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

Abstract

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.

Antiapoptotic effects of cannabidiol in an experimental model of cognitive decline induced by brain iron overload

“…A previous study indicated that CBD attenuates the imbalance between Bcl-2/Bax, upregulating the anti-apoptotic protein Bcl-2, which in turn maintains the integrity of the outer mitochondrial membrane, in an animal model of multiple sclerosis 46 . In agreement, we have previously demonstrated that CBD protects against mitochondrial injury 13,30 , converging to prevent the activation of the intrinsic apoptotic pathway. Using a model of HD, Valdeolivas and coworkers 47 have suggested the involvement of CB1 and CB2 cannabinoid receptors as well as receptor-independent actions in the neuroprotective effects of a CBD-enriched botanical extract.…”

“…Since mitochondria are the main source of ROS, they are expected to become an important target of oxidative damage, which could explain functional alterations in these organelles in pathological conditions 45 . Moreover, mitochondria play a key role in regulating the intrinsic apoptotic pathway, and there is evidence indicating that iron affects mitochondrial homeostasis 13,30 , thus supporting the concept that iron effects are most pronounced in the intrinsic pathway. Nonetheless, more studies on the effects of iron on the extrinsic pathway are warranted.…”

“…Brains were quickly dissected and hippocampi were isolated and stored at −80 °C for subsequent Western Blotting or enzyme-linked immunosorbent (ELISA) assays. Sample size estimation was based on previously published papers from our research group reporting iron and CBD effects on biochemical parameters measured using western blot and ELISA 13,30 .…”

Is cannabidiol a drug acting on unconventional targets to control drug‐resistant epilepsy?

“…CBD restores the basal levels of hippocampal dynamin‐1‐like protein (DNM1L), caspase 3, and synaptophysin in animals with cell damage subsequent to iron loading . These effects are also associated with reversion of the iron‐induced mitochondrial deoxyribonucleic acid (mtDNA) deletions, the decreased epigenetic modulation of mtDNA, as well as restauration of the mitochondrial ferritin levels and succinate dehydrogenase activity . According to these studies, CBD induces epigenetic effects that results in the restauration of the normal cellular function and neuroprotection.…”

“…122 These effects are also associated with reversion of the iron-induced mitochondrial deoxyribonucleic acid (mtDNA) deletions, the decreased epigenetic modulation of mtDNA, as well as restauration of the mitochondrial ferritin levels and succinate dehydrogenase activity. 123 According to these studies, CBD induces epigenetic effects that results in the restauration of the normal cellular function and neuroprotection. Epigenetic effects induced by CBD hold promise as a future therapeutic strategy for drug-resistant epilepsy.…”