The Relationship Between the Renin-Angiotensin–Aldosterone System and NMDA Receptor-Mediated Signal and the Prevention of Retinal Ganglion Cell Death

Abstract

Citation: Kobayashi M, Hirooka K, Ono A, Nakano Y, Nishiyama A, Tsujikawa A. The relationship between the renin-angiotensin-aldosterone system and NMDA receptormediated signal and the prevention of retinal ganglion cell death. Invest Ophthalmol Vis Sci. 2017;58:139758: -140358: . DOI:10.1167 PURPOSE. Excitotoxicity, which is due to glutamate-induced toxic effects on the retinal ganglion cell (RGC), is one of several mechanisms of RGC loss. The renin-angiotensinaldosterone system (RAAS) has also been implicated in RGC death. Therefore, it is important to determine the exact relationship between the RAAS and N-methyl-d-aspartate (NMDA) receptor-mediated signal in order to prevent RGC death.METHODS. N-methyl-d-aspartate or aldosterone was injected into the vitreous body. After intravitreal injection of NMDA or aldosterone, animals were treated with spironolactone or memantine. Retinal damage was evaluated by measuring the number of RGCs at 4 weeks after local administration of aldosterone or at 2 weeks after local administration of NMDA. Vitreous humor levels of aldosterone were measured using enzyme immunoassay kits. RESULTS.A significantly decreased number of RGCs were observed after intravitreal injection of NMDA. Although spironolactone did not show any neuroprotective effects, memantine significantly reduced NMDA-induced degeneration in the retina. Furthermore, a significant decrease in the number of RGCs was observed after an intravitreal injection of aldosterone. While memantine did not exhibit any neuroprotective effects, spironolactone caused a significant reduction in the aldosterone-induced degeneration in the retina. There was no change in the aldosterone concentration in the vitreous humor after an NMDA injection.CONCLUSION. Our findings indirectly show that there is no relationship between the RAAS and NMDA receptor-mediated signal with regard to RGC death.Keywords: aldosterone, retinal ganglion cell, NMDA, glutamate W ithin the central nervous system, including the retina, glutamate functions as a major excitatory neurotransmitter. [1][2][3] Various diseases of the eye, which include glaucoma 4,5 and retinal ischemia, 6,7 have been shown to be associated with the glutamate receptor-mediated excitotoxicity. Glutamate excitotoxicity triggered by overactivation of the N-methyl-Daspartate (NMDA) receptors may be a potential risk factor for retinal ganglion cell (RGC) death.8 Indeed, it has been reported in an animal model that there is a decrease in the RGCs after an intravitreal injection of NMDA.9 One of the NMDA antagonists that has been demonstrated to have therapeutic potential against several central nervous system disorders is memantine (1-amino-3,5-dimethyladamantane). 10 Previous studies examined the use of memantine in several animal models of glaucoma and reported finding that this antagonist might possibility provide neuroprotection, although it was not successful in recent clinical trials. [11][12][13] Since multiple mechanisms can to lead to RGC death, this suggests that a neuroprotectant w...

Melanopsin+RGCs Are fully Resistant to NMDA-Induced Excitotoxicity

“…Excessive NMDA receptor stimulation may result in alterations of the Na + /K + homeostasis, excessive influx of large amounts of Ca 2+ into the cell [55], which may result in direct damage by activation of enzymes that damage DNA and cell membranes [56] and by the induction of apoptosis through activation of c-AMP [57]. Animal models of NMDA-induced retinal excitotoxicity are often used to explore molecular mechanisms of RGC apoptosis and its protection [58,59,60,61,62,63,64,65,66].…”

“…The susceptibility of RGCs to NMDA-mediated excitotoxicity has been studied previously in adult rats [58,62] and mice [59,67], as well as the effects of intravitreal NMDA on the specific type population of m + RGCs [59,67]. However, these were short term studies spanning up to 58 days after NMDA injection, and thus the short- and long-term effects of NMDA excitotoxicity on the population of RGCs expressing Brn3a have not been investigated so far.…”

Evaluation of the neuroprotective efficacy of the gramine derivative ITH12657 against NMDA-induced excitotoxicity in the rat retina

“…In addition, can also play a key role in many CNS diseases that involve neuronal death ( Almasieh et al, 2012 ). Animal models of NMDA-induced retinal excitotoxicity are often used to investigate molecular mechanisms of RGC apoptosis and the way to protect them ( Kobayashi et al, 2017 ; Fahrenthold et al, 2018 ; Pichavaram et al, 2018 ; Lambuk et al, 2019 ). The effects of NMDA-mediated excitotoxicity on RGCs have been previously investigated in adult rats ( Gomez-Vicente et al, 2015 ; Vidal-Villegas et al, 2019 ) and mice ( DeParis et al, 2012 ; Wang et al, 2018 ).…”

Melanopsin⁺RGCs Are Fully Resistant to NMDA-Induced Excitotoxicity

“…Excessive NMDA receptor stimulation may result in alterations of the Na + /K + homeostasis, excessive influx of large amounts of Ca 2+ into the cell [52] which may result in direct damage by activation of enzymes that damage DNA and cell membranes [53] and by the induction of apoptosis through activation of c-AMP [54]. Animal models of NMDA-induced retinal excitotoxicity are often used to explore molecular mechanisms of RGC apoptosis and its protection [55][56][57][58][59][60][61][62][63].…”

“…The susceptibility of RGCs to NMDA-mediated excitotoxicity has been studied previously in adult rats [55,59] and mice [56,64], as well as the effects of intravitreal NMDA on the specific type population of m + RGCs [56,64]. However, these were short term studies spanning up to 58 days after NMDA injection and thus the short-and long-term effects of NMDA excitotoxicity on the population of RGCs expressing Brn3a had not been investigated so far.…”