Pathophysiological Ionotropic Glutamate Signalling in Neuroinflammatory Disease as a Therapeutic Target

Abstract

Glutamate signalling is an essential aspect of neuronal communication involving many different glutamate receptors, and underlies the processes of memory, learning and synaptic plasticity. Despite neuroinflammatory diseases covering a range of maladies with very different biological causes and pathophysiologies, a central role for dysfunctional glutamate signalling is becoming apparent. This is not just restricted to the well-described role of glutamate in mediating neurodegeneration, but also includes a myriad of other influences that glutamate can exert on the vasculature, as well as immune cell and glial regulation, reflecting the ability of neurons to communicate with these compartments in order to couple their activity with neuronal requirements. Here, we discuss the role of pathophysiological glutamate signalling in neuroinflammatory disease, using both multiple sclerosis and Alzheimer’s disease as examples, and how current steps are being made to harness our growing understanding of these processes in the development of neuroprotective strategies. This review focuses in particular on N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisooxazol-4-yl) propionate (AMPA) type ionotropic glutamate receptors, although metabotropic, G-protein-coupled glutamate receptors may also contribute to neuroinflammatory processes. Given the indispensable roles of glutamate-gated ion channels in synaptic communication, means of pharmacologically distinguishing between physiological and pathophysiological actions of glutamate will be discussed that allow deleterious signalling to be inhibited whilst minimising the disturbance of essential neuronal function.

Retinal Glutamate Neurotransmission: From Physiology to Pathophysiological Mechanisms of Retinal Ganglion Cell Degeneration

“…Despite the different disease conditions (including both retinal and non-retinal pathologies), which can lead to degeneration of the retina in general, and RGCs in particular, they may be connected by a common mechanism involving glutamate excitotoxicity [ 148 , 149 ] that either initiates or leads to an exacerbation of retinal degeneration.…”

“…Conversely, NMDA receptor stimulation increases the uptake activity of glutamate transporters on Müller glia [ 46 ], indicating that there is bidirectional communication between retinal neurons and Müller glia. Additionally, NMDA receptors have been described to be an important link between glutamate excitotoxicity and neuroinflammation in neurodegenerative diseases [ 148 ]. For example, endothelial cells have been reported to express functional NMDA receptors that, if overstimulated by a glutamate excitotoxic insult, enhance immune infiltration by disrupting the blood–brain barrier in multiple sclerosis [ 211 ], which might imply a similar alteration during optic neuritis.…”

“…In addition, due to the essential roles that glutamatergic transmission has in mediating network communication, new strategies have aimed to interfere with degenerative signalling whilst leaving physiological signalling unimpaired [ 148 , 214 ]. One strategy has been to target retinal extrasynaptic NMDA receptors (avoiding those located at the synapse) through either the application of specific inhibitors such as memantine [ 359 , 360 , 361 ], targeting the extrasynaptic NMDAR-associated subunit NR2B with substances such as nafamostat or sepimostat [ 362 ], or by interfering with degeneration-promoting interactions between the NMDA receptor and its extrasynaptic partners, as was achieved through inhibiting the NMDA receptor-TRPM4 interface [ 202 ].…”

Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons

“…In addition, the overexpression of alpha-synuclein increases the phosphorylation of N-methyl-D-aspartate (NMDA) receptors, thereby increasing the formation of NR1 and NR2B subunits and the sensitivity of NMDA receptors to developing glutamate excitotoxicity [ 124 ]. Increased levels of glutamate in the intercellular space activates glutamate NMDA receptors, leading to a calcium overload and the death of DA neurons [ 125 , 126 , 127 ]. Alpha-synuclein can also enhance glutamate excitotoxicity by accelerating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor signaling [ 128 ].…”

Genetic Disruption of System xc- Mediated Glutamate Release from Astrocytes Increases Negative-Outcome Behaviors While Preserving Basic Brain Function in Rat

“…This has been challenging, in part, because neuronal targets are typically involved in multiple brain processes, which can impede the development of safe and effective CNS therapeutics. For example, glutamate signaling is often implicated in the pathology and treatment of CNS disorders because it is vital to neural physiology throughout the brain (Vandame et al, 2013; Fairless et al, 2021; Henter et al, 2021), yet few direct, CNS-active glutamatergic therapeutics exist because of the difficulty in obtaining an acceptable safety profile that doesn’t result in excessive reductions in efficacy.…”