Clinical picture of uveitis in the presence of ocular hypertension and improvement in disease course with dipeptide carnosine
I. M. Mikheytseva, N. V. Bondarenko, S. G. Kolomiichuk, T. I. Siroshtanenko
SI «The Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine»; Odesa, Ukraine
TO CITE THIS ARTICLE: Mykheitseva IM, Bondarenko NV, Kolomiichuk SG, Siroshtanenko TI. Clinical picture of uveitis in the presence of ocular hypertension and improvement in disease course with dipeptide carnosine. J.ophthalmol.(Ukraine).2020;6:55-61. http://doi.org/10.31288/oftalmolzh202115561
Background: Our previous studies have demonstrated that raised IOP can contribute to an increase in the severity of inflammatory processes in the anterior segment. Given the involvement of free radical processes in the pathogenesis of uveitis, it is reasonable to use antioxidative agents for the treatment of the disease. The naturally occurring dipeptide carnosine (beta-alanyl-L-histidine) is a highly bioavailable low-molecular hydrophilic antioxidant with a direct effect on certain oxidant species and indirect effect on the system protecting the body from radicals; it contributes to membrane stabilization and can improve inflammatory processes.
Purpose: To examine the features of the clinical course of experimental anterior uveitis developing in the presence of ophthalmic hypertension (OHT), and to improve the course with dipeptide carnosine.
Material and Methods: Thirty-four rabbits were divided into three groups (group 1, 10 animals with induced allergic uveitis; group 2, 12 animals with OHT induced prior to experimental allergic uveitis; and group 3, 12 animals treated with carnosine for experimental allergic uveitis in the presence of OHT). Animals underwent biomicroscopy, ophthalmoscopy and tonometry. The number of white blood cells (WBC) in the aqueous humor of the anterior chamber was assessed microscopically, and total protein concentration was determined with the Lawry assay.
Results: There were significant differences in the conjunctival and scleral injection (р=0.0001), pattern of keratic precipitates (р=0.0009), anterior chamber content (р=0.0034), pattern of posterior synechiae (р=0.0025), vitreous opacity (р=0.0338), and fundus pathology (р=0.0001) between groups of anterior uveitis-only and that with OHT. Even at four weeks of induced anterior uveitis, the number of WBC and the total protein in the aqueous humor of the anterior chamber were 14.3% (p > 0.05) and 27.5%, respectively, higher in in eyes of group 2 compared to eyes of group 1. The course of inflammatory process was significantly more severe in eyes with anterior uveitis in the presence of OHT than in eyes with uveitis-only, based on the comparison in major clinical signs in the anterior and posterior segments. Binocular instillation of carnosine solution in the conjunctival sac for 4 weeks resulted in a significant decrease in the severity of inflammatory process in the anterior and posterior segments in eyes of group 3, leading to an improved clinical picture and restoration of the blood-aqueous barrier and ciliary body transport, with a 45.8% decrease in the WBC and 31.6% decrease in total protein in the aqueous humor of the anterior chamber in treated eyes compared to untreated eyes with induced non-infectious anterior uveitis in the presence of OHT (р < 0.01).
Conclusion: Integration of carnosine into the therapeutic regimen for ocular inflammation in the presence of raised IOP would substantially improve treatment outcomes and reduce the complication rate.
Keywords: anterior uveitis, ocular hypertension, carnosine, rabbits
1.Grechanyĭ MP, Chentsova OB, Kil'diushevskiĭ AV. [Ethiology, pathogenesis and prospects for treating autoimmune eye diseases]. Vestn Oftalmol. Sep-Oct 2002;118(5):47-51. Russian.
2.Herbert HM, Viswanathan A, Jackson H, Lightman SL. Risk factors for elevated intraocular pressure in uveitis. J Glaucoma. 2004;13:96–9.
3.Kopaienko AI. [Ocular hypertension in patients with endogenous anterior uveitis: risk factors and treatment]. Tavricheskiĭ mediko-biologicheskiĭ vestnik. 2010; 13(1):113-5. Russian.
4.Kurysheva NI, Vinetskaia MI, Erichev VP, Demchuk ML, Kuryshev SI. [Contribution of free-radical reactions of chamber humor to the development of primary open-angle glaucoma].Vestn Oftalmol. 1996 Sep-Oct;112(4):3-5. Russian.
5.Alekseev VN, Martynova EB, Sadkov VI. [Role of peroxidation in the pathogenesis of primary open-angle glaucoma]. Oftalmol Zh. 2000;1:12-7. Russian.
6.Ko M, Peng P, Ma M. Dynamic changes in reactive oxygen species and antioxidant levels in retinas in experimental glaucoma. Free Radic Biol Med. 2005 Aug 1;39(3):365-73.
7.Ielskiĭ VN, Mykheitseva IM. [Dysregulatory aspects of the glaucomatous process (review of the literature and own investigations]. Zhurnal NAMN Ukrainy. 2011;17(3):235-44. Russian.
8.Mikheitseva IM, Bondarenko NV, Kolomiichuk SG, Siroshtanenko TI. Oxidation and peroxidation in the uvea of the rabbit eyes with experimental uveitis and ocular hypertension. J Ophthalmol (Ukraine). 2019;4:57-63.
9.Boldyrev AA, Aldini G, Derave W. Physiology and Pathophysiology of Carnosine. Physiol Rev. 2013 Oct;93(4):1803-45.
10.Babizhayev МА, Kasus-Jacobi A. State of the Art Clinical Efficacy and Safety Evaluation of N-acetylcarnosine Dipeptide Ophthalmic Prodrug. Principles for the Delivery, Self-Bioactivation, Molecular Targets and Interaction With a Highly Evolved Histidyl-Hydrazide Structure in the Treatment and Therapeutic Management of a Group of Sight-Threatening Eye Diseases. Curr Clin Pharmacol. 2009;4(1):4-37.
11.Volkov OA. [Biological role of carnosine ant its use in ophthalmology (minisurvey of literature)]. Biomeditsinskaia khimiia. 2005;51(5):481-4. Russian.
12.Information Bulletin No. 19 issued 10.10.2019, based on Pat. of Ukraine №137,107; MPK (2019.01) А61К 9/00. [Method for inducing non-infectious uveitis in the presence of ocular hypertension]. Authors: Mykheitseva IM, Kolomiichuk SG, Bondarenko NV, Siroshtanenko TI. Owner: State Institution Filatov Institute of Eye Diseases and Tissue Therapy, NAMS of Ukraine.
13.Larson E, Howlet B, Jagendorf A. Artificial reductant enhancement of the Lowry method for protein determination. Anal Biochem. 1986 Jun;155(2):243-8.
14.Chesnokova NB, Neroev VV, Beznos OV, Beyshenova GA, Panova IG, Tatikolov AS. [Effects of dexamethasone and superoxide dismutase instillations on clinical course of uveitis and local biochemical processes (experimental study)]. Vestn Oftalmol. 2015 May-Jun;131(3):71-5. Russian.
15.Pavliuchenko KP, Kravtsova NB. [Effect of thiotriazolin and acetylcysteine in the intensity of inflammatory process in experimental uveitis]. Oftalmol Zh. 2006;6:46-9. Russian.
16.Babizhayev MA, Yermakova VN, Sakina NL. N-alpha-acetylcarnosine is a prodrug of L-carnosine in ophthalmic application as antioxidant. Clin Chim Acta. 1996 Oct 15;254(1):1-21.
17.Min J, Senut MC, Rajanikant K, et al. Differential neuroprotective effects of carnosine, anserine, and N-acetyl carnosine against permanent focal ischemia. J Neurosci Res. 2008 Oct;86(13):2984-91.
18.Oganesian AA, Minasian AG, Seiranian VM, Akopian VE. [Efficacy of N-acetylcarnosine in diabetic retinopathy]. Med nauka Armenii, NAN RA. 2009;2:57-67. Russian.
19.Iarygina EG, Prokopieva VD, Bokhan NA. [Oxidative stress and its improvement with]. Uspekhi sovremennogo estestvoznaniia. 2015;4:106-13. Russian.
20.Babizhayev M. A. Generation of reactive oxygen species in the anterior eye segment. Synergistic codrugs of N-acetylcarnosine lubricant eye drops and mitochondria-targeted antioxidant act as a powerful therapeutic platform for the treatment of cataracts and primary open-angle glaucoma. BBA Clin. 2016 Dec;19:49–68.
21.Savko VV, Khelifi Amani, Parkhomenko TV. [Effect of allergic uveitis on peroxidation characteristics of lipids of the aqueous humor of the anterior chamber in experimental glaucoma]. Oftalmol Zh. 2010;6:52-4. Russian.
22.Rosen GM, Pou S, Ramos CL, Cohen MS, Britigan BE. Free radicals and phagocytic cells. FASEB Journal. 1995;9:200–9.
23.Karbyshev MS, Abdullaiev ShP. Editor, Shestopalov AV. [Biochemistry of Oxidative Stress: A Guidance Manual]. Pirogov Russian National Research Medical University: Moscow. 2018; Russian.
24.Savko VV, Khelifi Amani. [Lipid peroxidation and state of enzymatic antioxidant system in experimental hypertension in animals with allerfic uveitis treated with lipoflavon and acetylcysteine]. Oftalmol Zh. 2011;4:61-6. Russian.
The authors declare no conflict of interest which could influence their opinions on the subject or the materials presented in the manuscript.