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

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.

It is still not for the old iron: adjuvant effects of carbonyl iron in experimental autoimmune encephalomyelitis induction.

Experimental autoimmune encephalomyelitis (EAE) is a model of multiple sclerosis. Dark Agouti rats immunized with spinal cord homogenate (SCH) and carbonyl iron (CI), as an adjuvant, develop severe hyperacute form of EAE. They succumb to EAE earlier and have higher clinical scores and lethality rate in comparison to counterparts immunized with SCH + complete Freund's adjuvant. There is no difference in the number of cells or in histological presentation of the CNS infiltrates of rats immunized with the two adjuvants. However, there are more granulocytes, NK and NKT cells, and less CD4(+) T cells in the spinal cord infiltrates of SCH + CI-immunized animals. Nitric oxide (NO)-generating enzyme inducible NO synthase have higher expression in spinal cord of SCH + CI-immunized rats, and this corresponds to more intensive nitrotyrosine formation in the CNS tissue of these rats. Abundant infiltration of granulocytes and NK cells into the CNS and excessive generation of peroxynitrite within the CNS of SCH + CI-immunized rats might account for the severe neurological deficits induced by immunization with CI. These factors should be closely examined in the fulminant forms of multiple sclerosis and acute disseminated encephalomyelitis, as they could represent a promising targets for therapy.

Mitochondrial damage, cytotoxicity and apoptosis in iron-potentiated alcoholic liver fibrosis: amelioration by taurine.

Taurine effectively prevents ischemia-induced apoptosis in the cardiomyocytes and hypothalamic nuclei. The present study explores the influence of taurine on mitochondrial damage, oxidative stress and apoptosis in experimental liver fibrosis. Male albino Wistar rats were divided into six groups and maintained for a period of 60 days as follows: Group I, control; Group II, ethanol treatment [6 g/(kg/day)]; Group III, fibrosis induced by ethanol and iron (0.5% w/w); Group IV, ethanol + iron + taurine (2% w/v); Group V, ethanol + taurine treatment and Group VI, control + taurine treatment. Hepatocytes isolated from ethanol plus iron-treated rats showed decreased cell viability and redox ratio, increased reactive oxygen species formation, lipid peroxidation, DNA fragmentation, and formation of apoptotic bodies. Liver mitochondria showed increased susceptibility to swell, diminished activities of mitochondrial respiratory chain complexes and antioxidants. Taurine administration to fibrotic rats restored mitochondrial function, reduced reactive oxygen species formation, prevented DNA damage, and apoptosis. Thus taurine might contribute to the amelioration of the disease process.