Neuroprotective effects of gypenosides in experimental autoimmune optic neuritis

Zhang, Hong-Kan; Yuan, Y.; Zhao, Zhenni; Li, Kaijun; Du, Yi; Hu, Qiuming; He, Jianfeng

doi:10.18240/ijo.2017.04.07

Cited by 11 publications

(11 citation statements)

References 24 publications

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“…However, previous studies assessing optic nerve and retinal pathology in autoimmune ON reported little to no difference between the CFA-only group and healthy controls in inflammatory pathology and neuro-axonal degeneration [2, 57]. Our results suggests that IRL changes in EAE are primarily influenced by pRNFL changes over time; yet previous OCT studies investigating pRNFL changes in EAE mice report contradictory findings [3, 32]. This may be due to the use of different species and immunisation protocols, but also because of methodological limitations as the pRNFL is a relatively thin structure in rodents and thus difficult to segment accurately on its own.…”

Section: Discussioncontrasting

confidence: 60%

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Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

Manogaran

Samardzija

Schad

et al. 2019

acta neuropathol commun

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The exact mechanisms and temporal sequence of neurodegeneration in multiple sclerosis are still unresolved. The visual pathway including its unmyelinated retinal axons, can serve as a prototypic model of neurodegeneration in experimental optic neuritis. We conducted a longitudinal study combining retinal imaging through optical coherence tomography (OCT) with immunohistochemical analyses of retinal and optic nerve tissue at various time points in experimental autoimmune encephalomyelitis (EAE). Inner retinal layer (IRL) thickness was measured in 30 EAE and 14 healthy control C57BL/6 J mice using OCT. Distribution of marker proteins was assessed by immunofluorescence staining and retinal mRNA levels were assayed using real-time PCR. Histological morphology was evaluated on light and electron microscopy images. Signs of inflammatory edema 11 days post immunisation coincided with IRL thickening, while neuro-axonal degeneration throughout the disease course contributed to IRL thinning observed after 20 days post immunisation. Retinal pathology, including axonal transport impairment, was observed early, prior to cellular infiltration (i.e. T-cells) in the optic nerve 11 days post immunisation. Yet, the effects of early retinal damage on OCT-derived readouts were outweighed by the initial inflammatory edema. Early microglial activation and astrocytosis was detected in the retina prior to retinal ganglion cell loss and persisted until 33 days post immunisation. Müller cell reactivity (i.e. aquaporin-4 and glutamine synthetase decrease) presented after 11 days post immunisation in the IRL. Severe neuro-axonal degeneration was observed in the optic nerve and retina until 33 days post immunisation. Initial signs of retinal pathology subsequent to early glial activity, suggests a need for prophylactic treatment of optic neuritis. Following early inflammation, Müller cells possibly respond to retinal pathology with compensatory mechanisms. Although the majority of the IRL damage observed is likely due to retrograde degeneration following optic neuritis, initial pathology, possibly due to gliosis, may contribute further to IRL thinning. These results add morphological substrate to our OCT findings. The extent and rapid onset of axonal and neuronal damage in this model appears relevant for testing interventions scaled to human optic neuritis. Electronic supplementary material The online version of this article (10.1186/s40478-019-0768-5) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 60%

“…Several studies have assessed retinal pathology using OCT in experimental models of ON [3, 11, 16, 28–32]. In particular, studies have revealed initial phases of IRL thickening [11, 31] around the optic nerve head (ONH) followed by severe thinning at later stages of the disease in EAE mice compared to healthy controls [16].…”

Section: Introductionmentioning

confidence: 99%

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

Manogaran

Samardzija

Schad

et al. 2019

acta neuropathol commun

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“…Treatment with Gp exerted protective effects on retinal nerve fibers and axons. These results strongly indicate that the Gp might be a useful supplement for optic neuritis treatment (Zhang et al 2017).…”

Section: Discussionmentioning

confidence: 57%

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

Zhang

Yuan

et al. 2020

J Mol Neurosci

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Our 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 H 2 O 2 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 H 2 O 2-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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“…Mice were placed on a platform after anaesthesia and pupil dilation and adjusted to ensure that the incident beam was perpendicular to the central cornea and passed through the pupil. The retinal thickness of mice at a circle with a diameter of 3.45 mm (system setting) using the optic disc as the centre was measured by OCT with a 25D lens (50744, Heidelberg, Germany) 45 . After the measurement of live animals, the mice were anaesthetised and cardiac perfused with 4% paraformaldehyde in phosphate buffer.…”

Section: Methodsmentioning

confidence: 99%

The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro

et al. 2021

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The glaucoma-associated E50K mutation in optineurin (OPTN) is known to affect autophagy and cause the apoptosis of retinal ganglion cells (RGCs), but the pathogenic mechanism remains unclear. In this study, we investigated whether the OPTN (E50K) mutation caused TDP-43 aggregation by disrupting autophagy in vivo and in vitro. OPTN (E50K) mutant mice were generated and analysed for genotype and phenotype. Adeno-associated virus type 2 vectors containing either GFP only, GFP-tagged wild-type OPTN or GFP-tagged E50K-mutated OPTN were used to transfect R28 cells. Loss of RGCs decreased retinal thickness and visual impairment were observed in OPTN (E50K) mice compared with WT mice. Moreover, overexpression of E50K OPTN induced R28 cell apoptosis. Increased p62/SQSTM1 and LC3-II levels indicated that autophagic flux was inhibited and contributed to TDP-43 aggregation in vivo and in vitro. We found that rapamycin effectively reduced the aggregation of TDP-43 in OPTN (E50K) mice and decreased the protein levels of p62/SQSTM1 and the autophagic marker LC3-II. Moreover, rapamycin increased the RGC number and visual function of E50K mice. In addition, we also observed increased cytoplasmic TDP-43 in the spinal cord and motor dysfunction in 24-month-old OPTN (E50K) mice, indicating that TDP-43 accumulation may be the common pathological mechanism of glaucoma and amyotrophic lateral sclerosis (ALS). In conclusion, the disruption of autophagy by OPTN (E50K) affected the degradation of TDP-43 and may play an important role in OPTN (E50K)-mediated glaucomatous retinal neurodegeneration.

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Neuroprotective effects of gypenosides in experimental autoimmune optic neuritis

Abstract: Treatment with gypenosides exerts protective effects on retinal nerve fibers and axons in EAON. When combined with gypenosides, methylprednisolone reduces demyelination in the acute stage of EAON.

Cited by 11 publications

References 24 publications

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

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

The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro

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