Endothelin-1 Enhances Glutamate-Induced Retinal Cell Death, Possibly through ET_AReceptors

Abstract

PURPOSE.To determine the modification of the glutamate-induced death of retinal neurons by endothelin (ET)-1. METHODS. Cultured retinal neurons from fetal rats were exposed to glutamate (1.0 mM) alone or glutamate with ET-1 (10 Ϫ10-10 Ϫ7 M) for 10 minutes. Neuronal death was assessed by the trypan blue exclusion or TUNEL assays at 2, 6, and 24 hours after the exposure. The effects of adding BQ-123 or BQ-788, ET A , and ET B receptor antagonists, respectively, in combination with ET-1 was also assessed. RESULTS. Immunohistochemical analyses showed that the ETs as well as ET A and ET B receptors were expressed on cultured retinal neurons consisting mainly of amacrine cells. A brief exposure of the cultured retinal neurons to glutamate alone significantly increased the number of dead cells, and the addition of ET-1 with glutamate caused a further significant increase in retinal neuronal death compared with the cells exposed to glutamate alone. A significant increase in neuronal death was detected at doses of 10 nM of ET-1 and higher after a 24-hour exposure (P Ͻ 0.05, Dunnett), whereas brief exposure of neurons to up to 1 M ET-1 alone did not cause delayed cell death of neurons. BQ-123 (10 nM) suppressed the enhancement of retinal toxicity caused by ET-1 (10 nM), whereas BQ-788 had no significant effect. CONCLUSIONS. These results indicate that ET-1 enhances glutamate-induced retinal cell death, possibly through ET A receptors. ET-1 may act synergistically with glutamate to damage retinal neurons under hypoxic conditions. (Invest Ophthalmol Vis Sci. 2005;46:4684 -4690)

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

“…It should be noted that ET-1, a potent vasoconstrictor, is overexpressed in endothelial cells in the setting of DR and enhances glutamate-induced neurotoxicity in retinal neural cells. 41,42 In addition, it is worth mentioning that through ETB-R, ET-1 contributes to retinal ganglion cell loss in rat models of glaucoma and optic nerve injury. 23,43 Moreover, progressive retinal neurodegeneration Figure 6.…”

Involvement of Endothelin-1 in the Pathophysiology of Normal-Tension Glaucoma

“…Resch et al indicated that dual inhibition of ET receptors by bosentan increased ocular blood flow both in patients with glaucoma and in healthy subjects [40] . On the other hand, we suggested that ET-1 may act synergistically with glutamate to damage retinal neurons under hypoxic conditions through ETA receptors [41] . In addition, we verified that ET-1 caused the death of retinal neurons through activation of nitric oxide synthase and production of superoxide anions, which were upregulated by ETA receptor-mediated activation of NADPH oxidase [42,43] .…”

Expression and Localization of Endothelin-1 and its Receptors in the Spiral Ganglion Neurons of Mouse

“…Previous studies reported that ET-1 and its two receptors, ETAR and ETBR, were distributed widely in the central and peripheral nervous systems (Giaid et al 1989(Giaid et al , 1991Inagaki et al 1991;Hemsen and Lundberg 1991;Kobayashi et al 2005;Damon 1998;Kurokawa et al 1997;Fernandes et al 1999;Isaka et al 2007); however, there were few reports about their existence in the spiral ganglion (Xu et al 2008;Franz et al 1997;Jinnouchi et al 1997). Spiral ganglion in the cochlea is the primary neuron of the afferent system in the auditory transmission and is an important sensory neuron in the periphery nervous system.…”

“…Endothelin-1 enhances the response of dorsal root ganglion neurons to capsaicin via ETAR and enhances glutamate-induced retinal cell death, possibly through ETAR (Yamamoto et al 2006;Kobayashi et al 2005). Activation of ETAR may contribute to angiotensin-induced suppression of renal sensory nerve activation in conditions of lowsodium diet (Kopp et al 2007).…”

“…A number of reports demonstrated the presence of ET-1 immunoreactivity and mRNA expression in the nervous system, such as in the spiral cord, brain, enteric plexuses, retinal neurons, as well as sympathetic and sensory ganglia (Giaid et al 1989(Giaid et al , 1991Inagaki et al 1991;Hemsen and Lundberg 1991;Kobayashi et al 2005;Damon 1998). Its two receptors, ETAR and ETBR, were also distributed widely in central and peripheral nervous systems (Kurokawa et al 1997;Fernandes et al 1999;Isaka et al 2007).…”