Regulation of Excitatory Amino Acid Transmission in the Retina: Studies on Neuroprotection

Abstract

Excitotoxicity occurs in neurons due to the accumulation of excitatory amino acids such as glutamate in the synaptic and extrasynaptic locations. In the retina, excessive glutamate concentrations trigger a neurotoxic cascade involving several mechanisms, including the elevation of intracellular calcium (Ca and the activation of α-amino-3-hydroxy 5-methyl-4-iso-xazole-propionic acid/kainate (AMPA/KA) and N-methyl-d-aspartate (NMDA) receptors leading to retinal degeneration. Both ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs) are present in the mammalian retina. Indeed, due to the abundant expression of GluRs, the mammalian retina is highly susceptible to excitotoxic neurodegeneration. Excitotoxicity has been postulated to present a common downstream mechanism for several stimuli, including hypoglycemia, hypoxia, ischemia, and chronic neurodegenerative diseases. Experimental approaches to the study of neuroprotection in the retina have utilized insults that trigger hypoxia, hypoglycemia, or excitotoxicity. Using these experimental approaches, the neuroprotective potential of GluR agents, including the NMDA receptor modulators (MK801, ifenprodil, memantine); AMPA/KA receptor antagonist (CNQX); Group II and III mGluR agonists (LY354740, quisqualate); and Ca-channel blockers (diltiazem, lomerizine, verapamil, ω-conotoxin), and others (pituitary adenylate cyclase activating polypeptide, neuropeptide Y, acetylcholine receptor agonists) have been elucidated. In addition to corroborating the exocytotic role of excitatory amino acids in retinal degeneration, these studies affirm that multiple mechanism/s contribute to the prevention of damage caused by excitotoxicity in the retina. Therefore, it is feasible that several pathways are involved in protecting the retina from toxic insults in ocular neurodegenerative conditions such as glaucoma and retinal ischemia. Furthermore, these experimental models are viable tools for evaluating therapeutic candidates in ocular neuropathies.

VEGFD Protects Retinal Ganglion Cells and, consequently, Capillaries against Excitotoxic Injury

“…14,15 In the eye, excitotoxicity has been linked to glaucoma, retinal ischemia, and diabetic retinopathy. [16][17][18][19][20] Indeed, high concentrations of glutamate or NMDA delivered via intravitreal injections can be utilized as a tool to cause RGC death in vivo. [21][22][23][24][25][26] We performed a single intravitreal injection of 10 nmol of NMDA in adult mice and analyzed NMDA-induced RGC death at two different time points (day 1 [d1] and day 7 [d7]) (Figure 1).…”

Pin1 Is Regulated by CaMKII Activation in Glutamate-Induced Retinal Neuronal Regulated Necrosis

“…Some reports have indicated that all iGluRs are expressed in the retinal neuron cultures, while NMDARs are mainly responsible for glutamate induced retinal neurons death (Otori et al, 1998; Fang et al, 2010). Others have reported that non-NMDARs (AMPAR/KAR and mGluRs) also play key roles in glutamate mediated cell death in cultured retinal neurons (Dhingra and Vardi, 2012; Opere et al, 2018). To uncover the mechanism of Pin1 activation induced by glutamate, the distinct GluR subtypes involved in the glutamate-induced, first, retinal RN should be investigated.…”

“…It has been reported that retinal neurons express all of the glutamate receptor subtypes (Luo et al, 2001; Fang et al, 2010). Some reports have indicated that retinal excitotoxicity was mediated by both non-NMDAR and NMDAR, whereas other studies have found an entirely non-NMDAR-mediated retinal neuronal death (Luo et al, 2001; Opere et al, 2018). Such differences may be partially due to the maturational changes of retinal neurons and the difference in cell culture environment (Luo et al, 2001).…”

Oxidative Stress in Optic Neuropathies

“…Moreover, despite welladjusted IOP, 15% of glaucoma patients become blind and as many as 42% lose sight in one eye [31]. In this regard, growing evidence obtained from both animal models and clinical studies has revealed risk factors other than elevated IOP and aging, which include vascular dysfunction [32][33][34][35], glutamate excitotoxicity [36][37][38], mitochondrial dysfunction [39][40][41], and oxidative stress [13,14,[42][43][44]. Given its higher prevalence, a vast proportion of studies attempting to decipher the association between oxidative stress and glaucoma have focused on POAG.…”