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Retinal Cell Death Induced by TRPV1 Activation Involves NMDA Signaling and Upregulation of Nitric Oxide Synthases

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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.

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Acknowledgments

The authors would like to thank Adilson S. Alves for technical assistance. Thanks are also due to Maria Fernanda R. Graciano (University of São Paulo) for critically reading the manuscript. Grant sponsors: FAPESP, CNPq (Brazil), and University of São Paulo (Brazil). M.L. and D.O.M. are the recipients of fellowships from FAPESP.

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  1. Laboratory 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

    Mauro Leonelli, Daniel O. Martins & Luiz R. G. Britto

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  1. Mauro Leonelli
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Correspondence to Mauro Leonelli.

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Leonelli, M., Martins, D.O. & Britto, L.R.G. Retinal Cell Death Induced by TRPV1 Activation Involves NMDA Signaling and Upregulation of Nitric Oxide Synthases. Cell Mol Neurobiol 33, 379–392 (2013). https://doi.org/10.1007/s10571-012-9904-5

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