Assessment of the correction of neuroretinal changes using 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyltaurinate in the modeling of POAG

Svetlana V. Efimenko; Mikhail V. Korokin; Oleg S. Gudyrev; Lyudmila M. Danilenko; Liliya V. Korokina; Aleksandr A.  Dolzhikov; Tatyana G. Pokrovskaya; Anastasia A. Ulyanova; Nikita S. Zhunusov; Yana S. Kochergina; Anton P. Danilenko; Anna A. Peresypkina

doi:10.18413/rrpharmacology.10.477

Authors

Svetlana V. Efimenko Belgorod State National Research University https://orcid.org/0000-0002-1041-9978
Mikhail V. Korokin Belgorod State National Research University https://orcid.org/0000-0001-5402-0697
Oleg S. Gudyrev Belgorod State National Research University https://orcid.org/0000-0003-0097-000X
Lyudmila M. Danilenko Belgorod State National Research University https://orcid.org/0000-0001-6101-8712
Liliya V. Korokina Belgorod State National Research University https://orcid.org/0000-0002-4115-1564
Aleksandr A. Dolzhikov Belgorod State National Research University https://orcid.org/0000-0001-7425-8416
Tatyana G. Pokrovskaya Belgorod State National Research University https://orcid.org/0000-0001-6802-5368
Anastasia A. Ulyanova Belgorod State National Research University https://orcid.org/0009-0007-8345-4209
Nikita S. Zhunusov Belgorod State National Research University https://orcid.org/0000-0002-1969-3615
Yana S. Kochergina Belgorod State National Research University https://orcid.org/0009-0003-8167-5666
Anton P. Danilenko Belgorod State National Research University https://orcid.org/0009-0001-2419-8109
Anna A. Peresypkina Belgorod State National Research University https://orcid.org/0000-0003-2829-9860

DOI:

https://doi.org/10.18413/rrpharmacology.10.477

Abstract

Introduction: Elevated intraocular pressure (IOP) has been identified as a major risk factor for the progression of primary open-angle glaucoma (POAG). However, the continued progression of POAG in some patients, despite the successful IOP reduction, indicates that IOP-independent mechanisms contribute to the development of optical neuropathy. Thus, it is relevant to further determine the molecular mechanisms of retinal ganglion cells (RGCs) death in order to develop therapeutic approaches independent of IOP in order to stop the progression of the disease. The aim: to research the correction possibility of experimental POAG induced by intracameral (i.c.)administration of hyaluronic acid using 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyltaurinate.

Materials and Methods: The study of the correction of neuroretinal changes on a model of POAG was carried out on Wistar rats. In order to correct POAG, 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyltaurinate (EHMP-NAT) was used at doses of 27.5 mg/kg intramuscularly (i.m.) and 0.5 mg/kg instillationally. Further, the effectiveness of the combination of timolol eye drops with i.m. EHMP-NAT was studied. The effectiveness of the studied agents was evaluated on the 67^th day of the experiment using ophthalmoscopic semi-quantitative assessment of the fundus condition, ocular tonometry, estimation of oxidative stress markers and markers involved in retinal apoptosis pathway using enzyme-linked immunosorbent assay (ELISA).

Results: On the model of POAG, it was shown that 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyltaurinate with the laboratory code EHMP-NAT has a pronounced neuro-, retinoprotectiveaction based on the data of ophthalmoscopy, semi-quantitative assessment of the fundus condition, ocular tonometry, estimation of oxidative stress markers (GSH, CAT, SOD) and markers involved in retinal apoptosis (BAX, BCL-2, Caspase-3). On the 67^th day of the experiment, the results of a comprehensive analysis revealed that the combination of EHMP-NAT 27.5 mg/kg i.m. + timolol 0.04 mg/kg instillationally has a more pronounced protective effect than EHMP-NAT 27.5 mg/kg i.m. in monotherapy in the POAG model.

Conclusion: The data obtained indicate the need for the combined use of drugs with a hypotensive effect to normalize IOP with neuroretinoprotective agents in the correction of POAG.

Graphical Abstract

Keywords:

2-ethyl-6-methyl-3-hydroxypyridinium N-acetyltaurinate, primary open-angle glaucoma, retinoprotection, neuroprotection

References

Alekseev IB, Volkova AV, Alekseeva LI (2022) Xalacom: possibilities and advantages of the drug in the treatment of patients with glaucoma. Bulletin of Ophthalmology [Vestnik Oftalmologii] 138(5): 119–125. https://doi.org/10.17116/oftalma2022138051119[PubMed]

Benozzi J, Nahum LP, Campanelli JL, Rosenstein R (2002) Effect of hyaluronic acid on intraocular pressure in rats. Investigative Ophthalmology & Visual Science 43(7): 2196–2200. [PubMed]

Cordeiro MF, Gandolfi S, Gugleta K, Normando EM, Oddone F (2024) How latanoprost changed glaucoma management. Acta Ophthalmologica 102(2): e140–e155. https://doi.org/10.1111/aos.15725 [PubMed]

Efimenko SV, Peresypkina AA, Pokrovskii MV, Korokin MV, Gudyrev OS, Bashuk VV, Danilenko LM (2023) Evaluation of the efficacy of 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyltaurinate and its combination with timolol in the correction of primary open-angle glaucoma in rats. Experimental and Clinical Pharmacology [Eksperimental’naya i Klinicheskaya Farmakologhiya] 86(10): 9–15. https://doi.org/10.30906/0869-2092-2023-86-9-9-15 [in Russian]

Froger N, Cadetti L, Lorach H, Martins J, Bemelmans AP, Dubus E, Degardin J, Pain D, Forster V, Chicaud L, Ivkovic I, Simonutti M, Fouquet S, Jammoul F, Léveillard T, Benosman R, Sahel JA, Picaud S (2012) Taurine provides neuroprotection against retinal ganglion cell degeneration. PloS One 7(10): e42017. https://doi.org/10.1371/journal.pone.0042017[PubMed]

Froger N, Jammoul F, Gaucher D, Cadetti L, Lorach H, Degardin J, Pain D, Dubus E, Forster V, Ivkovic I, Simonutti M, Sahel JA, Picaud S (2013) Taurine is a crucial factor to preserve retinal ganglion cell survival. Advances in Experimental Medicine and Biology 775: 69–83. https://doi.org/10.1007/978-1-4614-6130-2_6 [PubMed]

GBD 2019 Blindness and Vision Impairment Collaborators – GBD 2019 Blindness and Vision Impairment Collaborators, & Vision Loss Expert Group of the Global Burden of Disease Study (2021) Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the Right to Sight: an analysis for the Global Burden of Disease Study. The Lancet. Global Health 9(2): e144–e160. https://doi.org/10.1016/S2214-109X(20)30489-7 [PubMed]

Getmanova AM, Brezhnev AYu, Kuroyedov AV, Baranov VI, Dvornikov AS (2020) Systemic therapy a risk factor for glaucoma development and progression. Russian Journal of Clinical Ophthalmology [Rossiiskii Zhurnal Klinicheskoi Ofralmologhii] 20(4): 191–196. https://doi.org/10.32364/2311-7729-2020-20-4-191-196 [in Russian]

Jiang N, Li Z, Li Z, Zhang Y, Yu Z, Wan P, Zhu Y, Li Y, Su W, Zhuo Y (2020) Laquinimod exerts anti-inflammatory and antiapoptotic effects in retinal ischemia/reperfusion injury. International Iimmunopharmacology 88: 106989. https://doi.org/10.1016/j.intimp.2020.106989 [PubMed]

Ju WK, Perkins GA, Kim KY, Bastola T, Choi WY, Choi SH (2023) Glaucomatous optic neuropathy: Mitochondrial dynamics, dysfunction and protection in retinal ganglion cells. Progress in Retinal and Eye Research 95: 101136. https://doi.org/10.1016/j.preteyeres.2022.101136 [PubMed]

Kalatanova AV, Pobeda AS, Abasheva DA, Dolzhikov AA, Peresypkina AA, Pokrovskii MV (2021) Electroretinography in evaluation of neuroprotective effect in an experimental model of glaucoma. Bulletin of Ophthalmology [Vestnik Oftalmologii] 137(3): 86–92. https://doi.org/10.17116/oftalma202113703186 [PubMed] [in Russian]

Lambuk L, Iezhitsa I, Agarwal R, Agarwal P, Peresypkina A, Pobeda A, Ismail NM (2021) Magnesium acetyltaurate prevents retinal damage and visual impairment in rats through suppression of NMDA-induced upregulation of NF-κB, p53 and AP-1 (c-Jun/c-Fos). Neural Regeneration Research 16(11): 2330–2344. https://doi.org/10.4103/1673-5374.310691[PubMed]

Lambuk L, Jafri AJ, Arfuzir NN, Iezhitsa I, Agarwal R, Rozali KN, Agarwal P, Bakar NS, Kutty MK, Yusof AP, Krasilnikova A, Spasov A, Ozerov A, Ismail NM (2017) Neuroprotective effect of magnesium acetyltaurate against NMDA-induced excitotoxicity in rat retina. Neurotoxicity Research 31(1): 31–45. https://doi.org/10.1007/s12640-016-9658-9[PubMed]

Lu LJ, Tsai JC, Liu J (2017) Novel pharmacologic candidates for treatment of primary open-angle glaucoma. The Yale Journal of Biology and Medicine 90(1): 111–118. [PubMed]

McInnis J, Wang C, Anastasio N, Hultman M, Ye Y, Salvemini D, Johnson KM (2002) The role of superoxide and nuclear factor-kappaB signaling in N-methyl-D-aspartate-induced necrosis and apoptosis. The Journal of Pharmacology and Experimental Therapeutics 301(2): 478–487. https://doi.org/10.1124/jpet.301.2.478 [PubMed]

Movsisyan AB, Kuroedov AV, Arkharov MA, Prokhorenko VV, Chepurnov IA (2022) Epidemiological analysis primary open-angle glaucoma incidence and prevalence in Russia. Russian Journal of Clinical Ophthalmology 22(1): 3–10. https://doi.org/10.32364/2311-7729-2022-22-1-3-10 [in Russian]

Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N (2000) Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science (New York, N.Y.) 12;288(5468): 1053–1058. https://doi.org/10.1126/science.288.5468.1053 [PubMed]

Peresypkina A, Pazhinsky A, Danilenko L, Lugovskoy S, Pokrovskii M, Beskhmelnitsyna E, Solovev N, Pobeda A, Korokin M, Levkova E, Gubareva V, Korokina L, Martynova O, Soldatov V, Pokrovskii V. (2020) Retinoprotective effect of 2-ethyl-3-hydroxy-6-methylpyridine nicotinate. Biology (Basel) 9(3): 45. https://doi.org/10.3390/biology9030045 [PubMed]

Porter AG, Jänicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death and Differentiation 6(2): 99–104. https://doi.org/10.1038/sj.cdd.4400476 [PubMed]

Sakamoto K, Okuwaki T, Ushikubo H, Mori A, Nakahara T, Ishii K (2017) Activation inhibitors of nuclear factor kappa B protect neurons against the NMDA-induced damage in the rat retina. Journal of Pharmacological Sciences S1347-8613(17): 30162–30167. https://doi.org/10.1016/j.jphs.2017.09.031 [PubMed]

Schaffer S, Kim HW (2018) Effects and mechanisms of taurine as a therapeutic agent. Biomolecules & Therapeutics 26(3): 225–241. https://doi.org/10.4062/biomolther.2017.251 [PubMed]

Semeleva EV, Blinova EV, Zaborovsky AV, Gromova IA, Shukurov AS, Blinov DS, Turovsky EA, Vasilkina OV, Lobanova EG, Samishina EA, Mazov YA, Sokolov AI, Dergunova YV (2020) Metal-containing taurine compounds protect rat’s brain in reperfusion-induced injury. Research Results in Pharmacology 6(4): 43–49. https://doi.org/10.3897/rrpharmacology.6.59857

Ulbrich F, Lerach T, Biermann J, Kaufmann KB, Lagreze WA, Buerkle H, Loop T, Goebel U (2016) Argon mediates protection by interleukin-8 suppression via a TLR2/TLR4/STAT3/NF-κB pathway in a model of apoptosis in neuroblastoma cells in vitro and following ischemia-reperfusion injury in rat retina in vivo. Journal of Neurochemistry 138(6): 859–873. https://doi.org/10.1111/jnc.13662 [PubMed]

Voronina TA (2012) Mexidol: the spectrum of pharmacological effects. S.S. Korsakov Journal of Neurology and Psychiatry [Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova] 112(12): 86–90. [PubMed] [in Russian]

Weishaupt JH, Diem R, Kermer P, Krajewski S, Reed JC, Bähr M (2003) Contribution of caspase-8 to apoptosis of axotomized rat retinal ganglion cells in vivo. Neurobiology of Disease 13(2): 124–135. https://doi.org/10.1016/s0969-9961(03)00032-9 [PubMed]

Yu H, Huang X, Xie C, Song J, Zhou Y, Shi H, Chen M, Wu Y, Ruan Z, Deng L, Deng X, Lv Y, Luo Q, Dong J (2023) Transcriptomics reveals apigenin alleviates airway inflammation and epithelial cell apoptosis in allergic asthma via MAPK pathway. Phytotherapy Research: PTR 37(9): 4002–4017. https://doi.org/10.1002/ptr.7859 [PubMed]

Zhang N, Wang J, Li Y, Jiang B (2021) Prevalence of primary open angle glaucoma in the last 20 years: a meta-analysis and systematic review. Scientific Reports 11(1): 13762. https://doi.org/10.1038/s41598-021-92971-w [PubMed]

Author Contribution

Svetlana V. Efimenko, Belgorod State National Research University

MD, Postgraduate student of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: spotapova96@mail.ru; ORCID ID https://orcid.org/0000-0002-1041-9978. The author took part in conceptualization and direction development of the research, generation of key aims and objectives conducting experimental work, analysing the material, and writing the text of the article.

Mikhail V. Korokin, Belgorod State National Research University

Doct. Sci. (Medicine), Professor of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: mkorokin@mail.ru, ORCID ID https://orcid.org/0000-0001-5402-0697. The author took part in direction development of the research and in the analysis of the material.

Oleg S. Gudyrev, Belgorod State National Research University

Cand. Sci. (Medicine), Associate Professor of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: gudyrev@mail.ru; ORCID ID https://orcid.org/0000-0003-0097-000X. The author took part inprocessing the results obtained.

Lyudmila M. Danilenko, Belgorod State National Research University

Doct. Sci. (Pharmacy), Professor of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: Danilenko_L@mail.ru; ORCID ID https://orcid.org/0000-0001-6101-8712. The author was engaged in collection and interpretation of the data for the paper.

Liliya V. Korokina, Belgorod State National Research University

Cand. Sci. (Medicine), Associate Professor of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: korokina@bsu.edu.ru; ORCID ID https://orcid.org/0000-0002-4115-1564. The author was engaged in conducting the literature analysis.

Aleksandr A. Dolzhikov, Belgorod State National Research University

Doct. Sci. (Medicine), Professor, Professor of the Department of Human Anatomy and Histology, Belgorod State National Research University, Belgorod, Russia; e-mail: dolzhikov@bsu.edu.ru, ORCID ID https://orcid.org/0000-0001-7425-8416. The author took part in conceptualization and direction development of the research, and interpretation of the data for the paper.

Tatyana G. Pokrovskaya, Belgorod State National Research University

Doct. Sci. (Medicine), Professor of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: pokrovskaia-tg@mail.ru, ORCID ID https://orcid.org/0000-0001-6802-5368. The author took part in writing the article and processing the results obtained.

Anastasia A. Ulyanova, Belgorod State National Research University

Postgraduate student of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: ul-nastya@mail.ru; ORCID ID https://orcid.org/0009-0007-8345-4209. The author took part in enzyme-linked immunosorbent assay.

Nikita S. Zhunusov, Belgorod State National Research University

Teaching Assistant of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: zhunusov@bsu.edu.ru, ORCID ID https://orcid.org/0000-0002-1969-3615. The author participated in ocular tonometry and ophthalmoscopy conducting.

Yana S. Kochergina, Belgorod State National Research University

Forensic medical expert, Belgorod Bureau of Forensic Medicine, Belgorod State National Research University, Belgorod, Russia; e-mail: yana5568@mail.ru, ORCID ID https://orcid.org/0009-0003-8167-5666. The author participated in the article writing.

Anton P. Danilenko, Belgorod State National Research University

Postgraduate student of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: danilenko_a@bsu.edu.ru, ORCID ID https://orcid.org/0009-0001-2419-8109. The author took part in the experimental work.

Anna A. Peresypkina, Belgorod State National Research University

Doct. Sci. (Biology), Professor of the Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Belgorod, Russia; e-mail: peresypkina_a@bsu.edu.ru; ORCID ID https://orcid.org/0000-0003-2829-9860. The author consulted on the research idea and design of the study, and edited the text of the article.