##article.abstract##
Glaucoma is the main cause of irreversible blindness worldwide. In short, it is a multifactorial progressive optic neuropathy that correlates with retinal ganglion cell death, optic nerve head disturbances, and visual field disorders. Leuprolide acetate have recently been reported to have neurotrophic properties, the aim of this work was to determine whether it´s systemic administration holds up the neurodegenerative process in an experimental glaucoma model. Wistar rats divided into three groups were included: 1) a control group, 2) a hyaluronic acid-induced glaucoma group, and 3) a hyaluronic acid-induced glaucoma group treated with intramuscular leuprolide acetate. The eye electrical responses to light were recorded by simultaneous full-field electroretinography, and the eyes were processed for histological study. The results showed an improvement in the electrical activity, a recovery of fibers from the optic nerve as well as a reduction of the reactive astrogliosis in the leuprolide acetate treated group. In short, leuprolide acetate is a new potential alternative treatment in glaucoma, as it holds up the neurodegenerative process.##submission.citations##
Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90(3): 262-267. Available from: https://doi.org/10.1136/bjo.2005.081224
Adachi M, Takahashi K, Nishikawa M, Miki H, Uyama M. High intraocular pressure-induced ischemia and reperfusion injury in the optic nerve and retina in rats. Gra Arch Clin Exp Ophthalmol. 1996;234(7): 445-451. Available from: https://doi.org/10.1007/BF02539411
Zhang S, Wang H, Lu Q, Qing G, Wang N, Wang Y, et al. Detection of early neuron degeneration and accompanying glial responses in the visual pathway in a rat model of acute intraocular hypertension. Br Res. 2009;1303: 131-143. Available from: https://doi.org/10.1016/j.brainres.2009.09.029
Grozdanic SD, Sakaguchi DS, Kwon YH, Kardon RH, Sonea IM. Functional characterization of retina and optic nerve after acute ocular ischemia in rats. Invest Ophthalmol Vis Sci. 2003;44(6): 2597-2605. Available from: https://doi.org/10.1167/iovs.02-0600
Gallego-Ortega A, Norte-Muñoz M, de Imperial-Ollero JA, Bernal-Garro JM, Valiente-Soriano FJ, de la Villa Polo P, et al. Functional and morphological alterations in a glaucoma model of acute ocular hypertension. Prog Brain Res. 2020;256(1): 1-29. Available from: https://doi.org/10.1016/bs.pbr.2020.07.003
Williams PR, Benowitz LI, Goldberg JL, He Z. Axon regeneration in the mammalian optic nerve. Annu Rev Vis Sci. 2020;6: 195-213. Available from: https://doi.org/10.1146/annurev-vision-022720-094953
Rovere G, Nadal-Nicolas FM, Wang J, Bernal-Garro JM, García-Carrillo N, Villegas-Pérez MP, et al. Melanopsin-containing or non-melanopsin-containing retinal ganglion cell response to ocular hypertension with or without brain-derived neurotrophic factor neuroprotection. Investig Ophthalmol Vis Sci. 2016;57(15): 6652-6661. Available from: https://doi.org/10.1167/iovs.16-20146
Sapieha PS, Peltier M, Rendahl KG, Manning WC, Di Polo A. Fibroblast growth factor-2 gene delivery stimulates axon growth by adult retinal ganglion cells after acute optic nerve injury. Mol Cell Neurosci. 2003;24(3): 656-672. Available from: https://doi.org/10.1016/s1044-7431(03)00228-8
Logan A, Ahmed Z, Baird A, Gonzalez A, Berry M. Neurotrophic factor synergy is required for neuronal survival and disinhibited axon regeneration after CNS injury. Brain J Neurol. 2006;129(Pt 2): 490-502. Available from: https://doi.org/10.1093/brain/awh706
Jo SA, Wang E, Benowitz LI. Ciliary neurotrophic factor is an axogenesis factor for retinal ganglion cells. Neuroscience. 1999;89(2): 579-591. Available from: https://doi.org/10.1016/s0306-4522(98)00546-6
Hernández-Jasso I, Domínguez-Del-Toro E, Delgado-García JM, Quintanar JL. Recovery of sciatic nerve with complete transection in rats treated with leuprolide acetate: A gonadotropin-releasing hormone agonist. Neurosci Lett. 2020;739: 135439. Available from: https://doi.org/10.1016/j.neulet.2020.135439
Díaz Galindo C, Gómez-González B, Salinas E, Calderón-Vallejo D, Hernández-Jasso I, Bautista E, et al. Leuprolide acetate induces structural and functional recovery of injured spinal cord in rats. Neural Regen Res. 2015;10(11): 1819-1824. Available from: https://doi.org/10.4103/1673-5374.170311
Guzmán-Soto I, Salinas E, Hernández-Jasso I, Quintanar JL. Leuprolide acetate, a GnRH agonist, improves experimental autoimmune encephalomyelitis: a possible therapy for multiple sclerosis. Neurochem Res. 2012;37(10): 2190-2197. Available from: https://doi.org/10.1007/s11064-012-0842-x
Wilson AC, Meethal SV, Bowen RL, Atwood CS. Leuprolide acetate: a drug of diverse clinical applications. Exp Opinion Invest Drugs. 2007;16(11): 1851-1863. Available from: https://doi.org/10.1517/13543784.16.11.1851
Altamira-Camacho M, Medina-Aguiñaga D, Cruz Y, Calderón-Vallejo D, Kovacs K, Rotondo F, et al. Leuprolide acetate, a GnRH agonist, improves the neurogenic bowel in ovariectomized rats with spinal cord injury. Dig Dis Sci. 2020;65(2): 423-430. Available from: https://doi.org/10.1007/s10620-019-05783-4
Dubovy SR, Fernández MP, Echegaray JJ, Block NL, Unoki N, Pérez R, et al. Expression of hypothalamic neurohormones and their receptors in the human eye. Oncotarget. 2017;8(40): 66796-66814. Available from: https://doi.org/10.18632/oncotarget.18358
Moreno MC, Aldana Marcos HJ, Croxatto JO, Sande PH, Campanelli J, Jaliffa CO, et al. A new experimental model of glaucoma in rats through intracameral injections of hyaluronic acid. Exp Eye Res. 2005;81(1): 71-80. Available from: https://doi.org/10.1016/j.exer.2005.01.008
Nguyen CT, Tsai TI, He Z, Vingrys AJ, Lee PY, Bui BV. Simultaneous recording of electroretinography and visual evoked potentials in anesthetized rats. J Vis Exp. 2016;(113): e54158. Available from: https://doi.org/10.3791/54158
Bouhenni R, Dunmire J, Sewell A, Edward DP. Animal models of glaucoma. J Biomed Biotechnol. 2012: 692609. Available from: https://doi.org/10.1155/2012/692609
Pang I-H, Clark AF. Inducible rodent models of glaucoma. Prog Retin Eye Res. 2020;75: 100799. Available from: https://doi.org/10.1016/j.preteyeres.2019.100799
Benozzi J, Nahum LP, Campanelli JL, Rosenstein RE. Effect of hyaluronic acid on intraocular pressure in rats. Invest Ophthalmol Vis Sci. 2002;43(7): 2196-2200. Available from: https://iovs.arvojournals.org/article.aspx?articleid=2123361
Koppens Franzco J. Essentials in ophthalmology: glaucoma. Clin Experiment Ophthalmol. 2008;36(2): 187-188. Available from: https://doi.org/10.1111/j.1442-9071.2008.01688.x
Berry M, Carlile J, Hunter A. Peripheral nerve explants grafted into the vitreous body of the eye promote the regeneration of retinal ganglion cell axons severed in the optic nerve. J Neurocytol. 1996;25(2): 147-170. Available from: https://doi.org/10.1007/BF02284793
Yin Y, De Lima S, Gilbert H, Hanovice NJ, Peterson SL, Sand R, et al. Optic nerve regeneration: A long view. Restor Neurol Neurosci. 2019;37(6): 525-544. Available from: https://doi.org/10.3233/RNN-190960
Pernet V, Di Polo A. Synergistic action of brain-derived neurotrophic factor and lens injury promotes retinal ganglion cell survival but leads to optic nerve dystrophy in vivo. Brain J Neurol. 2006;129(Pt 4): 1014-1026. Available from: https://doi.org/10.1093/brain/awl015
Anderson MA, Burda JE, Ren Y, Ao Y, O’Shea T, Kawaguchi R, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature. 2016;532(7598): 195-200. Available from: https://doi.org/10.1038/nature17623
Sofroniew MV. Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. Neurosci Rev J Bringing Neurobiol Neurol Psychiatry. 2014;20(2): 160-172. Available from: https://doi.org/10.1177/1073858413504466
Georgiou AL, Guo L, Francesca Cordeiro MF, Salt TE. Electroretinogram and visual-evoked potential assessment of retinal and central visual function in a rat ocular hypertension model of glaucoma. Curr Eye Res. 2014;39(5): 472-486. Available from: https://doi.org/10.3109/02713683.2013.848902
Chun M, Ju W, Kim KY, Lee MY, Hofmann HD, Kirsch M, et al. Upregulation of ciliary neurotrophic factor in reactive Müller cells in the rat retina following optic nerve transection. Brain Res. 2000;868(2): 358-362. Available from: https://doi.org/10.1016/s0006-8993(00)02305-2
Valter K, Bisti S, Gargini C, Di Loreto S, Maccarone R, Cervetto L, Stone J; Time course of neurotrophic factor upregulation and retinal protection against light-induced damage after optic nerve section. Invest. Ophthalmol. Vis. Sci. 2005;46(5):1748-1754. Available from: https//doi.org/10.1167/iovs.04-0657
Gargini C, Bisti S, Demontis GC, Valter K, Stone J, Cervetto L. Electroretinogram changes associated with retinal upregulation of trophic factors: observations following optic nerve section. Neuroscience. 2004;126(3): 775-783. Available from: https://doi.org/10.1016/j.neuroscience.2004.04.028
Bok D, Yasumura D, Matthes MT, Ruiz A, Duncan JL, Chappelow AV, et al. Effects of adeno-associated virus-vectored ciliary neurotrophic factor on retinal structure and function in mice with a P216L rds/peripherin mutation. Exp Eye Res. 2002;74(6): 719-735. Available from: https://doi.org/10.1006/exer.2002.1176
Leibinger M, Andreadaki A, Gobrecht P, Levin E, Diekmann H, Fischer D. Boosting central nervous system axon regeneration by circumventing limitations of natural cytokine signaling. Mol Ther J Am Soc Gene Ther. 2016;24(10): 1712-1725. Available from: https://doi.org/10.1038/mt.2016.102
Zhang Y, Williams PR, Jacobi A, Wang C, Goel A, Hirano AA, et al. Elevating growth factor responsiveness and axon regeneration by modulating presynaptic inputs. Neuron. 2019;103(1): 39-51.e5. Available from: https://doi.org/10.1016/j.neuron.2019.04.033
Wirsig-Wiechmann C, Wiechmann A. Vole retina is a target for gonadotropin-releasing hormone. Brain Res. 2002;950(1-2): 210-207. Available from: https://doi.org/10.1016/S0006-8993(02)03039-1
Schang AL, Bleux C, Chenut MC, Ngô-Muller V, Quérat B, Jeanny JC, et al. Identification, and analysis of two novel sites of rat GnRH receptor gene promoter activity: the pineal gland and retina. Neuroendocrinology. 2013;97(2): 115-131. Available from: https://doi.org/10.1159/000337661
Dubovy SR, Fernandez MP, Echegaray JJ, Block NL, Unoki N, Perez R, et al. Expression of hypothalamic neurohormones and their receptors in the human eye. Oncotarget. 2017;8(40): 66796-66814. Available from: https://doi.org/10.18632/oncotarget.18358
Carmignoto G, Maffei L, Candeo P, Canella R, Comelli C. Effect of NGF on the survival of rat retinal ganglion cells following optic nerve section. J Neurosci. 1989;9(4): 1263-1272. Available from: https://doi.org/10.1523/JNEUROSCI.09-04-01263.1989
Barrera C, Kastin A, Fasold M, Banks W. Bidirectional saturable transport of LHRH across the blood-brain barrier. Am J Physiol. 1991;261(3 Pt 1): E312-318.
