Офтальмохирургия. 2019; : 78-91
Нейропротекторные свойства бримонидина
https://doi.org/10.25276/0235-4160-2019-3-78-91Аннотация
Цель. Анализ данных, полученных при обзоре рецензируемой научной литературы за период с 1991 г. по настоящее время, о механизмах нейродегенеративных изменений при глаукоме и возможностях нейропротекции; в частности анализ результатов лабораторных и клинических исследований, посвященных нейропротекторным свойствам Бримонидина. Нейродегенеративные процессы при глаукоме происходят вследствие ишемии и нарушения глазного кровотока, эксайтотоксичности, оксидативного стресса, нейровоспаления, а также уменьшения уровня нейротрофических факторов, дисфункции митохондрий, активации сигнальных путей апоптоза, нарушения функции белков и генетических причин. У пациентов с глаукомой эти процессы продолжаются несмотря на оптимизацию уровня внутриглазного давления. В исследованиях на животных доказано, что Бримонидин увеличивает способность ганглиозных клеток сетчатки (ГКС) выживать в неблагоприятных условиях. Механизм нейропротекторного действия Бримонидина многогранен. Препарат имеет мишени в сетчатке (альфа-2-адренорецепторы) и при использовании клинических дозировок достигает заднего сегмента глаза в достаточной для нейропротекции концентрации. Бримонидин оказывает влияние практически на все известные причины, приводящие к апоптозу клеток и нейродегенерации при глаукоме. Бримонидин снижает выраженность ишемии сетчатки, уменьшает влияние эксайтотоксичных аминокислот на ГКС, блокирует последствия оксидативного стресса, увеличивает продукцию нейротрофических факторов, регулирует функцию глиальных клеток и митохондрий. Его нейропротекторная эффективность доказана в экспериментах на животных моделях и в клинических исследованиях на людях. Бримонидин – единственный антиглаукомный препарат, прямое нейропротекторное действие которого доказано в нескольких рандомизированных клинических исследованиях. Бримонидин можно рекомендовать пациентам с глаукомой и диабетической ретинопатией для профилактики ухудшения зрительных функций, связанных с гибелью ГКС. Применение Бримонидина способствует сохранению, а в некоторых случаях улучшению поля зрения, контрастной чувствительности и зрительных функций в целом.
Список литературы
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26. Wheeler L, WoldeMussie E, Lai R. Role of alpha-2 agonists in neuroprotection. Surv Ophthalmol. 2003;48(Suppl.1): S47–51.
27. Kalapesi FB, Coroneo MT, Hill MA. Human ganglion cells express the alpha-2 adrenergic receptor: relevance to neuroprotection. Br J Ophthalmol. 2005;89(6): 758–63.
28. Prokosch V, Panagis L, Volk GF, Dermon C, Thanos S. Alpha2-adrenergic receptors and their core involvement in the process of axonal growth in retinal explants. Invest Ophthalmol Vis Sci. 2010;51(12): 6688–99.
29. Shinno K, Kurokawa K, Kozai S, Kawamura A, Inada K, Tokushige H. The Relationship of Brimonidine Concentration in Vitreous Body to the Free Concentration in Retina/Choroid Following Topical Administration in Pigmented Rabbits. Curr Eye Res. 2017;42(5): 748–53.
30. Yoles E, Wheeler LA, Schwartz M. Alpha2adrenoreceptor agonists are neuroprotective in a rat model of optic nerve degeneration. Invest Ophthalmol Vis Sci. 1999;40(1): 65–73.
31. Ahmed FA, Hegazy K, Chaudhary P, Sharma SC. Neuroprotective effect of alpha(2) agonist (brimonidine) on adult rat retinal ganglion cells after increased intraocular pressure. Brain Res. 2001;913(2): 133–9.
32. Hernandez M, Urcola JH, Vecino E. Retinal ganglion cell neuroprotection in a rat model of glaucoma following brimonidine, latanoprost or combined treatments. Exp Eye Res. 2008;86(5): 798–06.
33. Wheeler LA, Woldemussie E. Alpha-2 adrenergic receptor agonists are neuroprotective in experimental models of glaucoma. Eur. J. Ophthalmol. 2001;11.
34. Lambert WS, Ruiz L, Crish SD, Wheeler LA, Calkins DJ. Brimonidine prevents axonal and somatic degeneration of retinal ganglion cell neurons. Mol Neurodegener. 2011;6(1): 4.
35. Pinar-Sueiro S, Urcola H, Rivas MA, Vecino E. Prevention of retinal ganglion cell swelling by systemic brimonidine in a rat experimental glaucoma model. Clin Exp Ophthalmol. 2011;39(8): 799–807.
36. Lindsey JD, Duong-Polk KX, Hammond D, Chindasub P, Leung CK, Weinreb RN. Differential protection of injured retinal ganglion cell dendrites by brimonidine. Invest Ophthalmol Vis Sci. 2015;56(3): 1789–804.
37. Saylor M, McLoon LK, Harrison AR, Lee MS. Experimental and clinical evidence for brimonidine as an optic nerve and retinal neuroprotective agent: an evidence-based review. Arch Ophthalmol. 2009.
38. Rosa RH Jr, Hein TW, Yuan Z, Xu W, Pechal MI, Geraets RL, Newman JM, Kuo L. Brimonidine evokes heterogeneous vasomotor response of retinal arterioles: diminished nitric oxide-mediated vasodilation when size goes small. Am J Physiol Heart Circ Physiol. 2006;291(1): H231–8.
39. Aktaş Z, Gurelik G, Akyurek N, Onol M, Hasanreisoğlu B. Neuroprotective effect of topically applied brimonidine tartrate 0,2% in endothelin1-induced optic nerve ischaemia model. Clin Exp Ophthalmol. 2007;35(6): 527–34.
40. Vidal-Sanz M, Lafuente MP, Mayor-Torroglosa S, Aguilera ME, Miralles de Imperial J, Villegas-Perez MP. Brimonidine’s neuroprotective effects against transient ischaemia-induced retinal ganglion cell death. Eur J Ophthalmol. 2001;11(Suppl.2): S36–40.
41. Lee D, Kim KY, Noh YH, Chai S, Lindsey JD, Ellisman MH, Weinreb RN, Ju WK. Brimonidine blocks glutamate excitotoxicity-induced oxidative stress and preserves mitochondrial transcription factor a in ischemic retinal injury. PLoS One. 2012;7(10): e47098.
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43. Jung KI, Kim JH, Park CK.α2-Adrenergic modulation of the glutamate receptor and transporter function in a chronic ocular hypertension model. Eur J Pharmacol. 2015;765: 274–83.
44. Ozdemir G, Tolun FI, Gul M, Imrek S. Retinal oxidative stress induced by intraocular hypertension in rats may be ameliorated by brimonidine treatment and N-acetyl cysteine supplementation. J Glaucoma. 2009;18(9): 662–5.
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48. Harun-Or-Rashid M, Hallbook F. Alpha 2-Adrenergic Receptor Agonist Brimonidine Stimulates ERK1/2 and AKT Signaling via Transactivation of EGF Receptors in the Human MIO-M1 Muller Cell Line. Curr Eye Res. 2019;44(1): 34–45.
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Fyodorov Journal of Ophthalmic Surgery. 2019; : 78-91
Neuroprotective properties of Brimonidine
https://doi.org/10.25276/0235-4160-2019-3-78-91Abstract
Purpose. To summarize relevant data from publications appearing in the peer-reviewed scientific literature since1991 about mechanisms of neurodegeneration in glaucoma and the possibilities of neuroprotection; in particular, analysis of the results of laboratory and clinical studies on the neuroprotective properties of Brimonidine. Neurodegenerative processes in glaucoma occur due to ischemia and ocular blood flow disturbance, excitotoxicity, oxidative stress, neuroinflammation, as well as decrease in the level of neurotrophic factors, mitochondrial dysfunction, activation of apoptosis signaling pathways, protein dysfunction and genetic causes. In patients with glaucoma, these processes continue despite the optimization of intraocular pressure. In animal studies, Brimonidine has been shown to increase the ability of retinal ganglion cells (RGC) to survive in stress conditions. The mechanism of neuroprotective action of Brimonidine is multifaceted. The effects of brimonidine are mediated by its interaction with alpha-2 adrenergic receptors that are present in the retina. Clinical dosing of the topical formulation of brimonidine results in brimonidine concentrations in the posterior segment that are sufficient for both pharmacological activity at alpha-2 adrenergic receptors and neuroprotection. Brimonidine inhibits almost all known causes of cell apoptosis and neurodegeneration in glaucoma.Brimonidine reduces the severity of retinal ischemia, reduces the effect of excitotoxic amino acids on RGC, blocks the effects of oxidative stress, increases the production of neurotrophic factors, and regulates the function of glial cells and mitochondria. Its neuroprotective efficacy has been proven in animal studies and in human clinical studies. Brimonidine is the only antiglaucoma drug whose direct neuroprotective effect has been proven in large randomized clinical trials. Brimonidine can be used in glaucoma and diabetic retinopathy to prevent visual impairment associated with RGC death. Brimonidine helps to preserve, and in some cases to improve the visual field, contrast sensitivity and visual functions in general.
References
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2. Sena DF, Lindsley K. Neuroprotection for treatment of glaucoma in adults. Cochrane Database Syst Rev. 2017;1: CD006539. Doi: 10.1002/14651858.CD006539.pub4.
3. Levene RZ. Low tension glaucoma: a critical review and new material. Surv Ophthalmol. 1980;24(6): 621–64.
4. Guymer C, Wood JP, Chidlow G, Casson RJ. Neuroprotection in glaucoma: recent advances and clinical translation. Clin Exp Ophthalmol. 2018.
5. Almasiesh M, Levin LA. Neuroprotection in glaucoma: animal models and clinical trials. Annu Rev Sci. 2017;3: 91–120. doi:10.1146/annurevvision102016-061422.
6. Varma R, Peeples P, Walt JG, Bramley TJ. Disease progression and the need for neuroprotection in glaucoma management. Am. J. Manag Care. 2008;14(1 Suppl.): S15–19.
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25. Yoshimura N. Retinal neuronal cell death: molecular mechanism and neuroprotection. Nippon Ganka Gakkai Zasshi. 2001;105(12): 884–902.
26. Wheeler L, WoldeMussie E, Lai R. Role of alpha-2 agonists in neuroprotection. Surv Ophthalmol. 2003;48(Suppl.1): S47–51.
27. Kalapesi FB, Coroneo MT, Hill MA. Human ganglion cells express the alpha-2 adrenergic receptor: relevance to neuroprotection. Br J Ophthalmol. 2005;89(6): 758–63.
28. Prokosch V, Panagis L, Volk GF, Dermon C, Thanos S. Alpha2-adrenergic receptors and their core involvement in the process of axonal growth in retinal explants. Invest Ophthalmol Vis Sci. 2010;51(12): 6688–99.
29. Shinno K, Kurokawa K, Kozai S, Kawamura A, Inada K, Tokushige H. The Relationship of Brimonidine Concentration in Vitreous Body to the Free Concentration in Retina/Choroid Following Topical Administration in Pigmented Rabbits. Curr Eye Res. 2017;42(5): 748–53.
30. Yoles E, Wheeler LA, Schwartz M. Alpha2adrenoreceptor agonists are neuroprotective in a rat model of optic nerve degeneration. Invest Ophthalmol Vis Sci. 1999;40(1): 65–73.
31. Ahmed FA, Hegazy K, Chaudhary P, Sharma SC. Neuroprotective effect of alpha(2) agonist (brimonidine) on adult rat retinal ganglion cells after increased intraocular pressure. Brain Res. 2001;913(2): 133–9.
32. Hernandez M, Urcola JH, Vecino E. Retinal ganglion cell neuroprotection in a rat model of glaucoma following brimonidine, latanoprost or combined treatments. Exp Eye Res. 2008;86(5): 798–06.
33. Wheeler LA, Woldemussie E. Alpha-2 adrenergic receptor agonists are neuroprotective in experimental models of glaucoma. Eur. J. Ophthalmol. 2001;11.
34. Lambert WS, Ruiz L, Crish SD, Wheeler LA, Calkins DJ. Brimonidine prevents axonal and somatic degeneration of retinal ganglion cell neurons. Mol Neurodegener. 2011;6(1): 4.
35. Pinar-Sueiro S, Urcola H, Rivas MA, Vecino E. Prevention of retinal ganglion cell swelling by systemic brimonidine in a rat experimental glaucoma model. Clin Exp Ophthalmol. 2011;39(8): 799–807.
36. Lindsey JD, Duong-Polk KX, Hammond D, Chindasub P, Leung CK, Weinreb RN. Differential protection of injured retinal ganglion cell dendrites by brimonidine. Invest Ophthalmol Vis Sci. 2015;56(3): 1789–804.
37. Saylor M, McLoon LK, Harrison AR, Lee MS. Experimental and clinical evidence for brimonidine as an optic nerve and retinal neuroprotective agent: an evidence-based review. Arch Ophthalmol. 2009.
38. Rosa RH Jr, Hein TW, Yuan Z, Xu W, Pechal MI, Geraets RL, Newman JM, Kuo L. Brimonidine evokes heterogeneous vasomotor response of retinal arterioles: diminished nitric oxide-mediated vasodilation when size goes small. Am J Physiol Heart Circ Physiol. 2006;291(1): H231–8.
39. Aktaş Z, Gurelik G, Akyurek N, Onol M, Hasanreisoğlu B. Neuroprotective effect of topically applied brimonidine tartrate 0,2% in endothelin1-induced optic nerve ischaemia model. Clin Exp Ophthalmol. 2007;35(6): 527–34.
40. Vidal-Sanz M, Lafuente MP, Mayor-Torroglosa S, Aguilera ME, Miralles de Imperial J, Villegas-Perez MP. Brimonidine’s neuroprotective effects against transient ischaemia-induced retinal ganglion cell death. Eur J Ophthalmol. 2001;11(Suppl.2): S36–40.
41. Lee D, Kim KY, Noh YH, Chai S, Lindsey JD, Ellisman MH, Weinreb RN, Ju WK. Brimonidine blocks glutamate excitotoxicity-induced oxidative stress and preserves mitochondrial transcription factor a in ischemic retinal injury. PLoS One. 2012;7(10): e47098.
42. Dong CJ, Guo Y, Agey P, Wheeler L, Hare WA. Alpha2 adrenergic modulation of NMDA receptor function as a major mechanism of RGC protection in experimental glaucoma and retinal excitotoxicity. Invest Ophthalmol Vis Sci. 2008;49(10): 4515–22.
43. Jung KI, Kim JH, Park CK.α2-Adrenergic modulation of the glutamate receptor and transporter function in a chronic ocular hypertension model. Eur J Pharmacol. 2015;765: 274–83.
44. Ozdemir G, Tolun FI, Gul M, Imrek S. Retinal oxidative stress induced by intraocular hypertension in rats may be ameliorated by brimonidine treatment and N-acetyl cysteine supplementation. J Glaucoma. 2009;18(9): 662–5.
45. Tatton WG, Chalmers-Redman RM, Tatton NA. Apoptosis and anti-apoptosis signalling in glaucomatous retinopathy. Eur J Ophthalmol. 2001;11.
46. Fujita Y, Sato A, Yamashita T. Brimonidine promotes axon growth after optic nerve injury through Erk phosphorylation. Cell Death Dis. 2013;4: e763.
47. Gao H, Qiao X, Cantor LB, WuDunn D. Upregulation of brain-derived neurotrophic factor expression by brimonidine in rat retinal ganglion cells. Arch Ophthalmol. 2002;120(6): 797–803.
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