PGE2 and PGF2α [96]. In the retina of diabetic animal models, increased expression of COX-2 and PGE2 was found, and it seems that COX-2 has a pivotal role in DR pathogenesis since the inhibition of COX-2 but not COX-1 reduced the levels of PGE2 [97]. Retinal inflammatory reactions such as ICAM-1 expression and leukostasis were blocked after COX-2 inhibition [98]. Aspirin, sodium salicylate and sulfasalazine prevented capillary cell apoptosis and vessel degeneration while COX-2 inhibitors reduced vessel degeneration, vascular leakage and capillary cell apoptosis [99–101]. Moreover, retinal microaneurysm development was decreased by high doses of aspirin (900 mg/ day), as shown by the Early Treatment DR study and the Dipyridamole Aspirin Microangiopathy of Diabetes Study [102, 103]. While COX-2 inhibitors have the potential to increase the incidence of strokes and heart attacks, their use in clinical trial being discouraged [104], local COX-2 inhibitors have shown reduction of DR sigs similar to systemic COX-2 [105].

#### **4.3 SAR 1118**

It is a small-molecule antagonist of leukocyte function-associated antigen (LFA)-1 a cell surface adhesion molecule of the β2 (CD18) family of integrin receptors expressed on leukocytes, and intercellular adhesion molecule (ICAM)-1, expressed by endothelial cells. SAR 1118 inhibits the binding of LFA-1, to ICAM1–1, being capable of preventing leukocytes adhesion to endothelial cells in vivo [106]. Rao et al. found that SAR 1118 eye drops significantly reduced BRB breakdown and leukostasis in a dose dependent manner [106].

#### **4.4 Etanercept, infliximab**

Both drugs block TNF-α induced inflammation. High dose of etanercept reduced leukocyte adhesion and suppressed BRB breakdown, reduced ICAM-1 expression but it did not reduced the expression of CD11a, CD11b and CD18, and neither changed the retinal vascular endothelial growth factor levels [14]. After Infliximab administration, BCVA improved and CMT decreased [107]. But caution should be taken since intravitreal use of TNF-α inhibitors has proved to induce intraocular inflammation [56].

#### **4.5 Anti-CD49a neutralizing antibody**

Integrin alpha 4 (CD49d), in complex with integrin beta1, forms very late antigen-4 (VLA-4), which interacts with vascular cell adhesion molecule-1**,** being involved in leukocyte adhesion. Iliaki et al. showed that injection of an anti-alpha 4 integrin/CD49d neutralizing antibody reduced the diabetes induced upregulation of NF- kappaB activation, VEGF, and TNF-alpha protein levels and significantly reduced diabetes-induced leukocyte adhesion and vascular leakage [108].

#### **4.6 Vitamins C and E**

Another key mediator in inflammation is oxidative stress. Vitamin C attenuated the development of acellular capillaries [109] and vitamin E reversed some changes in the retinal vessels of diabetic patients [110].

#### **4.7 Soluble RAGE, LR-90**

The receptor for advanced glycation end products (AGEs) has been implicated in the pathogenesis of diabetic complications. When soluble RAGE, a competitor of cellular RAGE for its ligands was administered, neuronal dysfunction and reduced development of capillary lesions was proved by Barile et al. in mouse diabetic models [111].

#### **4.8 Apocynin, statin**

NAPDH oxidase activity blocking by apocynin reduces oxidative stress. Previous studies showed that by blocking NADPH oxidase, oxidative stress, retinal inflammation, vessel leakage as well as neovascularization are prevented [5].

#### **4.9 Captopril, Telmisartan, Talsartan, Olmesartan, candesartan, Enalapril**

The RAS system is involved in different DR pathways, such as oxidative stress and AGEs. Captopril proved to inhibit capillary degeneration in early stages of DR, while Losartan (an AT1R blocker) and Enalapril (angiotensin converting enzyme inhibitor) reduced the progression of DR by 70% and 65% respectively [112]. Retinal adherent leukocyte was significantly suppressed by telmisartan or valsartan [113].

#### **4.10 Plasma kallikrein inhibitors: KVD001 and THR-149**

Plasma kallikrein is involved in both VEGF-mediated and VEGF-independent mechanisms of DME. In a Phase 1B study, KVD001, a novel intravitreous plasma kallikrein selective competitive inhibitor was administered in DME eyes [114]. The authors of the previous study reported that KVD001 was safe and well tolerated while a significant number of eyes experienced a reduction of CRT (central retinal thickness) and BCVA improvement. Another recent Phase 2A study evaluated patients who received either a sham, a high dose or a low dose of 4 intravitreal injections of KVD001 at monthly intervals [115]. There were no statistical differences between the number of gained letters, neither regarding the central subfield thickness (CST) nor the diabetic retinopathy severity scale (DRSS) but only 32.5% of patients from the 6 μg dose group experienced a reduction in vision compared to 54.5% of patients from the sham group (p = 0.042) [116]. THR-149 is a reversible peptide inhibitor of plasma kallikrein, by inhibiting the release of bradykinin in the vitreous. Since it is VEGF-independent, anti-VEGF nonresponding patients could benefit from its effect. A Phase 1 study in which 12 patients were followed, proved THR-149 is safe and well tolerated while BCVA improved since day 1 and maintained until month 3 [117].

#### **5. Conclusions**

In accordance with the presented studies, multiple local laboratory and imaging biomarkers are involved in the onset and progression of DR, which could support and improve the screening, treatment and follow-up of these patients.

*Local Inflammatory Biomarkers and Potential Inflammation-Targeting Therapies in Diabetic… DOI: http://dx.doi.org/10.5772/intechopen.99807*

The encouraging positive effects of several tested drugs on BCVA but also on anatomical outcomes are likely to provide a background for further research.
