Exploring NMDAR pathways in ischemic stroke: implications for neurotoxic and neuroprotective mechanisms and therapeutic strategies

Jun 9, 2025Naunyn-Schmiedeberg's archives of pharmacology

NMDAR pathways in stroke: roles in brain cell damage and protection and possible treatments

AI simplified

Abstract

N-Methyl-D-Aspartate Receptor (NMDAR) signaling is critically involved in the brain's response to ischemic injury.

NMDAR activation may trigger glutamate excitotoxicity, initiating neurotoxic processes.
This cascade can lead to mitochondrial dysfunction and the production of reactive oxygen species (ROS).
Increased neuronal injury is associated with the activation of apoptotic pathways, including p53-mediated and Notch signaling.
Necroptosis is identified as a significant cell death mechanism during ischemic injury.
Disruption of the blood-brain barrier (BBB) may exacerbate brain damage following ischemic events.
Distinct roles of synaptic and extrasynaptic NMDAR activation are explored in the context of neuroprotective signaling.

AI simplified

Stroke is one of the leading causes of disability and mortality worldwide, with ischemic stroke representing the most prevalent and devastating form. This review offers an in-depth exploration of the critical role of N-Methyl-D-Aspartate Receptor (NMDAR) signaling in mediating the brain's response to ischemic injury. NMDAR activation triggers glutamate excitotoxicity, setting off a cascade of neurotoxic events that lead to mitochondrial dysfunction and the generation of reactive oxygen species (ROS). These damaging processes not only intensify neuronal injury but also activate apoptotic pathways, including p53-mediated and Notch signaling. Furthermore, the review highlights necroptosis as a key cell death mechanism in ischemic injury and examines the subsequent disruption of the blood-brain barrier (BBB), which exacerbates brain damage. In the context of neuroprotective signaling, we explore the distinct roles of synaptic and extrasynaptic NMDAR activation, neurotrophic factor-mediated signaling, and the intricate crosstalk between neurotoxic and neuroprotective pathways. This review also explores novel hypotheses and emerging perspectives in NMDAR-mediated ischemic stroke, highlighting potential mechanisms and therapeutic implications. Additionally, it covers cutting-edge experimental approaches to investigate NMDAR function in stroke and provides critical insights into conflicting findings in NMDAR research, addressing key controversies and their impact on future studies. Therapeutic strategies targeting ischemic stroke are critically examined, with an emphasis on potential interventions that could mitigate the effects of ischemia. The review also highlights ongoing clinical trials investigating novel therapeutic approaches and outlines the future direction of ischemic stroke therapy. This comprehensive review offers a deep understanding of the complex molecular mechanisms involved in ischemic stroke via NMDAR and provides valuable insights into the promising therapeutic avenues that could lead to more effective treatments.

Full Text

Full text is available at the source.

View full text (PDF) ↗View full text (HTML) ↗

Abstract

Full Text

Related papers

what lands in your inbox each week: