AI Article Synopsis

  • A new series of GluN2B NMDAR antagonists have been developed and tested, showing potential as anti-stroke therapies by enhancing neuroprotective effects compared to existing treatments.
  • Approximately half the compounds in this series outperformed the standard NBP in protecting hippocampal neurons from NMDA-induced toxicity, with compounds 45e and 45f showing similar effectiveness to ifenprodil, a known antagonist.
  • Compound 45e stands out due to its strong neuroprotective activity and selectivity for the GluN1/GluN2B receptor, along with promising bioavailability and safety in toxicity tests, suggesting it could be a valuable candidate for future stroke treatments.

Article Abstract

In this work, a novel structural series of brain-penetrant GluN2B NMDAR antagonists were designed, synthesized and biologically evaluated as anti-stroke therapeutic agents via merging the structures of NBP and known GluN2B ligands. Approximately half of them exhibited superior neuroprotective activity to NBP against NMDA-induced neurotoxicity in hippocampal neurons at 10 μM, and compound 45e and 45f exerted equipotent activity to ifenprodil, an approved GluN2B- selective NMDAR antagonist. In particular, 45e, with the most potent neuroprotective activity throughout this series, displayed dramatically enhanced activity (K = 3.26 nM) compared to ifenprodil (K = 14.80 nM) in Radioligand Competitive Binding Assay, and remarkable inhibition (IC = 79.32 nM) against GluN1/GluN2B receptor-mediated current in Patch Clamp Assay. Meanwhile, 45e and its enantiomers exhibited low inhibition rate against the current mediated by other investigated receptors at the concentration of 10 μM, indicating their favorable selectivity for GluN1/GluN2B. In the rat model of middle cerebral artery ischemia (MCAO), 45e exerted comparable therapeutic efficacy to ifenprodil at the same dosage. In addition to the attractive in vitro and in vivo potency, 45e displayed a favorable bioavailability (F = 63.37%) and an excellent brain exposure. In further repeated dose toxicity experiments, compound 45e demonstrated an acceptable safety profile. With the above merits, 45e is worthy of further functional investigation as a novel anti-stroke therapeutic agent.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2021.113876DOI Listing

Publication Analysis

Top Keywords

anti-stroke therapeutic
12
brain-penetrant glun2b
8
glun2b nmdar
8
nmdar antagonists
8
therapeutic agents
8
neuroprotective activity
8
compound 45e
8
45e
7
discovery novel
4
novel brain-penetrant
4

Similar Publications

It has been reported that the PI3K/AKT signaling pathway plays a key role in the pathogenesis of ischemic stroke. As a result, the development of drugs targeting the PI3K/AKT signaling pathway has attracted increasing attention from researchers. This article reviews the pathological mechanisms and advancements in research related to the signaling pathways in ischemic stroke, with a focus on the PI3K/AKT signaling pathway.

View Article and Find Full Text PDF

Targeting the neurovascular unit: Therapeutic potential of traditional Chinese medicine for the treatment of stroke.

Heliyon

October 2024

Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese Medicine and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.

Stroke poses a significant global health challenge due to its elevated disability and mortality rates, particularly affecting developing nations like China. The neurovascular unit (NVU), a new concept encompassing neurons, brain microvascular endothelial cells, pericytes, astrocytes, microglia, and the extracellular matrix, has gained prominence in recent years. Traditional Chinese medicine (TCM), deeply rooted in Chinese history, employs a combination of acupuncture and herbal treatments, demonstrating significant efficacy across all stages of stroke, notably during recovery.

View Article and Find Full Text PDF
Article Synopsis
  • Esculetin (ESC) is a natural compound used in traditional Chinese medicine that helps protect the brain during strokes.
  • The study found that ESC helps reduce brain damage and improve behavior in mice after a stroke by affecting a protein called CKLF1.
  • Blocking CKLF1 with ESC also lowers the number of immune cells that can cause more damage, showing that it could be a good treatment for strokes in the future.
View Article and Find Full Text PDF

Objective: To explore whether the regulation of matrix metalloproteinase 9 (MMP-9)/ tissue inhibitors of MMPs (TIMPs) gene expression through histone acetylation is a possible mechanism by which electroacupuncture (EA) protects blood-brain barrier (BBB) integrity in a middle cerebral artery occlusion (MCAO) rat model.

Methods: Male Sprague-Dawley rats were divided into four groups: the sham group, the MCAO group, the MCAO + EA (MEA) group, and the MCAO + EA + HAT inhibitor (HATi) group. The MCAO model was generated by blocking the middle cerebral artery.

View Article and Find Full Text PDF

Excitotoxicity due to excessive activation of NMDARs is one of the main mechanisms of neuronal death during ischemic stroke. Previous studies have suggested that activation of either synaptic or extrasynaptic GluN2B-containing NMDARs results in neuronal damage, whereas activation of GluN2A-containing NMDARs promotes neuronal survival against ischemic insults. This study applied a systematic , , and approach to the discovery of novel and potential GluN1/2A NMDAR positive allosteric modulators (PAMs).

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!