Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models

Emma Puighermanal (), Marta Luna-Sánchez, Alejandro Gella, Gunter van der Walt, Andrea Urpi, María Royo, Paula Tena-Morraja, Isabella Appiah, Maria Helena de Donato, Fabien Menardy, Patrizia Bianchi, Anna Esteve-Codina, Laura Rodríguez-Pascau, Cristina Vergara, Mercè Gómez-Pallarès, Giovanni Marsicano, Luigi Bellocchio, Marc Martinell, Elisenda Sanz, Sandra Jurado, Francesc Xavier Soriano, Pilar Pizcueta and Albert Quintana ()
Additional contact information
Emma Puighermanal: Universitat Autònoma de Barcelona
Marta Luna-Sánchez: Universitat Autònoma de Barcelona
Alejandro Gella: Universitat Autònoma de Barcelona
Gunter van der Walt: Universitat Autònoma de Barcelona
Andrea Urpi: Universitat Autònoma de Barcelona
María Royo: CSIC-UMH
Paula Tena-Morraja: Universitat de Barcelona
Isabella Appiah: Universitat Autònoma de Barcelona
Maria Helena de Donato: Universitat Autònoma de Barcelona
Fabien Menardy: Universitat Autònoma de Barcelona
Patrizia Bianchi: Universitat Autònoma de Barcelona
Anna Esteve-Codina: Centro Nacional de Análisis Genómico (CNAG)
Laura Rodríguez-Pascau: Minoryx Therapeutics SL
Cristina Vergara: Gosselies
Mercè Gómez-Pallarès: Universitat Autònoma de Barcelona
Giovanni Marsicano: U1215 Neurocentre Magendie
Luigi Bellocchio: U1215 Neurocentre Magendie
Marc Martinell: Minoryx Therapeutics SL
Elisenda Sanz: Universitat Autònoma de Barcelona
Sandra Jurado: CSIC-UMH
Francesc Xavier Soriano: Universitat de Barcelona
Pilar Pizcueta: Minoryx Therapeutics SL
Albert Quintana: Universitat Autònoma de Barcelona

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Mutations in mitochondrial energy-producing genes lead to a heterogeneous group of untreatable disorders known as primary mitochondrial diseases (MD). Leigh syndrome (LS) is the most common pediatric MD and is characterized by progressive neuromuscular affectation and premature death. Here, we show that daily cannabidiol (CBD) administration significantly extends lifespan and ameliorates pathology in two LS mouse models, and improves cellular function in fibroblasts from LS patients. CBD delays motor decline and neurodegenerative signs, improves social deficits and breathing abnormalities, decreases thermally induced seizures, and improves neuropathology in affected brain regions. Mechanistically, we identify peroxisome proliferator-activated receptor gamma (PPARγ) as a key nuclear receptor mediating CBD’s beneficial effects, while also providing proof of dysregulated PPARγ expression and activity as a common feature in both mouse neurons and fibroblasts from LS patients. Taken together, our results provide the first evidence for CBD as a potential treatment for LS.

Date: 2024
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DOI: 10.1038/s41467-024-51884-8

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