<scp>EphA4</scp>/<scp>ephrinA3</scp> reverse signaling mediated downregulation of glutamate transporter <scp>GLAST</scp> in Müller cells in an experimental glaucoma model

Xu, Lei; Wang, Hong‐Ning; Cheng, Shuo; Li, Fang; Miao, Yanying; Lei, Bo; Gao, Feng; Wang, Zhongfeng

doi:10.1002/glia.24307

Cited by 6 publications

(4 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inflammatory responses have been identified as crucial in the pathogenesis of neurodegenerative diseases 44–46 . Retinal injury triggers the activation of vascular inflammation and glial cells, including microglia, astrocytes, and Müller cells 23,47 . To explore whether oral melatonin supplementation can affect retinal inflammation in EAAC1 −/− mice, we conducted immunofluorescence staining using antibodies against CD45, Iba1/CD68, GFAP, and vimentin, which are markers of leukocytes, microglia/macrophages and their activated form, astrocytes, and Müller cells, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…[44][45][46] Retinal injury triggers the activation of vascular inflammation and glial cells, including microglia, astrocytes, and Müller cells. 23,47 To explore whether oral melatonin supplementation can affect retinal inflammation in EAAC1 −/− mice, we conducted immunofluorescence staining using antibodies against CD45, Iba1/CD68, GFAP, and vimentin, which are markers of leukocytes, microglia/macrophages and their activated form, astrocytes, and Müller cells, respectively. Our data showed a noteworthy rise in CD45-positive cells as well as Iba1/ CD68 double-positive cells among EAAC1 −/− mice, indicating activation of inflammatory responses, and melatonin administration effectively alleviated these inflammatory responses (Figure 7A-D).…”

Section: Melatonin Alleviated the Inflammatory Response In Eaac1 −/− ...mentioning

confidence: 99%

See 1 more Smart Citation

Melatonin prevents EAAC1 deletion‐induced retinal ganglion cell degeneration by inhibiting apoptosis and senescence

Hu,

Feng,

Huang

et al. 2023

Journal of Pineal Research

View full text Add to dashboard Cite

Normal tension glaucoma (NTG) is referred to as a progressive degenerative disorder of the retinal ganglion cells (RGCs), resulting in nonreversible visual defects, despite intraocular pressure levels within the statistically normal range. Current therapeutic strategies for NTG yield limited benefits. Excitatory amino acid carrier 1 (EAAC1) knockout (EAAC1−/−) in mice has been shown to induce RGC degeneration without elevating intraocular pressure, mimicking pathological characteristics of NTG. In this study, we explored whether daily oral administration of melatonin could block RGCs loss and prevent retinal morphology and function defects associated with EAAC1 deletion. We also explored the molecular mechanisms underlying EAAC1 deletion‐induced RGC degeneration and the neuroprotective effects of melatonin. Our RNA sequencing and in vivo data indicated EAAC1 deletion caused elevated oxidative stress, activation of apoptosis and cellular senescence pathways, and neuroinflammation in RGCs. However, melatonin administration efficiently prevented these detrimental effects. Furthermore, we investigated the potential role of apoptosis‐ and senescence‐related redox‐sensitive factors in EAAC1 deletion‐induced RGCs degeneration and the neuroprotective effects of melatonin administration. We observed remarkable upregulation of p53, whereas NRF2 and Sirt1 expression were significantly decreased in EAAC1−/− mice, which were prevented by melatonin treatment, suggesting that melatonin exerted its neuroprotective effects possibly through modulating NRF2/p53/Sirt1 redox‐sensitive signaling pathways. Overall, our study provided a solid foundation for the application of melatonin in the management of NTG.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Melatonin Alleviated the Inflammatory Response In Eaac1 −/− ...mentioning

confidence: 99%

Melatonin prevents EAAC1 deletion‐induced retinal ganglion cell degeneration by inhibiting apoptosis and senescence

Hu,

Feng,

Huang

et al. 2023

Journal of Pineal Research

View full text Add to dashboard Cite

show abstract

“…In addition, it has been demonstrated that reduced expression of EphrinA3 activated the PI3K/Akt pathway in the glaucoma model (Zhou et al, 2023) and the miR-204-5p/EphA4 axis activated the PI3K/AKT pathway, ameliorating neurological injury in ischemic stroke (Shi et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

“…Numerous studies have demonstrated that the Ephrin ligand and Eph receptor system regulate a number of physiological and pathological processes that may be engaged in the pathological process of cerebral ischemic damage (Goldshmit et al., 2011; Li et al., 2012; Yang et al., 2014). In addition, it has been demonstrated that reduced expression of EphrinA3 activated the PI3K/Akt pathway in the glaucoma model (Zhou et al., 2023) and the miR‐204‐5p/EphA4 axis activated the PI3K/AKT pathway, ameliorating neurological injury in ischemic stroke (Shi et al., 2023).…”

Section: Introductionmentioning

confidence: 99%

Cognitive‐exercise dual‐task promotes cognitive function recovery in chronic cerebral ischemia male rats through regulating PI3K/Akt signaling pathway via inhibition of EphrinA3/EphA4

Zhang,

Tao,

Sun

et al. 2023

J of Neuroscience Research

View full text Add to dashboard Cite

Chronic cerebral ischemia (CCI) can lead to vascular cognitive impairment, but therapeutic options are limited. Cognitive‐exercise dual‐task (CEDT), as a potential rehabilitation intervention, can attenuate cognitive impairment. However, the related mechanisms remain unclear. In this study, 2‐vessel occlusion (2‐VO) in male SD rats was performed to establish the CCI model. The rats were treated with cognitive, exercise, or CEDT intervention for 21 days. The Morris water maze (MWM) test was used to assess cognitive ability. TUNEL staining was used to detect the neuronal apoptosis. Immunofluorescence, RT‐qPCR and Western blot were used to detect the protein or mRNA levels of EphrinA3, EphA4, p‐PI3K, and p‐Akt. The results showed that CEDT could improve performance in the MWM test, reverse the increased expression of EphrinA3 and EphA4, and the reduced expression of p‐PI3K and p‐Akt in CCI rats, which was superior to exercise and cognitive interventions. In vitro, oxygenglucose deprivation (OGD) challenge of astrocytes and neuronal cells were used to mimic cerebral ischemia. Immunofluorescence assay revealed that the levels of MAP‐2, p‐PI3K, and p‐Akt were reduced in EphrinA3 overexpressed cells after OGD stimulation. Finally, the knock‐down of EphrinA3 by shRNA significantly promoted the recovery of cognitive function and activation of PI3K/Akt after CEDT treatment in CCI rats. In conclusion, our study suggests that CEDT promotes cognitive function recovery after CCI by regulating the signaling axis of EphrinA3/EphA4/PI3K/Akt.

show abstract

MicroRNA‐146a‐5p protects retinal ganglion cells through reducing neuroinflammation in experimental glaucoma

Zhou,

Yang,

et al. 2024

Glia

View full text Add to dashboard Cite

Neuroinflammation plays important roles in retinal ganglion cell (RGC) degeneration in glaucoma. MicroRNA‐146 (miR‐146) has been shown to regulate inflammatory response in neurodegenerative diseases. In this study, whether and how miR‐146 could affect RGC injury in chronic ocular hypertension (COH) experimental glaucoma were investigated. We showed that in the members of miR‐146 family only miR‐146a‐5p expression was upregulated in COH retinas. The upregulation of miR‐146a‐5p was observed in the activated microglia and Müller cells both in primary cultured conditions and in COH retinas, but mainly occurred in microglia. Overexpression of miR‐146a‐5p in COH retinas reduced the levels pro‐inflammatory cytokines and upregulated the levels of anti‐inflammatory cytokines, which were further confirmed in the activated primary cultured microglia. Transfection of miR‐146a‐5p mimic increased the percentage of anti‐inflammatory phenotype in the activated BV2 microglia, while transfection of miR‐146a‐5p inhibitor resulted in the opposite effects. Transfection of miR‐146a‐5p mimic/agomir inhibited the levels of interleukin‐1 receptor associated kinase (IRAK1) and TNF receptor associated factor 6 (TRAF6) and phosphorylated NF‐κB subunit p65. Dual luciferase reporter gene assay confirmed that miR‐146a‐5p could directly target IRAK1 and TRAF6. Moreover, downregulation of IRAK1 and TRAF6 by siRNA techniques or blocking NF‐κB by SN50 in cultured microglia reversed the miR‐146a‐5p inhibitor‐induced changes of inflammatory cytokines. In COH retinas, overexpression of miR‐146a‐5p reduced RGC apoptosis, increased RGC survival, and partially rescued the amplitudes of photopic negative response. Our results demonstrate that overexpression of miR‐146a‐5p attenuates RGC injury in glaucoma by reducing neuroinflammation through downregulating IRAK1/TRAF6/NF‐κB signaling pathway in microglia.

show abstract

EphA4/ephrinA3 reverse signaling mediated downregulation of glutamate transporter GLAST in Müller cells in an experimental glaucoma model

Cited by 6 publications

References 98 publications

Melatonin prevents EAAC1 deletion‐induced retinal ganglion cell degeneration by inhibiting apoptosis and senescence

Melatonin prevents EAAC1 deletion‐induced retinal ganglion cell degeneration by inhibiting apoptosis and senescence

Cognitive‐exercise dual‐task promotes cognitive function recovery in chronic cerebral ischemia male rats through regulating PI3K/Akt signaling pathway via inhibition of EphrinA3/EphA4

MicroRNA‐146a‐5p protects retinal ganglion cells through reducing neuroinflammation in experimental glaucoma

Contact Info

Product

Resources

About