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Anandamide-Induced Neuroprotection of Cortical Neurons Relies on Metabolic/Redox Regulation and Mitochondrial Dynamics

Year: 2025

Type: article

Abstract: Mitochondrial disruption is a key mechanism in the etiology of neurodegenerative diseases. Promoting mitochondrial dynamics and renewal of the mitochondrial network can restore its function and sustain neuronal viability. Although a growing body of evidence implicates endocannabinoid signaling in the regulation of mitochondrial function, its neuroprotective role in neurodegenerative diseases remains largely unexplored. Clarifying this relationship is crucial for understanding the therapeutic efficacy of the endocannabinoid system. This study aimed to evaluate whether endocannabinoid signaling via PPARγ and CB 1 receptors regulates mitochondrial biogenesis and dynamics, exerting neuroprotective actions. Primary cortical neuronal cultures were subject to energy deficiency and excitotoxicity with 3-nitropropionic acid (3NP) and quinolinic acid (QUIN). Neurons were pretreated with the endogenous cannabinoid anandamide (AEA 100 nM), and cell viability and lipid peroxidation levels were characterized. To further explore mitochondrial status, immunofluorescence, western blot, and qPCR of mitochondrial proteins or genes were carried out. The metabolic status was assessed by oxygen consumption and extracellular acidification rates. Intracellular calcium levels and PPARγ transactivation were also analyzed. 3NP + QUIN induced neuronal damage, while AEA treatment afforded a neuroprotective effect. The use of selective receptor antagonists indicated that AEA neuroprotection depends on both PPARγ and CB 1 receptors. AEA also increased mitochondrial biogenesis, fission markers and OXPHOS function, while delayed Ca 2+ levels and induced PPARγ transactivation. In conclusion, AEA afforded neuroprotection secondary to increased mitochondrial biogenesis and redox regulation triggered by the activation of CB 1 and the nuclear receptor PPARγ.

Source: Molecular Neurobiology

DOI: 10.1007/s12035-025-05514-z