Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases

Abstract

The excitatory neurotransmission of the central nervous system (CNS) mainly involves glutamate and its receptors, especially N-methyl-D-Aspartate receptors (NMDARs). These receptors have been extensively described on neurons and, more recently, also on other cell types. Nowadays, the study of their differential expression and function is taking a growing place in preclinical and clinical research. The diversity of NMDAR subtypes and their signaling pathways give rise to pleiotropic functions such as brain development, neuronal plasticity, maturation along with excitotoxicity, blood-brain barrier integrity, and inflammation. NMDARs have thus emerged as key targets for the treatment of neurological disorders. By their large extracellular regions and complex intracellular structures, NMDARs are modulated by a variety of endogenous and pharmacological compounds. Here, we will present an overview of NMDAR functions on neurons and other important cell types involved in the pathophysiology of neurodegenerative, neurovascular, mental, autoimmune, and neurodevelopmental diseases. We will then discuss past and future development of NMDAR targeting drugs, including innovative and promising new approaches.

The Emerging Role of N-Methyl-D-Aspartate (NMDA) Receptors in the Cardiovascular System: Physiological Implications, Pathological Consequences, and Therapeutic Perspectives

“…In addition, the endovascular infusion of Glunomab reduced the incidence of intracellular aneurysms by blocking tPA-dependent activation of endothelial NMDARs in mice ( Table 4 ) [ 150 ]. These preliminary findings strongly support the notion that targeting endothelial NMDARs could represent a promising therapeutic strategy to attenuate BBB dysfunction in neurological disorders as severe as epilepsy, multiple sclerosis, and stroke [ 151 ]. In addition, intraluminal infusion of amyloid-β (1–40) reduced extracellular Ca 2+ entry through endothelial NMDARs and attenuated endothelium-dependent dilation in mouse cerebral arteries ( Table 4 ) [ 88 ].…”

“…Thus, defective endothelial NMDAR signaling could contribute to the impaired hemodynamic response (and possibly to loss in neuronal regulation by endothelium-derived NO) in neurodegenerative diseases such as AD. Finally, anti-NMDAR autoimmune encephalitis is a rare neurological disorder that is caused by autoreactive anti-NMDAR autoantibodies targeting GluN1 and produced by B lymphocytes [ 151 , 152 ]. This in turn results in NMDAR hypo-responsiveness and leads to a decline in cognitive function and neuropsychiatric symptoms [ 153 ].…”

Synthesis and Biological Evaluation of Enantiomerically Pure (R)- and (S)-[18F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA receptors

“…[5][6][7] While NMDA receptors are key players in neurophysiology, contributing to memory and learning via modulation of synaptic plasticity, the GluN2B subunit-carrying NMDA receptor has been implicated in the pathophysiology of various neurological disorders. [8][9][10][11][12][13][14][15][16] Indeed, the role of overstimulation of the excitatory GluN2B subunit in the development of several CNS-related pathologies has been corroborated, 17,18 whereas targeting GluN2B-mediated excitotoxicity has been suggested as a promising therapeutic strategy for various diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, traumatic brain injury, neuropathic pain and depression. [19][20][21][22][23][24][25][26][27][28][29][30] Early efforts to develop NMDA receptor antagonists prompted the discovery of NMDA receptor channel blockers such as phencyclidine (PCP), thienylcyclohexylpiperidine (TCP), ketamine, memantine, and MK-801 (dizocilpine).…”

“…Despite their well-documented therapeutic e cacy, most of these "broad-spectrum" antagonists were associated with a poor safety pro le, potentially owing to the lack of subunit-selectivity. 17,31,32 As such, more recent attempts have focused on the development of GluN2B-selective antagonists, which has become feasible since the discovery of the N-terminal domain (NTD) binding site that is located at the interface between GluN1 and GluN2B. 33 Several GluN2Bselective antagonists have been reported to date -some of which have been advanced to humans, including CP101,606 (traxoprodil) 30 , MK-0657 (CERC-301) 34 and EVT-101 (NCT01128452).…”

Effects of N-methyl-D-aspartate receptor knockdown and hypoxia/reoxygenation injury on the neuronal proteome and transcriptome

“…Activation of NMDAR is also associated with neurological sequelae after hypoxic injury ( Chen et al, 2006 ; Ji et al, 2021 ). Therefore, NMDAR is a molecular target with strong therapeutic significance ( Seillier et al, 2022 ). In previous research, NMDAR specific antagonists could significantly inhibit neuronal apoptosis in ischemic brain injury models ( Mishra et al, 2011 ; Yu et al, 2015 ).…”