CHOP deletion and anti-neuroinflammation treatment with hesperidin synergistically attenuate NMDA retinal injury in mice.
Animals
Blotting, Western
Calcium-Binding Proteins
/ metabolism
Cytokines
/ metabolism
Disease Models, Animal
Drug Synergism
Gene Deletion
Hesperidin
/ therapeutic use
Immunohistochemistry
In Situ Nick-End Labeling
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microfilament Proteins
/ metabolism
Microglia
/ metabolism
N-Methylaspartate
/ toxicity
NF-kappa B
/ metabolism
Neuroprotection
Oxidative Stress
/ drug effects
Real-Time Polymerase Chain Reaction
Retinal Diseases
/ chemically induced
Retinal Ganglion Cells
/ drug effects
Transcription Factor CHOP
/ deficiency
CHOP deficiency
Hesperidin
NMDA
Neuroprotection
Retinal ganglion cells
Journal
Experimental eye research
ISSN: 1096-0007
Titre abrégé: Exp Eye Res
Pays: England
ID NLM: 0370707
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
22
02
2021
revised:
26
08
2021
accepted:
01
11
2021
pubmed:
10
11
2021
medline:
28
12
2021
entrez:
9
11
2021
Statut:
ppublish
Résumé
Glaucoma is a leading cause of blindness worldwide and is characterized by degeneration associated with the death of retinal ganglion cells (RGCs). It is believed that glaucoma is a group of heterogeneous diseases with multifactorial pathomechanisms. Here, we investigate whether anti-inflammation treatment with an ER stress blockade can selectively promote neuroprotection against NMDA injury in the RGCs. Retinal excitotoxicity was induced with an intravitreal NMDA injection. Microglial activation and neuroinflammation were evaluated with Iba1 immunostaining and cytokine gene expression. A stable HT22 cell line transfected with an NF-kB reporter was used to assess NF-kB activity after hesperidin treatment. CHOP-deficient mice were used as a model of ER stress blockade. Retinal cell death was evaluated with a TUNEL assay. As results, in the NMDA injury group, Iba1-positive microglia increased 6 h after NMDA injection. Also at 6 h, pro-inflammatory cytokines and chemokine increased, including TNFα, IL-1b, IL-6 and MCP-1. In addition, the MCP-1 promoter-driven EGFP signal, which we previously identified as a stress signal in injured RGCs, also increased; hesperidin treatment suppressed this inflammatory response and reduced stressed RGCs. In CHOP-deficient mice that received an NMDA injection, the gene expression of pro-inflammatory cytokines, chemokines, markers of active microglia, and inflammatory regulators was greater than in WT mice. In WT mice, hesperidin treatment partially prevented retinal cell death after NMDA injury; this neuroprotective effect was enhanced in CHOP-deficient mice. These findings demonstrate that ER stress blockade is not enough by itself to prevent RGC loss due to neuroinflammation in the retina, but it has a synergistic neuroprotective effect after NMDA injury when combined with an anti-inflammatory treatment based on hesperidin.
Identifiants
pubmed: 34752818
pii: S0014-4835(21)00392-4
doi: 10.1016/j.exer.2021.108826
pii:
doi:
Substances chimiques
Aif1 protein, mouse
0
Calcium-Binding Proteins
0
Cytokines
0
Ddit3 protein, mouse
0
Microfilament Proteins
0
NF-kappa B
0
Transcription Factor CHOP
147336-12-7
N-Methylaspartate
6384-92-5
Hesperidin
E750O06Y6O
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
108826Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.