Novel insights into mitochondrial molecular targets of iron-induced neurodegeneration: Reversal by cannabidiol

• Published in: Brain research bulletin Vol. 139; pp. 1 - 8
• Main Authors: da Silva, Vanessa Kappel, de Freitas, Betânia Souza, Dornelles, Victória Campos, Kist, Luiza Wilges, Bogo, Maurício Reis, Silva, Milena Carvalho, Streck, Emílio Luiz, Hallak, Jaime Eduardo, Zuardi, Antônio Waldo, Crippa, José Alexandre S., Schröder, Nadja
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2018
• Subjects: 5-Methylcytosine - analogs & derivatives; 5-Methylcytosine - metabolism; Animals; Animals, Newborn; Cannabidiol; Cannabidiol - therapeutic use; Creatine Kinase - metabolism; Disease Models, Animal; DNA Methylation - drug effects; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Female; Gene Expression Regulation - drug effects; Hippocampus - drug effects; Hippocampus - metabolism; Iron; Iron Carbonyl Compounds - toxicity; Male; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial ferritin; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; mtDNA methylation; Muscle Proteins - genetics; Muscle Proteins - metabolism; NADH Dehydrogenase - genetics; NADH Dehydrogenase - metabolism; Neurodegeneration; Neurodegenerative Diseases - chemically induced; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - pathology; Pregnancy; Rats; Rats, Wistar; Cannabidiol; Mitochondria; Mitochondrial ferritin; Iron; Neurodegeneration; mtDNA methylation
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/j.brainresbull.2018.01.014

•Iron overload increased relative mtDNA deletions in the hippocampus of adult rats.•Methylation and hydroxymethylation of hippocampal mtDNA were reduced by iron.•Iron reduced mitochondrial ferritin expression and succinate dehydrogenase activity.•Cannabidiol (CBD) reversed iron-induced effects on mtDNA hydroxymethylation.•Mitochondrial ferritin and succinate dehydrogenase activity were recovered by CBD. Evidence has demonstrated iron accumulation in specific brain regions of patients suffering from neurodegenerative disorders, and this metal has been recognized as a contributing factor for neurodegeneration. Using an experimental model of brain iron accumulation, we have shown that iron induces severe memory deficits that are accompanied by oxidative stress, increased apoptotic markers, and decreased synaptophysin in the hippocampus of rats. The present study aims to characterize iron loading effects as well as to determine the molecular targets of cannabidiol (CBD), the main non-psychomimetic compound of Cannabis sativa, on mitochondria. Rats received iron in the neonatal period and CBD for 14 days in adulthood. Iron induced mitochondrial DNA (mtDNA) deletions, decreased epigenetic modulation of mtDNA, mitochondrial ferritin levels, and succinate dehydrogenase activity. CBD rescued mitochondrial ferritin and epigenetic modulation of mtDNA, and restored succinate dehydrogenase activity in iron-treated rats. These findings provide new insights into molecular targets of iron neurotoxicity and give support for the use of CBD as a disease modifying agent in the treatment of neurodegenerative diseases.