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Cannabinoid CB1 Receptor Activation Mitigates N-Methyl- d -aspartate Receptor-Mediated Neurotoxicity

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide Alzheimer’s disease (AD) is characterized by synaptic dysfunction and excitotoxicity, yet effective therapeutic strategies remain limited. This study explores the functional and physical interplay between cannabinoid CB 1 receptors (CB 1 Rs) and N -methyl- d -aspartate receptors (NMDARs), which are implicated in AD pathology. Using bioluminescence resonance energy transfer and imaging assays in HEK-293T cells, we demonstrate a direct interaction between CB 1 R and the N1 subunit of NMDAR, supporting the formation of receptor complexes. Functional assays further reveal a bidirectional negative crosstalk: NMDA attenuates CB 1 R-mediated cAMP inhibition, while CB 1 R activation reduces NMDA-induced calcium influx and mitogen-activated protein kinase signaling pathway activation. This negative crosstalk suggests the existence of receptor–receptor interactions with functional consequences. Complexes of CB 1 Rs and N 1 subunits of NMDARs are present in both neurons and microglia, and their expression is upregulated in response to Aβ 1–42 and in cells derived from the APP Sw/Ind AD model mice. However, upregulation did not always correlate with stronger CB 1 R–NMDAR cross-modulation, suggesting that cell-specific signalosome composition shapes the signaling outcome. Functionally, CB 1 R activation confers neuroprotection: It rescues neurite loss induced by NMDA and Aβ 1–42, highlighting the therapeutic potential of modulating CB 1 R–NMDAR interactions. These findings support a model in which CB 1 R–NMDAR interactions, through dynamic functional cross-modulation, finely tune excitotoxic and inflammatory signaling pathways. This mechanism offers therapeutic prospects for addressing cannabinoid-glutamatergic interactions.

Source: ACS Pharmacology & Translational Science

DOI: 10.1021/acsptsci.5c00230