NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(5), P. 639 - 639

Published: May 15, 2024

Neurodegenerative disorders (NDs) include a range of chronic conditions characterized by progressive neuronal loss, leading to cognitive, motor, and behavioral impairments. Common examples Alzheimer's disease (AD) Parkinson's (PD). The global prevalence NDs is on the rise, imposing significant economic social burdens. Despite extensive research, mechanisms underlying remain incompletely understood, hampering development effective treatments. Excitotoxicity, particularly glutamate-mediated excitotoxicity, key pathological process implicated in NDs. Targeting N-methyl-D-aspartate (NMDA) receptor, which plays central role holds therapeutic promise. However, challenges, such as blood-brain barrier penetration adverse effects, extrapyramidal have hindered success many NMDA receptor antagonists clinical trials. This review explores molecular antagonists, emphasizing their structure, function, types, future prospects treating research competitive noncompetitive quest for treatments still faces hurdles. partly because same that necessitates blockage under also responsible normal physiological function receptors. Allosteric modulation receptors presents potential alternative, with GluN2B subunit emerging attractive target due its enrichment presynaptic extrasynaptic receptors, are major contributors excitotoxic-induced cell death. low side-effect profiles, selective like ifenprodil radiprodil encountered obstacles poor bioavailability Moreover, selectivity these often relative, they been shown bind other GluN2 subunits, albeit minimally. Recent advancements developing phenanthroic naphthoic acid derivatives offer promise enhanced GluN2B, GluN2A or GluN2C/GluN2D improved pharmacodynamic properties. Additional challenges antagonist conflicting preclinical results, well complexity neurodegenerative poorly defined subtypes. Although multifunctional agents targeting multiple degenerative processes being explored, data limited. Designing antagonists/modulators polycyclic moieties multitarget properties would be addressing disorders. understanding structure coupled collaborative efforts drug design, imperative realizing antagonists/modulators.

Language: Английский

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Identification of Common Brain Protein and Genetic Loci Between Parkinson's Disease and Lewy Body Dementia

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(4)

Published: April 1, 2025

ABSTRACT Background Parkinson's disease (PD) and Lewy body dementia (LBD) have many common features, including clinical manifestations, neurochemistry, pathology, but little is known about their shared brain proteins genetic factors. Methods To identify susceptibility‐related that are between PD LBD patients, proteome‐wide association studies (PWASs) were conducted by integrating human protein quantitative trait loci (pQTLs) with large‐scale genome‐wide (GWASs) of both diseases. Subsequently, pleiotropy‐informed conditional false discovery rate (pleioFDR) analysis was performed to risk LBD. Finally, the downregulation these genes in different states validated differential gene expression analysis. Results PWASs identified 12 nine proteins, among which TMEM175 ( z = −7.25, P 4.12E‐13; −6.02, 1.75E‐09) DOC2A −4.13, 3.71E‐05; −3.91, 9.08E‐05) shared. PleioFDR revealed five mapped eight associated LBD, significant (ConjFDR 5.74E‐03). Differential verified significantly downregulated midbrains patients p 1.19E‐02), further exploration also dramatically substantia nigra 1.16E‐02) incidental 7.52E‐03). Moreover, induced pluripotent stem cell‐derived dopaminergic neurons from 4.60E‐02). Conclusion Dysregulation may confer be partly responsible for comorbidity. Our results factors elucidated basis

Language: Английский

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Genetic associations between immune-related plasma proteins and neurodegenerative diseases

Neurological Research, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 10

Published: Jan. 1, 2025

Background Immune dysregulation is commonly associated with neurodegenerative diseases (NDs), yet the underlying causes and mechanisms still require further investigation.

Language: Английский

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Progress on the development of prediction tools for detecting disease causing mutations in proteins

Computers in Biology and Medicine, Journal Year: 2024, Volume and Issue: 185, P. 109510 - 109510

Published: Dec. 4, 2024

Language: Английский

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