A Topical Formulation of Melatoninergic Compounds Exerts Strong Hypotensive and Neuroprotective Effects in a Rat Model of Hypertensive Glaucoma

Melatonin is of great importance for regulating several eye processes, including pressure homeostasis. Melatonin in combination with agomelatine has been recently reported to reduce intraocular pressure (IOP) with higher efficacy than each compound alone. Here, we used the methylcellulose (MCE) rat model of hypertensive glaucoma, an optic neuropathy characterized by the apoptotic death of retinal ganglion cells (RGCs), to evaluate the hypotensive and neuroprotective efficacy of an eye drop nanomicellar formulation containing melatonin/agomelatine. Eye tissue distribution of melatonin/agomelatine in healthy rats was evaluated by HPLC/MS/MS. In the MCE model, we assessed by tonometry the hypotensive efficacy of melatonin/agomelatine. Neuroprotection was revealed by electroretinography; by levels of inflammatory and apoptotic markers; and by RGC density. The effects of melatonin/agomelatine were compared with those of timolol (a beta blocker with prevalent hypotensive activity) or brimonidine (an alpha 2 adrenergic agonist with potential neuroprotective efficacy), two drugs commonly used to treat glaucoma. Both melatonin and agomelatine penetrate the posterior segment of the eye. In the MCE model, IOP elevation was drastically reduced by melatonin/agomelatine with higher efficacy than that of timolol or brimonidine. Concomitantly, gliosis-related inflammation and the Bax-associated apoptosis were partially prevented, thus leading to RGC survival and recovered retinal dysfunction. We suggest that topical melatoninergic compounds might be beneficial for ocular health.

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Neuroprotective effects of tempol on retinal ganglion cells in a partial optic nerve crush rat model with and without iron load

Experimental Eye Research ◽

10.1016/j.exer.2009.10.013 ◽

2010 ◽

Vol 90 (2) ◽

pp. 254-260 ◽

Cited By ~ 18

Author(s):

Sebastian Thaler ◽

Michal Fiedorowicz ◽

Robert Rejdak ◽

Tomasz J. Choragiewicz ◽

Dorota Sulejczak ◽

...

Keyword(s):

Optic Nerve ◽

Retinal Ganglion Cells ◽

Rat Model ◽

Ganglion Cells ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Neuroprotective Effects ◽

Nerve Crush ◽

Iron Load

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Statin-mediated neuroprotective effects on retinal ganglion cells involve modulation of caspase levels after acute retinal ischaemia/reperfusion

Aktuelle Neurologie ◽

10.1055/s-2006-953412 ◽

2006 ◽

Vol 33 (S 1) ◽

Author(s):

C. Schmeer ◽

S. Tausch ◽

O.W. Witte ◽

S. Isenmann

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Neuroprotective Effects ◽

Ischaemia Reperfusion ◽

Retinal Ischaemia

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Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells

Pharmaceutics ◽

10.3390/pharmaceutics13050647 ◽

2021 ◽

Vol 13 (5) ◽

pp. 647

Author(s):

Henry T. Hsueh ◽

Yoo-Chun Kim ◽

Ian Pitha ◽

Matthew D. Shin ◽

Cynthia A. Berlinicke ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Rat Model ◽

Kinase Inhibitor ◽

Ganglion Cells ◽

Corneal Neovascularization ◽

Therapeutic Effects ◽

Subconjunctival Injection ◽

Retinal Ganglion ◽

Drug Concentrations ◽

Complementary Strategy

Glaucoma is the leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is one of the major risk factors for glaucoma onset and progression, and available pharmaceutical interventions are exclusively targeted at IOP lowering. However, degeneration of retinal ganglion cells (RGCs) may continue to progress despite extensive lowering of IOP. A complementary strategy to IOP reduction is the use of neuroprotective agents that interrupt the process of cell death by mechanisms independent of IOP. Here, we describe an ion complexation approach for formulating microcrystals containing ~50% loading of a protein kinase inhibitor, sunitinib, to enhance survival of RGCs with subconjunctival injection. A single subconjunctival injection of sunitinib-pamoate complex (SPC) microcrystals provided 20 weeks of sustained retina drug levels, leading to neuroprotection in a rat model of optic nerve injury. Furthermore, subconjunctival injection of SPC microcrystals also led to therapeutic effects in a rat model of corneal neovascularization. Importantly, therapeutically relevant retina drug concentrations were achieved with subconjunctival injection of SPC microcrystals in pigs. For a chronic disease such as glaucoma, a formulation that provides sustained therapeutic effects to complement IOP lowering therapies could provide improved disease management and promote patient quality of life.

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Neuroprotective Effects of C-Type Natriuretic Peptide on Rat Retinal Ganglion Cells

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.09-5049 ◽

2010 ◽

Vol 51 (7) ◽

pp. 3544 ◽

Cited By ~ 14

Author(s):

Jia Ma ◽

Wenhan Yu ◽

Yun Wang ◽

Guiqun Cao ◽

Suping Cai ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Natriuretic Peptide ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Neuroprotective Effects

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Inherited glaucoma in DBA/2J mice: Pertinent disease features for studying the neurodegeneration

Visual Neuroscience ◽

10.1017/s0952523805225130 ◽

2005 ◽

Vol 22 (5) ◽

pp. 637-648 ◽

Cited By ~ 208

Author(s):

RICHARD T. LIBBY ◽

MICHAEL G. ANDERSON ◽

IOK-HOU PANG ◽

ZACHARY H. ROBINSON ◽

OLGA V. SAVINOVA ◽

...

Keyword(s):

Optic Nerve ◽

Ganglion Cells ◽

The Elderly ◽

Nerve Degeneration ◽

Retinal Ganglion ◽

Cell Degeneration ◽

Future Studies ◽

Age Related ◽

Iop Elevation ◽

Mechanistic Basis

The glaucomas are neurodegenerative diseases involving death of retinal ganglion cells and optic nerve head excavation. A major risk factor for this neurodegeneration is a harmfully elevated intraocular pressure (IOP). Human glaucomas are typically complex, progressive diseases that are prevalent in the elderly. Family history and genetic factors are clearly important in human glaucoma. Mouse studies have proven helpful for investigating the genetic and mechanistic basis of complex diseases. We previously reported inherited, age-related progressive glaucoma in DBA/2J mice. Here, we report our updated findings from studying the disease in a large number of DBA/2J mice. The period when mice have elevated IOP extends from 6 months to 16 months, with 8–9 months representing an important transition to high IOP for many mice. Optic nerve degeneration follows IOP elevation, with the majority of optic nerves being severely damaged by 12 months of age. This information should help with the design of experiments, and we present the data in a manner that will be useful for future studies of retinal ganglion cell degeneration and optic neuropathy.

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Neuroprotective effects of exogenous erythropoietin in Wistar rats by downregulating apoptotic factors to attenuate N-methyl-D-aspartate-mediated retinal ganglion cells death

PLoS ONE ◽

10.1371/journal.pone.0223208 ◽

2020 ◽

Vol 15 (4) ◽

pp. e0223208 ◽

Cited By ~ 1

Author(s):

Wen-Sheng Cheng ◽

I-Hung Lin ◽

Kathy Ming Feng ◽

Zhi-Yang Chang ◽

Yu Chuan Huang ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Wistar Rats ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Neuroprotective Effects ◽

Cells Death ◽

Apoptotic Factors

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Gypenosides Prevent H2O2-Induced Retinal Ganglion Cell Apoptosis by Concurrently Suppressing the Neuronal Oxidative Stress and Inflammatory Response

Journal of Molecular Neuroscience ◽

10.1007/s12031-019-01468-9 ◽

2020 ◽

Vol 70 (4) ◽

pp. 618-630 ◽

Cited By ~ 1

Author(s):

Hong-Kan Zhang ◽

Yuan Ye ◽

Kai-Jun Li ◽

Zhen-ni Zhao ◽

Jian-Feng He

Keyword(s):

Oxidative Stress ◽

Optic Neuritis ◽

Ganglion Cells ◽

Nerve Fibers ◽

Inflammatory Factors ◽

Heme Oxygenase 1 ◽

Protective Effects ◽

Retinal Ganglion ◽

Apoptotic Pathway ◽

Neuroprotective Effects

AbstractOur previous study demonstrated that gypenosides (Gp) exert protective effects on retinal nerve fibers and axons in a mouse model of experimental autoimmune optic neuritis. However, the therapeutic mechanisms remain unclear. Thus, in this study, a model of oxidative damage in retinal ganglion cells (RGCs) was established to investigate the protective effect of Gp, and its possible influence on oxidative stress in RGCs. Treatment of cells with H2O2 induced RGC injury owing to the generation of intracellular reactive oxygen species (ROS). In addition, the activities of antioxidative enzymes decreased and the expression of inflammatory factors increased, resulting in an increase in cellular apoptosis. Gp helped RGCs to become resistant to oxidation damage by directly reducing the amount of ROS in cells and exerting protective effects against H2O2-induced apoptosis. Treatment with Gp also reduced the generation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and increased nuclear respiratory factor 2 (Nrf-2) levels so as to increase the levels of heme oxygenase-1 (HO-1) and glutathione peroxidase 1/2 (Gpx1/2), which can enhance antioxidation in RGCs. In conclusion, our data indicate that neuroprotection by Gp involves its antioxidation and anti-inflammation effects. Gp prevents apoptosis through a mitochondrial apoptotic pathway. This finding might provide novel insights into understanding the mechanism of the neuroprotective effects of gypenosides in the treatment of optic neuritis.

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Neuroprotective effects of transplanted olfactory ensheathing cells on axotimized retinal ganglion cells in adult rats

Neuroscience Research ◽

10.1016/j.neures.2007.06.1090 ◽

2007 ◽

Vol 58 ◽

pp. S90

Author(s):

Mingmei Wu ◽

Bing Hou ◽

Hao Yang ◽

Na Luo ◽

Xi-Ying Jiao ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Olfactory Ensheathing Cells ◽

Retinal Ganglion ◽

Neuroprotective Effects ◽

Adult Rats ◽

Ensheathing Cells

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Brazilian Green Propolis Protects against Retinal Damage In Vitro and In Vivo

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nek005 ◽

2006 ◽

Vol 3 (1) ◽

pp. 71-77 ◽

Cited By ~ 41

Author(s):

Yuta Inokuchi ◽

Masamitsu Shimazawa ◽

Yoshimi Nakajima ◽

Shinsuke Suemori ◽

Satoshi Mishima ◽

...

Keyword(s):

Oxidative Stress ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Water Soluble ◽

Retinal Damage ◽

Retinal Ganglion ◽

Neuroprotective Effects ◽

Brazilian Green Propolis

Propolis, a honeybee product, has gained popularity as a food and alternative medicine. Its constituents have been shown to exert pharmacological (anticancer, antimicrobial and anti-inflammatory) effects. We investigated whether Brazilian green propolis exerts neuroprotective effects in the retinain vitroand/orin vivo.In vitro, retinal damage was induced by 24 h hydrogen peroxide (H2O2) exposure, and cell viability was measured by Hoechst 33342 and YO-PRO-1 staining or by a resazurin–reduction assay. Propolis inhibited the neurotoxicity and apoptosis induced in cultured retinal ganglion cells (RGC-5, a rat ganglion cell line transformed using E1A virus) by 24 h H2O2 exposure. Propolis also inhibited the neurotoxicity induced in RGC-5 cultures by staurosporine. Regarding the possible underlying mechanism, in pig retina homogenates propolis protected against oxidative stress (lipid peroxidation), as also did trolox (water-soluble vitamin E). In micein vivo, propolis (100 mg kg−1; intraperitoneally administered four times) reduced the retinal damage (decrease in retinal ganglion cells and in thickness of inner plexiform layer) induced by intravitrealin vivo N-methyl-d-aspartate injection. These findings indicate that Brazilian green propolis has neuroprotective effects against retinal damage bothin vitroandin vivo, and that a propolis-induced inhibition of oxidative stress may be partly responsible for these neuroprotective effects.

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