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Updated: May 15, 2026
Examination of Anatomical Features of Retinal Ganglion Cells Under N-methyl-D-aspartic Acid (NMDA)-induced Excitotoxicity
Published on: September 19, 2025
Retinal cell death induced by TRPV1 activation involves NMDA signaling and upregulation of nitric oxide synthases
Mauro Leonelli1, Daniel O Martins, Luiz R G Britto
1Laboratory of Cellular Neurobiology, Department of Physiology & Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, 05508-000, Brazil. mauroleonelli@yahoo.com.br
Abstract:
The activation of the transient receptor potential vanilloid type 1 channel (TRPV1) has been correlated with oxidative and nitrosative stress and cell death in the nervous system. Our previous results indicate that TRPV1 activation in the adult retina can lead to constitutive and inducible nitric oxide synthase-dependent protein nitration and apoptosis. In this report, we have investigated the potential effects of TRPV1 channel activation on nitric oxide synthase (NOS) expression and function, and the putative participation of ionotropic glutamate receptors in retinal TRPV1-induced protein nitration, lipid peroxidation, and DNA fragmentation. Intravitreal injections of the classical TRPV1 agonist capsaicin up-regulated the protein expression of the inducible and endothelial NOS isoforms. Using 4,5-diaminofluorescein diacetate for nitric oxide (NO) imaging, we found that capsaicin also increased the production of NO in retinal blood vessels. Processes and perikarya of TRPV1-expressing neurons in the inner nuclear layer of the retina were found in the vicinity of nNOS-positive neurons, but those two proteins did not colocalize. Retinal explants exposed to capsaicin presented high protein nitration, lipid peroxidation, and cell death, which were observed in the inner nuclear and plexiform layers and in ganglion cells. This effect was partially blocked by AP-5, a NMDA glutamate receptor antagonist, but not by CNQX, an AMPA/kainate receptor antagonist. These data support a potential role for TRPV1 channels in physiopathological retinal processes mediated by NO, which at least in part involve glutamate release.
Insights
Activation of the transient receptor potential vanilloid type 1 (TRPV1) channel in the retina increases nitric oxide (NO) production and causes cell damage. This TRPV1 channel activity involves glutamate receptors and contributes to retinal physiopathology.
Area of Science:
- Neuroscience
- Ophthalmology
- Molecular Biology
Background:
- Transient receptor potential vanilloid type 1 (TRPV1) channel activation is linked to oxidative stress and neuronal cell death.
- Previous studies show TRPV1 activation in the retina causes protein nitration and apoptosis dependent on nitric oxide synthase (NOS).
Purpose of the Study:
- To investigate TRPV1 activation effects on nitric oxide synthase (NOS) expression and function in the retina.
- To explore the role of ionotropic glutamate receptors in TRPV1-induced retinal damage, including protein nitration, lipid peroxidation, and DNA fragmentation.
Main Methods:
- Intravitreal injections of capsaicin, a TRPV1 agonist.
- Nitric oxide (NO) imaging using 4,5-diaminofluorescein diacetate.
- Analysis of NOS isoform expression.
- Assessment of protein nitration, lipid peroxidation, and DNA fragmentation in retinal explants.
- Pharmacological blockade using NMDA (AP-5) and AMPA/kainate (CNQX) receptor antagonists.
Main Results:
- Capsaicin treatment upregulated inducible and endothelial NOS isoforms and increased NO production in retinal blood vessels.
- TRPV1 activation led to significant protein nitration, lipid peroxidation, and cell death in the inner nuclear and plexiform layers, and ganglion cells.
- These damaging effects were partially inhibited by the NMDA receptor antagonist AP-5, but not by the AMPA/kainate receptor antagonist CNQX.
- TRPV1-expressing neurons and nNOS-positive neurons were in proximity but did not colocalize.
Conclusions:
- TRPV1 channel activation in the retina promotes NO production and oxidative damage, contributing to retinal physiopathology.
- Glutamate release, particularly involving NMDA receptors, plays a partial role in TRPV1-mediated retinal damage.
- TRPV1 channels are implicated in retinal physiopathological processes involving NO and glutamate signaling.
