Therapeutics
Continued from page 11
11 Bockmann, S and Paegelow, I. Kinins and kinin receptors: importance for the activation of leukocytes. J Leukoc Biol, 2000. 68(5): p. 587-92. 12 Duchene, J et al. A novel inflammatory pathway involved in leukocyte recruitment: role for the kinin B1 receptor and the chemokine CXCL5. J Immunol, 2007. 179(7): p. 4849-56. 13 Ehrenfeld, P et al. Activation of kinin B1 receptors induces chemotaxis of human neutrophils. J Leukoc Biol, 2006. 80(1): p. 117-24. 14 Ma, JX et al. Expression and cellular localization of the kallikrein-kinin system in human ocular tissues. Exp Eye Res, 1996. 63(1): p. 19-26. 15 Bastian, S et al. Interleukin 8 (IL-8) induces the expression of kinin B1 receptor in human lung fibroblasts. Biochem Biophys Res Commun, 1998. 253(3): p. 750-5. 16 Abdouh, M et al. Retinal plasma extravasation in streptozotocin-diabetic rats mediated by kinin B(1) and B(2) receptors. Br J Pharmacol, 2008. 154(1): p. 136-43. 17 Phipps, JA and Feener, EP. The kallikrein-kinin system in diabetic retinopathy: lessons for the kidney. Kidney Int, 2008. 73(10): p. 1114-9. 18 Pouliot, M et al. Topical Treatment With the Kinin B1 Receptor Antagonist, FOV2304, Inhibits Diabetic Retinopathy (DR) in Rats. ARVO 2010, 5611-D732, Fort- Lauderdale, May 2-6, 2010. 19 Pruneau, D et al. Targeting the kallikrein-kinin system as a new therapeutic approach to diabetic retinopathy. Curr Opin Investig Drugs, 2010. 11(5): p. 507-14.
Diabetic retinopathy and inflammation Immunological processes play an important part in diabetic retinopathy. Diabetic retinopathy is char- acterised by typical features of low-level inflamma- tion such as elevated levels of circulating and vitre- ous cytokines, chemokines and growth factors. Chronic retinal leukostasis, the increased adher- ence of leukocytes to the capillary endothelium, leads to vascular leakage and haemorrhage6. Thus, targeting inflammation is another investi- gational approach to target diabetic retinopathy. Corticosteroids, established anti-inflammatory agents, are able to slow the progression of diabetic retinopathy, as demonstrated by a recent study; however, the authors concluded that any treatment used routinely to prevent PDR should have a favourable safety profile considering the high inci- dence of elevation of intra-ocular pressure and cataracts associated with intravitreal steroids10. Corticosteroids are injected intravitreally, and various extended-release corticosteroids for the long-term treatment of DME are currently under investigation (ie Iluvien® and Ozurdex®).
The kallikrein-kinin system in diabetic retinopathy
The kallikrein-kinin system (KKS) is a multi-pro- tein system that controls blood circulation and kid- ney function, and promotes inflammation and pain in pathological conditions. Plasma kallikrein trig- gers the contact cascade with its major components kallikrein and bradykinin. Kallikrein and the Hagemann factor (factor XIIa) autoactivate each other and subsequently stimulate the conversion of prekallikrein to kallikrein, leading the cleavage of high-molecular-weight kininogen (HMWK) to bradykinin. The biological downstream effects of the KKS are mediated by bradykinin, a peptide hormone that activates the G-protein coupled
receptors (GPCRs), kinin B1 and B2 receptors (B1R and B2R). The B2R is constitutively expressed in vascular and neuronal cells. The inducible B1R plays a major role in neutrophil recruitment and chemotaxis11-13 (Figure 1).
The activation of the kallikrein-kinin system has been shown to induce a host of proinflamma- tory responses.
Retinal inflammation is involved in the develop- ment of diabetic retinopathy, and accumulating evidence demonstrates a pivotal role for the KKS in the development of diabetic retinopathy. The KKS system is expressed in the human eye14, and high levels of carbonic anhydrase (CA-1), prekallikrein, IL-1, IL-8, TNF and IL-6 were found in the vit- reous of diabetic patients when compared to
12
healthy volunteers. CA-1 induces retinal oedema and haemorrhage through activation of the KKS, and IL-1, IL-8 and glucose upregulate the expres-
sion of B1R in vessels and leukocytes15. Furthermore, B1R messengerRNA (mRNA) was markedly increased in the retina of rats with strep-
tozotocin (STZ)-induced diabetes16. Phipps et al were able to show that intravitreous injection of recombinant plasma kallikrein induced retinal oedema and haemorrhage in diabetic rats, whereas systemic treatment with a kallikrein inhibitor reduced retinal vascular leakage17. Recent studies have shown that FOV-2304, a
non-peptide kinin B1R antagonist, abolished reti- nal vascular permeability, as well as leukostasis and leukocyte infiltration, hallmarks of diabetic retinopathy, in streptozotocin-induced diabetic rats18. Additionally, diabetes-induced up-regula- tion of the many mRNAs, such as endothelial nitric
oxide synthase (eNOS), nitric oxide (NO), B1R, B2R, VEGF and VEGF receptor type 2, was reversed after seven days eye-drop treatment of
FOV-230418. Current studies are evaluating the convenient and safe eye-drop formulation of FOV- 2304 in rabbits, a species with an eye volume sim- ilar to the human eye. The pharmacological block-
ade of the KKS system, in particular the kinin B1R, may provide an innovative and promising treat- ment approach for diabetic retinopathy19. DDW
Dr Didier Pruneau joined Fovea Pharmaceuticals in 2006 as head of scientific operations. Fovea Pharmaceuticals, a start-up company specialising in ocular diseases, was acquired by Sanofi-Aventis in October 2009 to build-up the Ophthalmology branch of the group. Before joining Fovea Pharmaceuticals, he successively headed a Cardiovascular Research Unit, a Receptor Pharmacochemistry Group and the Department of Pharmacology of Fournier Pharma that became part of Solvay Pharma in 2005. Didier Pruneau holds a PhD in biochemistry and a masters degree (Valedictorian) in pharmacology from the Paris V University. He was a post-doctoral fellow in car- diovascular pharmacology at Baker Medical Research Institute, Melbourne, Australia. He authored and co-authored 79 peer-reviewed scien- tific publications and about seventy scientific com- munications. He has been an invited speaker at various scientific meetings, including Gordon Research Conferences.
Drug Discovery World Summer 2010
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92