Torres Román, Ana LauraGavaldà Vives, TàniaSimón Sánchez, SamuelAparicio Trejo, Omar EmilianoPedraza Chaverri, JoséLópez Goerne, TessyOrtega Gómez, AletteTinkov, Alexey A.Aschner, MichaelGalve Roperh, IsmaelSantamaría, Abel2026-04-082026-04-082025-11-24Torres-Román, A.L., Gavaldà-Vives, T., Simón-Sánchez, S. et al. Anandamide-Induced Neuroprotection of Cortical Neurons Relies on Metabolic/Redox Regulation and Mitochondrial Dynamics. Mol Neurobiol 63, 153 (2026). https://doi.org/10.1007/s12035-025-05514-z0893-764810.1007/s12035-025-05514-zhttps://hdl.handle.net/20.500.14352/134487Open access funding provided by Universidad Autonoma Metropolitana (BIDIUAM) This project was funded by the Consejo Nacional de Humanidades, Ciencias y Tecnologías (CONAHCyT, Mexico), which has now become the Secretaría de Ciencias, Humanidades, Tecnología e Innovación (SECIHTI), by grant number 809272 given to Ana Laura Torres-Román, as well as by the Programa de Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, the CannaLatan network (CYTED #220RT0002) to A.L.T.-R. and I.G.-R., and PI21/0938 Instituto de Salud Carlos III to I.G-R. Grant IN202725 from PAPPIT (DGAPA, UNAM) was given to J.P.-C. None of the sponsors were involved in design, collection, analysis or interpretation of data, or in writing reports or decisions to submit the article for publication.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 CB1 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 CB1 receptors. AEA also increased mitochondrial biogenesis, fission markers and OXPHOS function, while delayed Ca2+ levels and induced PPARγ transactivation. In conclusion, AEA afforded neuroprotection secondary to increased mitochondrial biogenesis and redox regulation triggered by the activation of CB1 and the nuclear receptor PPARγ.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal article1559-1182https://doi.org/10.1007/s12035-025-05514-zhttps://link.springer.com/article/10.1007/s12035-025-05514-zopen access612.8616.8612.8.015Endocannabinoid SystemAnandamidePPARγ receptorCannabinoid receptorsEnergy metabolismMitochondrial dynamicsNeurociencias (Biológicas)Fisiología2490 Neurociencias3205.07 Neurología2490.02 Neuroquímica2490.01 Neurofisiología2411 Fisiología Humana