scholarly journals Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction

2020 ◽  
Author(s):  
James R Tribble ◽  
Amin Otmani ◽  
Shanshan Sun ◽  
Sevannah A Ellis ◽  
Gloria Cimaglia ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Neurodegenerative Disease ◽  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Retinal Ganglion Cell ◽  
Cell Function ◽  
Ganglion Cells ◽  
Neuroprotective Effect ◽  
Retinal Ganglion ◽  
Neuroprotective Therapy

AbstractNicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. Repleting NAD via dietary supplementation of nicotinamide (a precursor to NAD) is effective in preventing retinal ganglion cell neurodegeneration in mouse models. Supporting this, short-term oral nicotinamide treatment in human glaucoma patients provides a recovery of retinal ganglion cell function implying a protection of visual function. Despite this, the mechanism of neuroprotection and full effects of nicotinamide on retinal ganglion cells is unclear. Glaucoma is a complex neurodegenerative disease in which a mix of healthy, stressed, and degenerating retinal ganglion cells co-exist, and in which retinal ganglion cells display compartmentalized degeneration across their visual trajectory. Therefore, we assess the effects of nicotinamide on retinal ganglion cells in normal physiological conditions and across a range of glaucoma relevant insults. We confirm neuroprotection afforded by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We define a small molecular weight metabolome for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption that can be prevented by nicotinamide. Nicotinamide provides these neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term NAM treatment as a neuroprotective therapy for human glaucoma.One Sentence SummaryThe NAD precursor nicotinamide has a potent neuroprotective effect in the retina and optic nerve, targeting neuronal function, metabolism, and mitochondrial function.

scholarly journals Clinical electrophysiology of the optic nerve and retinal ganglion cells

Eye ◽  
2021 ◽  
Author(s):  
Oliver R. Marmoy ◽  
Suresh Viswanathan
Keyword(s):  
Optic Nerve ◽  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Retinal Ganglion Cell ◽  
Cell Function ◽  
Ganglion Cells ◽  
Pattern Electroretinogram ◽  
Photopic Negative Response ◽  
Clinical Electrophysiology ◽  
Retinal Ganglion

AbstractClinical electrophysiological assessment of optic nerve and retinal ganglion cell function can be performed using the Pattern Electroretinogram (PERG), Visual Evoked Potential (VEP) and the Photopic Negative Response (PhNR) amongst other more specialised techniques. In this review, we describe these electrophysiological techniques and their application in diseases affecting the optic nerve and retinal ganglion cells with the exception of glaucoma. The disease groups discussed include hereditary, compressive, toxic/nutritional, traumatic, vascular, inflammatory and intracranial causes for optic nerve or retinal ganglion cell dysfunction. The benefits of objective, electrophysiological measurement of the retinal ganglion cells and optic nerve are discussed, as are their applications in clinical diagnosis of disease, determining prognosis, monitoring progression and response to novel therapies.

scholarly journals Neuroprotection of retinal ganglion cells by the sigma-1 receptor agonist pridopidine in models of experimental glaucoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michal Geva ◽  
Noga Gershoni-Emek ◽  
Luana Naia ◽  
Philip Ly ◽  
Sandra Mota ◽  
...  
Keyword(s):  
Ganglion Cell ◽  
Retinal Degeneration ◽  
Retinal Ganglion Cells ◽  
Retinal Ganglion Cell ◽  
Ganglion Cells ◽  
Neuroprotective Effect ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Sigma 1 Receptor ◽  
Sigma 1

AbstractOptic neuropathies such as glaucoma are characterized by retinal ganglion cell (RGC) degeneration and death. The sigma-1 receptor (S1R) is an attractive target for treating optic neuropathies as it is highly expressed in RGCs, and its absence causes retinal degeneration. Activation of the S1R exerts neuroprotective effects in models of retinal degeneration. Pridopidine is a highly selective and potent S1R agonist in clinical development. We show that pridopidine exerts neuroprotection of retinal ganglion cells in two different rat models of glaucoma. Pridopidine strongly binds melanin, which is highly expressed in the retina. This feature of pridopidine has implications to its ocular distribution, bioavailability, and effective dose. Mitochondria dysfunction is a key contributor to retinal ganglion cell degeneration. Pridopidine rescues mitochondrial function via activation of the S1R, providing support for the potential mechanism driving its neuroprotective effect in retinal ganglion cells.

scholarly journals Dynamic Expression of HDAC3 in db/db Mouse RGCs and Its Relationship with Apoptosis and Autophagy

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yuhong Fu ◽  
Ying Wang ◽  
Xinyuan Gao ◽  
Huiyao Li ◽  
Yue Yuan
Keyword(s):  
Diabetic Retinopathy ◽  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Retinal Ganglion Cell ◽  
Ganglion Cells ◽  
Control Group ◽  
Diabetic Patients ◽  
Retinal Ganglion ◽  
Glucose Levels ◽  
Dynamic Expression

Background. Diabetic retinopathy (DR) is a severe complication of diabetes mellitus. DR is considered as a neurovascular disease. Retinal ganglion cell (RGC) loss plays an important role in the vision function disorder of diabetic patients. Histone deacetylase3 (HDAC3) is closely related to injury repair and nerve regeneration. The correlation between HDAC3 and retinal ganglion cells in diabetic retinopathy is still unclear yet. Methods. To investigate the chronological sequence of the abnormalities of retinal ganglion cells in diabetic retinopathy, we choose 15 male db/db mice (aged 8 weeks, 12 weeks, 16 weeks, 18 weeks, and 25 weeks; each group had 3 mice) as diabetic groups and 3 male db/m mice (aged 8 weeks) as the control group. In this study, we examined the morphological and immunohistochemical changes of HDAC3, Caspase3, and LC3B in a sequential manner by characterizing the process of retinal ganglion cell variation. Results. Blood glucose levels and body weights of db/db mice were significantly higher than that of the control group, P<0.01. Compared with the control group, the number of retinal ganglion cells decreased with the duration of disease increasing. HDAC3 expression gradually increased in RGCs of db/db mice. Caspase3 expression gradually accelerated in RGCs of db/db mice. LC3B expression dynamically changed in RGCs of db/db mice. HDAC3 was positively correlated with Caspase3 expression (r=0.7424), P<0.01. HDAC3 was positively correlated with LC3B expression (r=0.7336), P<0.01. Discussion. We clarified the dynamic expression changes of HDAC3, Caspase3, and LC3B in retinal ganglion cells of db/db mice. Our results suggest the HDAC3 expression has a positive correlation with apoptosis and autophagy.

scholarly journals Midget retinal ganglion cell dendritic and mitochondrial degeneration is an early feature of human glaucoma

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
James R Tribble ◽  
Asta Vasalauskaite ◽  
Tony Redmond ◽  
Robert D Young ◽  
Shoaib Hassan ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Animal Models ◽  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Retinal Ganglion Cell ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Face Scanning ◽  
Block Face ◽  
Scanning Electron

Abstract Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. However, the earliest degenerative events that occur in human glaucoma are relatively unknown. Work in animal models has demonstrated that retinal ganglion cell dendrites remodel and atrophy prior to the loss of the cell soma. Whether this occurs in human glaucoma has yet to be elucidated. Serial block face scanning electron microscopy is well established as a method to determine neuronal connectivity at high resolution but so far has only been performed in normal retina from animal models. To assess the structure–function relationship of early human glaucomatous neurodegeneration, regions of inner retina assessed to have none-to-moderate loss of retinal ganglion cell number were processed using serial block face scanning electron microscopy (n = 4 normal retinas, n = 4 glaucoma retinas). This allowed detailed 3D reconstruction of retinal ganglion cells and their intracellular components at a nanometre scale. In our datasets, retinal ganglion cell dendrites degenerate early in human glaucoma, with remodelling and redistribution of the mitochondria. We assessed the relationship between visual sensitivity and retinal ganglion cell density and discovered that this only partially conformed to predicted models of structure–function relationships, which may be affected by these early neurodegenerative changes. In this study, human glaucomatous retinal ganglion cells demonstrate compartmentalized degenerative changes as observed in animal models. Importantly, in these models, many of these changes have been demonstrated to be reversible, increasing the likelihood of translation to viable therapies for human glaucoma.

Brn3b/Brn3c double knockout mice reveal an unsuspected role for Brn3c in retinal ganglion cell axon outgrowth

Development ◽  
2002 ◽  
Vol 129 (2) ◽  
pp. 467-477 ◽  
Author(s):  
Steven W. Wang ◽  
Xiuqian Mu ◽  
William J. Bowers ◽  
Dong-Seob Kim ◽  
Daniel J. Plas ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Retinal Ganglion Cell ◽  
Knockout Mice ◽  
Ganglion Cells ◽  
Axon Outgrowth ◽  
Retinal Ganglion ◽  
Double Knockout ◽  
Ganglion Cell Axon

In mice, Brn3 POU domain transcription factors play essential roles in the differentiation and survival of projection neurons within the retina, inner ear, dorsal root and trigeminal ganglia. During retinal ganglion cell differentiation, Brn3b is expressed first, followed by Brn3a and Brn3c. Targeted deletion of Brn3b, but not Brn3a or Brn3c, leads to a loss of most retinal ganglion cells before birth. However, as a few retinal ganglion cells are still present in Brn3b–/– mice, Brn3a and Brn3c may partially compensate for the loss of Brn3b. To examine the role of Brn3c in retinal ganglion cell development, we generated Brn3b/Brn3c double knockout mice and analyzed their retinas and optic chiasms. Retinal ganglion cell axons from double knockout mice were more severely affected than were those from Brn3b-deficient mice, indicating that Brn3c was required for retinal ganglion cell differentiation and could partially compensate for the loss of Brn3b. Moreover, Brn3c had functions in retinal ganglion cell differentiation separate from those of Brn3b. Ipsilateral and misrouted projections at the optic chiasm were overproduced in Brn3b–/– mice but missing were entirely in optic chiasms of Brn3b/Brn3c double knockout mice, suggesting that Brn3c controlled ipsilateral axon production. Forced expression of Brn3c in Brn3b–/– retinal explants restored neurite outgrowth, demonstrating that Brn3c could promote axon outgrowth in the absence of Brn3b. Our results reveal a complex genetic relationship between Brn3b and Brn3c in regulating the retinal ganglion cell axon outgrowth.

The number, morphology, and distribution of retinal ganglion cells and optic axons in the Australian lungfishNeoceratodus forsteri(Krefft 1870)

2006 ◽  
Vol 23 (2) ◽  
pp. 257-273 ◽  
Author(s):  
HELENA J. BAILES ◽  
ANN E.O. TREZISE ◽  
SHAUN P. COLLIN
Keyword(s):  
Optic Nerve ◽  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Ganglion Cell Layer ◽  
Ganglion Cells ◽  
Cell Layer ◽  
Amacrine Cells ◽  
Resolving Power ◽  
Retinal Ganglion ◽  
Retrograde Labelling

Australian lungfishNeoceratodus forsterimay be the closest living relative to the first tetrapods and yet little is known about their retinal ganglion cells. This study reveals that lungfish possess a heterogeneous population of ganglion cells distributed in a horizontal streak across the retinal meridian, which is formed early in development and maintained through to adult stages. The number and complement of both ganglion cells and a population of putative amacrine cells within the ganglion cell layer are examined using retrograde labelling from the optic nerve and transmission electron-microscopic analysis of axons within the optic nerve. At least four types of retinal ganglion cells are present and lie predominantly within a thin ganglion cell layer, although two subpopulations are identified, one within the inner plexiform and the other within the inner nuclear layer. A subpopulation of retinal ganglion cells comprising up to 7% of the total population are significantly larger (>400 μm2) and are characterized as giant or alpha-like cells. Up to 44% of cells within the retinal ganglion cell layer represent a population of presumed amacrine cells. The optic nerve is heavily fasciculated and the proportion of myelinated axons increases with body length from 17% in subadults to 74% in adults. Spatial resolving power, based on ganglion cell spacing, is low (1.6–1.9 cycles deg−1,n= 2) and does not significantly increase with growth. This represents the first detailed study of retinal ganglion cells in sarcopterygian fish, and reveals that, despite variation amongst animal groups, trends in ganglion cell density distribution and characteristics of cell types were defined early in vertebrate evolution.

scholarly journals Lepidium sativum as candidate against excitotoxicity in retinal ganglion cells

2021 ◽  
Vol 12 (1) ◽  
pp. 247-259
Author(s):  
Abeer Al-Dbass ◽  
Musarat Amina ◽  
Nawal M. Al Musayeib ◽  
Amira A. El-Anssary ◽  
Ramesa Shafi Bhat ◽  
...  
Keyword(s):  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Retinal Ganglion Cell ◽  
Ganglion Cells ◽  
Cell Damage ◽  
Tail Length ◽  
Glutamate Excitotoxicity ◽  
Control Group ◽  
Retinal Ganglion ◽  
Blank Control Group

Abstract Glutamate excitotoxicity is considered one of the major causes of retinal ganglion cell death in many retinal diseases. Retinal ganglion cell degeneration causes severe blindness since visual signals from the eye to the brain are conducted only through retinal ganglion cells. Objective: We aimed to explore the potential ameliorative effects of L. sativum against glutamate excitotoxicity-induced retinal ganglion cell damage. Methods: Pure retinal ganglion cells were divided into a control group (untreated); L. sativum-treated groups in which retinal ganglion cells were treated with 5, 10, 50, or 100 µg/mL L. sativum seed extract for 2 h; glutamate-treated groups in which cells were treated with 5, 10, 50, or 100 µM glutamate for 48 h; and L. sativum/glutamate groups [pretreatment with L. sativum for 2 h (50 or 100 µg/mL) before glutamate treatment at 100 µM for 48 h]. Cell damage was assessed by comet assay and cell viability was by MTT test. Results: Tailed DNA, tail length, and tail moment of the 50 and 100 mM glutamate-treated groups were significantly greater than those of the blank control group, while the L. sativum-treated groups demonstrated nonsignificantly different tailed DNA, tail length, and tail moment compared with the blank control group, but significantly lower values compared with the glutamate-treated groups. Conclusion: L. sativum ameliorated the cell viability in retinal ganglion cells after high-concentration glutamate exposure. L. sativum seed extracts were efficient anti-excitotoxic and antioxidant agent that might improve the clinical presentation of many neurological disorders.

scholarly journals Slit2 is essential for correct retinal ganglion cell axon fasciculation and midline crossing in the zebrafish

2020 ◽  
Author(s):  
Camila Davison ◽  
Flavio R. Zolessi
Keyword(s):  
Optic Nerve ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Ganglion Cells ◽  
Axon Growth ◽  
Amacrine Cells ◽  
Optic Chiasm ◽  
Retinal Ganglion ◽  
Functional Connection ◽  
Optic Nerves

ABSTRACTThe functional connection of the retina with the brain implies the extension of retinal ganglion cells axons through a long and tortuous path. Slit-Robo signaling has been implicated in axon growth and guidance in several steps of this journey. Here, we analyzed in detail the expression pattern of slit2 in zebrafish embryos by whole-mount fluorescent in situ hybridization, to extend previous work on this and other species. Major sites of expression are amacrine cells in the retina from 40 hpf, as well as earlier expression around the future optic nerve, anterior to the optic chiasm, two prominent cell groups in the anterior forebrain and the ventral midline of the caudal brain and spinal cord. To further characterize slit2 function in retinal axon growth and guidance, we generated and phenotypically characterized a null mutant for this gene, using CRISPR-Cas9 technology. Although no evident defects were found on intraretinal axon growth or in the formation of the optic tracts or tectal innervation, we observed very characteristic and robust impairment on axon fasciculation at the optic nerves and chiasm. The optic nerves appeared thicker and defasciculated only in maternal-zygotic mutants, while a very particular unilateral nerve-splitting phenotype was evident at the optic chiasm in a good proportion of both zygotic and maternal-zygotic mutants. Our results support the idea of a channeling role for Slit molecules in retinal ganglion cell axons at the optic nerve level, in addition to a function in the segregation of axons coming from each nerve at the optic chiasm.

Voltage-gated Na+ channel EOIII-segment-like immunoreactivity in fish retinal ganglion cells

2000 ◽  
Vol 17 (4) ◽  
pp. 647-655 ◽  
Author(s):  
MASAYASU YOSHIKAWA ◽  
KAJ ANDERSON ◽  
HIRONOBU SAKAGUCHI ◽  
JOHN G. FLANNERY ◽  
PAUL G. FITZGERALD ◽  
...  
Keyword(s):  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Retinal Ganglion Cell ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Western Blots ◽  
Voltage Gated ◽  
Molecular Weights ◽  
Α And Β Subunits ◽  
Cell Somata

Although single-channel and whole-cell patch-clamp recordings have demonstrated the presence of Na+ currents in retinal ganglion cell somata, it has not previously been reported that an anti-Na+-channel antiserum stains both retinal ganglion cell somata and proteins with molecular weights corresponding to complexes of α and β subunits. We probed adult goldfish retinas for Na+ channel-like immunoreactivity with a polyclonal antibody directed against the EOIII segment of vertebrate voltage-gated Na+ channels. In vertical sections and whole mounts, this antibody consistently stained the somata, axons, and proximal dendrites of retinal ganglion cells. Some somata in the proximal third of the inner nuclear layer were also stained. In Western blots, this antibody specifically stained multiple protein bands from retina and optic nerve, all with apparent molecular weights between 200 and 315 kDa. The largest of these molecular weights agrees with that reported previously for complexes of α and β subunits in mammalian neurons, including retinal ganglion cells. The intermediate and lowest molecular weights are consistent with the presence of multiple Na+ channel α subunits, either in individual proximal retinal neurons or in different morphological subtypes.

scholarly journals Survival of retinal ganglion cells after damage to the occipital lobe in humans is activity dependent

2019 ◽  
Vol 286 (1897) ◽  
pp. 20182733 ◽  
Author(s):  
Colleen L. Schneider ◽  
Emily K. Prentiss ◽  
Ania Busza ◽  
Kelly Matmati ◽  
Nabil Matmati ◽  
...  
Keyword(s):  
Visual Cortex ◽  
Visual Field ◽  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Retinal Ganglion Cell ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Visual Ability ◽  
Activity Dependent

Damage to the optic radiations or primary visual cortex leads to blindness in all or part of the contralesional visual field. Such damage disconnects the retina from its downstream targets and, over time, leads to trans-synaptic retrograde degeneration of retinal ganglion cells. To date, visual ability is the only predictor of retinal ganglion cell degeneration that has been investigated after geniculostriate damage. Given prior findings that some patients have preserved visual cortex activity for stimuli presented in their blind field, we tested whether that activity explains variability in retinal ganglion cell degeneration over and above visual ability. We prospectively studied 15 patients (four females, mean age = 63.7 years) with homonymous visual field defects secondary to stroke, 10 of whom were tested within the first two months after stroke. Each patient completed automated Humphrey visual field testing, retinotopic mapping with functional magnetic resonance imaging, and spectral-domain optical coherence tomography of the macula. There was a positive relation between ganglion cell complex (GCC) thickness in the blind field and early visual cortex activity for stimuli presented in the blind field. Furthermore, residual visual cortex activity for stimuli presented in the blind field soon after the stroke predicted the degree of retinal GCC thinning six months later. These findings indicate that retinal ganglion cell survival after ischaemic damage to the geniculostriate pathway is activity dependent.

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