scholarly journals Emodin protected against retinal ischemia insulted neurons through the downregulation of protein overexpression of β-catenin and vascular endothelium factor

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Howard Wen-Haur Chao ◽  
Yu-Kuang Chen ◽  
Jorn-Hon Liu ◽  
Hwai-Tzong Pan ◽  
Hsin-May Lin ◽  
...  
Keyword(s):  
Ganglion Cells ◽  
Retinal Thickness ◽  
Glucose Deprivation ◽  
Retinal Ischemia ◽  
Cresyl Violet ◽  
Inner Retina ◽  
Retrograde Labelling ◽  
Intravitreous Injection ◽  
Vehicle Treatment ◽  
Vegf Protein

Abstract Background Emodin has been proved to have an anti-ischemic effect on the brain, however little research has been done on its effect on vision-threatening retinal ischemia. Thus, an investigation was carried out into the hypothetical efficacy of emodin against retinal ischemia and the role of β-catenin/VEGF in its therapeutic mechanism. Methods Retinal ischemia, followed by reperfusion (IR), was inducted by raising the intraocular pressure of a Wistar rat’s eye to 120 mmHg for 60 min. Additionally, pre-ischemic/post-ischemic intravitreous injections of emodin (4, 10 and 20 μM) or vehicle were carried out on the eye with retinal ischemia. MTT assay, electroretinograms, cresyl violet staining retinal thickness measurements, and fluorogold retrograde labelling of retinal ganglion cells (RGCs) as well as Western blotting were carried out. Results Cultured RGC-5 cells subjected to oxygen glucose deprivation (OGD) were used to confirm the effective concentrations of emodin (administered 1 h pre-OGD, pre-OGD emodin). The most effective and significant (P = 0.04) dose of pre-OGD emodin was observed at 0.5 μM (cell viability: 47.52 ± 3.99%) as compared to pre-OGD vehicle treatment group (38.30 ± 2.51%). Furthermore, pre-ischemic intravitreous injection of 20 μM emodin (Emo20 + IR = 0.99 ± 0.18, P < 0.001) significantly attenuated the ischemia induced reduction in ERG b-wave amplitude, as compared to pre-ischemic intravitreous vehicle (Vehicle+IR = 0.04 ± 0.02). Post-ischemic intravitreous 20 μM emodin also significantly (P < 0.001) attenuated the ischemia associated b-wave reduction (IR + Em20 = 0.24 ± 0.09). Compared with pre-ischemic intravitreous vehicle (Vehicle+IR; whole retina thickness = 71.80 ± 1.08 μm; inner retina thickness = 20.97 ± 0.85 μm; RGC =2069.12 ± 212.82/0.17mm2), the significant (P < 0.001) protective effect was also present with pre-ischemic administration of emodin. This was shown by observing cresyl violet stained retinal thickness (Emo20 + IR: whole retina = 170.10 ± 0.10 μm; inner retina = 70.65 ± 2.06 μm) and retrograde fluorogold immunolabeled RGC density (4623.53 ± 179.48/0.17mm2). As compared to the normal control (the ratio of β-catenin/VEGF to β-actin was set as 1 in the Sham group), the β-catenin/VEGF protein level significantly (P < 0.001) increased after retinal ischemia and when pre-ischemic intravitreous vehicle (Vehicle+IR = 1.64 ± 0.14/7.67 ± 2.57) was carried out. However, these elevations were significantly (P = 0.02) attenuated by treatment with emodin 20 μM (Emo20 + IR = 1.00 ± 0.19/1.23 ± 0.44). Conclusions The present results suggest that emodin might protect against retinal ischemia insulted neurons such as RGCs by significantly downregulating the upregulation of β-catenin/VEGF protein that occurs during ischemia.

S-Allyl L-Cysteine Protects the Retina Against Kainate Excitotoxicity in the Rat

2014 ◽  
Vol 42 (03) ◽  
pp. 693-708 ◽  
Author(s):  
Hsiao-Ming Chao ◽  
Ing-Ling Chen ◽  
Jorn-Hon Liu
Keyword(s):  
Ganglion Cells ◽  
Wistar Rat ◽  
Retinal Ischemia ◽  
Kainate Receptors ◽  
Mrna Levels ◽  
Intravitreous Injection ◽  
Gfap Immunoreactivity ◽  
Matrix Metalloproteinases 9 ◽  
Kainate Excitotoxicity

Excitotoxicity has been proposed to play a pivotal role in retinal ischemia. Retinal ischemia-associated ocular disorders are vision threatening. The aim was to also examine whether and how S-allyl L-cysteine (SAC) can protect the retina against kainate excitotoxicity. In vivo retinal excitotoxicity was induced by an intravitreous injection of 100 μM kainate into a Wistar rat eye for 1 day. The management and mechanisms involved in the processes were evaluated by electrophysiology, immunohistochemistry, histopathology, and various biochemical approaches. In the present study, the cultured retinal cells were shown to possess kainate receptors. The defined retinal excitotoxic changes were characterized by a decrease in electroretinogram (ERG) b-wave amplitudes, a loss of the fluorogold retrograde labeled retinal ganglion cells (RGCs), an increase in the apoptotic cells in the RGC layer, and an increase in vimentin or glial fibrillary acidic protein (GFAP) immunoreactivity, a marker for Müller cells. An up-regulation in the mRNA levels of inducible nitric oxide synthase (iNOS) and matrix metalloproteinases-9 (MMPs-9) was also detected in the retina subjected to kainate excitoxicity. Importantly, the excitotoxicity-induced alterations were significantly blunted when 100 μM SAC and/or the kainate receptor antagonist CNQX was applied. Conclusively, SAC would seem to protect the retina against kainate excitotoxicity via an inhibition of the up-regulation of iNOS and MMP-9 as well as a modulation of glial activation and apoptosis.

scholarly journals HIF inhibitor topotecan has a neuroprotective effect in a murine retinal ischemia-reperfusion model

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7849 ◽  
Author(s):  
Hiromitsu Kunimi ◽  
Yukihiro Miwa ◽  
Yusaku Katada ◽  
Kazuo Tsubota ◽  
Toshihide Kurihara
Keyword(s):  
Intraocular Pressure ◽  
Visual Evoked Potentials ◽  
Retinal Thickness ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Retinal Ischemia ◽  
Retinal Ganglion ◽  
Neuroprotective Effects ◽  
Retinal Neurodegeneration

Purpose The therapeutic approach for retinal ganglion cell (RGC) degeneration has not been fully established. Recently, it has been reported that hypoxia-inducible factor (HIF) may be involved with retinal neurodegeneration. In this study, we investigated neuroprotective effects of a HIF inhibitor against RGC degeneration induced in a murine model of retinal ischemia-reperfusion (I/R). Methods Eight-weeks-old male C57/BL6J mice were treated with intraperitoneal injection of a HIF inhibitor topotecan (1.25 mg/kg) for 14 days followed by a retinal I/R procedure. Seven days after the I/R injury, the therapeutic effect was evaluated histologically and electrophysiologically. Results The increase of HIF-1α expression and the decrease of retinal thickness and RGC number in I/R were significantly suppressed by administration of topotecan. Impaired visual function in I/R was improved by topotecan evaluated with electroretinogram and visual evoked potentials. Conclusions Topotecan administration suppressed HIF-1a expression and improved RGC survival resulting in a functional protection against retinal I/R. These data indicated that the HIF inhibitor topotecan may have therapeutic potentials for RGC degeneration induced with retinal ischemia or high intraocular pressure.

Abstract TP101: Intra-arterial IL-1α is Well Tolerated and Neuroprotective After Experimental Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Kathleen E Salmeron ◽  
Michael E Maniskas ◽  
Amanda Trout ◽  
Emmanuel Pinteaux ◽  
Justin F Fraser ◽  
...  
Keyword(s):  
Side Effects ◽  
Cortical Neurons ◽  
Glucose Deprivation ◽  
Cresyl Violet ◽  
Current Standard ◽  
Preclinical Research ◽  
Vessel Occlusion ◽  
Post Stroke ◽  
Primary Mouse

Endovascular thrombectomy and t-PA are the only current standard of care treatments for emergent large vessel occlusion (ELVO) stroke. Despite rising recanalization rates, stroke remains the leading cause of long-term disability worldwide suggesting that additional therapies are needed. Severe stroke morbidity may be due, in part, to the acute and sustained inflammatory stroke response. Preclinical research has supported anti-inflammatory agents in limiting brain injury and improving functional outcome; however, the post-stroke inflammatory cascade appears to have both beneficial and deleterious effects, necessitating careful therapeutic translation. We have recently demonstrated that delayed (3 day) post-stroke intravenous (IV) administration of the interleukin (IL)-1α (one of the two major isoforms of the pro-inflammatory family of cytokine IL-1), promoted, rather than suppressed, post-stroke angiogenesis in the transient middle cerebral artery occlusion (MCAo) mouse model. In this study, we aimed to show a therapeutic efficacy of IL-1α in neuroprotection. We investigated the potential for IL-1α, administered acutely IV or intra-arterial (IA) (n=5) after mouse MCAo, to also be neuroprotective. We noted that IV IL-1α (1 ng) is neuroprotective (as measured by cresyl violet stained infarct volumes) with mild, transient side effects (blunted hypertension and bradycardia) that were well tolerated, and with better functional recovery in free motion behavioral tests. IA IL-1α (0.1 ng) administration was even more neuroprotective without the systemic changes seen with IV treatment. Additionally, we noted that IL-1α is directly neuroprotective of primary mouse cortical neurons exposed to oxygen and glucose deprivation conditions in vitro . Taken together, these results suggest that IL-1α could be therapeutic after stroke when administered IV or IA, and the latter may eliminate potentially harmful hemodynamic side effects.

scholarly journals Eye Opener in Stroke

Stroke ◽  
2019 ◽  
Vol 50 (8) ◽  
pp. 2197-2206 ◽  
Author(s):  
Hung Nguyen ◽  
Jea Young Lee ◽  
Paul R. Sanberg ◽  
Eleonora Napoli ◽  
Cesar V. Borlongan
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Glucose Deprivation ◽  
Retinal Ischemia ◽  
Artery Occlusion ◽  
Oxygen Glucose Deprivation ◽  
Retinal Pigmented Epithelium ◽  
Pigmented Epithelium ◽  
Cerebral Artery Occlusion ◽  
Epithelium Cells

Background and Purpose— Retinal ischemia is a major cause of visual impairment in stroke patients, but our incomplete understanding of its pathology may contribute to a lack of effective treatment. Here, we investigated the role of mitochondrial dysfunction in retinal ischemia and probed the potential of mesenchymal stem cells (MSCs) in mitochondrial repair under such pathological condition. Methods— In vivo, rats were subjected to middle cerebral artery occlusion then randomly treated with intravenous MSCs or vehicle. Laser Doppler was used to evaluate the blood flow in the brain and the eye, while immunohistochemical staining assessed cellular degeneration at days 3 and 14 poststroke. In vitro, retinal pigmented epithelium cells were exposed to either oxygen-glucose deprivation or oxygen-glucose deprivation and coculture with MSCs, and subsequently, cell death and mitochondrial function were examined immunocytochemically and with Seahorse analyzer, respectively. Results— Middle cerebral artery occlusion significantly reduced blood flow in the brain and the eye accompanied by mitochondrial dysfunction and ganglion cell death at days 3 and 14 poststroke. Intravenous MSCs elicited mitochondrial repair and improved ganglion cell survival at day 14 poststroke. Oxygen-glucose deprivation similarly induced mitochondrial dysfunction and cell death in retinal pigmented epithelium cells; coculture with MSCs restored mitochondrial respiration, mitochondrial network morphology, and mitochondrial dynamics, which likely attenuated oxygen-glucose deprivation-mediated retinal pigmented epithelium cell death. Conclusions— Retinal ischemia is closely associated with mitochondrial dysfunction, which can be remedied by stem cell-mediated mitochondrial repair.

scholarly journals Deleterious Effect of NMDA Plus Kainate on the Inner Retinal Cells and Ganglion Cell Projection of the Mouse

2020 ◽  
Vol 21 (5) ◽  
pp. 1570 ◽  
Author(s):  
Estrella Calvo ◽  
Santiago Milla-Navarro ◽  
Isabel Ortuño-Lizarán ◽  
Violeta Gómez-Vicente ◽  
Nicolás Cuenca ◽  
...  
Keyword(s):  
Ganglion Cell ◽  
Deleterious Effect ◽  
Wave Amplitude ◽  
Ganglion Cells ◽  
Outer Nuclear Layer ◽  
Retinal Ganglion ◽  
Inner Retina ◽  
Glutamate Receptor Agonists ◽  
The Right ◽  
Anterograde Labeling

Combined administration of N-Methyl-D-Aspartate (NMDA) and kainic acid (KA) on the inner retina was studied as a model of excitotoxicity. The right eye of C57BL6J mice was injected with 1 µL of PBS containing NMDA 30 mM and KA 10 mM. Only PBS was injected in the left eye. One week after intraocular injection, electroretinogram recordings and immunohistochemistry were performed on both eyes. Retinal ganglion cell (RGC) projections were studied by fluorescent-cholerotoxin anterograde labeling. A clear decrease of the retinal “b” wave amplitude, both in scotopic and photopic conditions, was observed in the eyes injected with NMDA/KA. No significant effect on the “a” wave amplitude was observed, indicating the preservation of photoreceptors. Immunocytochemical labeling showed no effects on the outer nuclear layer, but a significant thinning on the inner retinal layers, thus indicating that NMDA and KA induce a deleterious effect on bipolar, amacrine and ganglion cells. Anterograde tracing of the visual pathway after NMDA and KA injection showed the absence of RGC projections to the contralateral superior colliculus and lateral geniculate nucleus. We conclude that glutamate receptor agonists, NMDA and KA, induce a deleterious effect of the inner retina when injected together into the vitreous chamber.

Regional distribution of nitrergic neurons in the inner retina of the chicken

2011 ◽  
Vol 28 (3) ◽  
pp. 205-220 ◽  
Author(s):  
MARTIN WILSON ◽  
NICK NACSA ◽  
NATHAN S. HART ◽  
CYNTHIA WELLER ◽  
DAVID I. VANEY
Keyword(s):  
Ganglion Cell ◽  
Ganglion Cells ◽  
Regional Distribution ◽  
Plexiform Layer ◽  
Visual Image ◽  
Amacrine Cells ◽  
Cell Types ◽  
Inner Plexiform Layer ◽  
Inner Retina ◽  
Neuronal Types

AbstractUsing both NADPH diaphorase and anti-nNOS antibodies, we have identified—from retinal flatmounts—neuronal types in the inner retina of the chicken that are likely to be nitrergic. The two methods gave similar results and yielded a total of 15 types of neurons, comprising 9 amacrine cells, 5 ganglion cells, and 1 centrifugal midbrain neuron. Six of these 15 cell types are ubiquitously distributed, comprising 3 amacrine cells, 2 displaced ganglion cells, and a presumed orthotopic ganglion cell. The remaining nine cell types are regionally restricted within the retina. As previously reported, efferent fibers of midbrain neurons and their postsynaptic partners, the unusual axon-bearing target amacrine cells, are entirely confined to the ventral retina. Also confined to the ventral retina, though with somewhat different distributions, are the “bullwhip” amacrine cells thought to be involved in eye growth, an orthotopic ganglion cell, and two types of large axon-bearing amacrine cells whose dendrites and axons lie in stratum 1 of the inner plexiform layer (IPL). Intracellular fills of these two cell types showed that only a minority of otherwise morphologically indistinguishable neurons are nitrergic. Two amacrine cells that branch throughout the IPL are confined to an equatorial band, and one small-field orthotopic ganglion cell that branches in the proximal IPL is entirely dorsal. These findings suggest that the retina uses different processing on different regions of the visual image, though the benefit of this is presently obscure.

A second episode of ganglion cell death takes place when an optic nerve regenerates for a second time in the frog

1993 ◽  
Vol 10 (2) ◽  
pp. 297-301 ◽  
Author(s):  
L. D. Beazley ◽  
J.E. Darby
Keyword(s):  
Cell Death ◽  
Optic Nerve ◽  
Ganglion Cell ◽  
Ganglion Cells ◽  
Cresyl Violet ◽  
Retinal Ganglion ◽  
Nerve Crush ◽  
Optic Nerve Regeneration ◽  
Ability To Regenerate ◽  
Ganglion Cell Death

AbstractWe have previously reported that during optic nerve regeneration in the frog, 30–40% of retinal ganglion cells die, the loss being complete within 10 weeks. In the present study, we crushed the optic nerve, waited 10 weeks, and then recrushed the nerve at the same site. Retinae were examined 10 weeks later. We estimated ganglion cell numbers from cresyl-violet-stained wholemounts and found a fall of 53% compared to normals. The loss was significantly greater than the losses of 36% and 35%, respectively, in frogs which received a single optic nerve crush and were examined 10 or 20–24 weeks later. The results indicate that a second episode of ganglion cell death took place when the optic nerve regenerated a second time. We conclude that ganglion cells in the frog are not comprised of two subpopulations, only one of which intrinsically possesses the ability to regenerate.

scholarly journals THE EFFECT OF DEPRIVATION OF GLUCOSE ON THE ULTRASTRUCTURE AND FUNCTION OF THE SUPERIOR CERVICAL GANGLION OF THE RAT IN VITRO

1966 ◽  
Vol 29 (2) ◽  
pp. 267-285 ◽  
Author(s):  
P. Nicolescu ◽  
M. Dolivo ◽  
C. Rouiller ◽  
C. Foroglou-Kerameus
Keyword(s):  
Synaptic Transmission ◽  
Ganglion Cells ◽  
Glucose Deprivation ◽  
Axonal Conduction ◽  
Electrophysiological Measurements ◽  
Cervical Ganglion ◽  
Cervical Sympathetic ◽  
Ultrastructure And Function ◽  
And Function

The superior cervical sympathetic ganglion of the rat kept in vitro in a bicarbonate-buffered Krebs' solution retains its capacity for synaptic transmission and axonal conduction during more than 36 hr. After glucose withdrawal, synaptic transmission is lost in 2½ hr and this loss is irreversible; on the other hand, axonal conduction can still be measured on the postganglionic nerve for more than 24 hr after glucose deprivation. Electrophysiological measurements as well as electron microscope studies revealed specific changes at the level of the presynaptic terminal processes, while the ganglion cells and the satellite cells remained relatively unaltered. The presynaptic lesion due to lack of glucose can be prevented by keeping the preparation in vitro at 6°C. This strongly suggests that this lesion results from a major disturbance of the metabolism of the presynaptic fibers.

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