Abstract
Iron accumulation in the brain has been recognized as a common feature of both normal aging and neurodegenerative diseases. Cognitive dysfunction has been associated to iron excess in brain regions in humans. We have previously described that iron overload leads to severe memory deficits, including spatial, recognition, and emotional memory impairments in adult rats. In the present study we investigated the effects of neonatal iron overload on proteins involved in apoptotic pathways, such as Caspase 8, Caspase 9, Caspase 3, Cytochrome c, APAF1, and PARP in the hippocampus of adult rats, in an attempt to establish a causative role of iron excess on cell death in the nervous system, leading to memory dysfunction. Cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa, was examined as a potential drug to reverse iron-induced effects on the parameters analyzed. Male rats received vehicle or iron carbonyl (30 mg/kg) from the 12th to the 14th postnatal days and were treated with vehicle or CBD (10 mg/kg) for 14 days in adulthood. Iron increased Caspase 9, Cytochrome c, APAF1, Caspase 3 and cleaved PARP, without affecting cleaved Caspase 8 levels. CBD reversed iron-induced effects, recovering apoptotic proteins Caspase 9, APAF1, Caspase 3 and cleaved PARP to the levels found in controls. These results suggest that iron can trigger cell death pathways by inducing intrinsic apoptotic proteins. The reversal of iron-induced effects by CBD indicates that it has neuroprotective potential through its anti-apoptotic action.
Highlights
Iron accumulation has been described in normal ageing in several brain regions and cell types
The present results showed that neonatal irontreatment led to significant changes in the concentration of apoptotic proteins, increasing all intrinsic apoptotic pathway proteins analyzed
Aiming to gain a better understanding of the mechanisms involved and trying to establish a possible causative role of iron overload in apoptosis, we have investigated key players in the apoptotic pathway in the hippocampus of adult rats submitted to iron overload in the neonatal period
Summary
Iron accumulation has been described in normal ageing in several brain regions and cell types. We found lipid peroxidation and oxidative damage associated with iron excess[6], increased apoptotic markers, Par[412] and Caspase 313, accumulation of ubiquitinated proteins[14], and reactive gliosis[15]. Iron treatment in the neonatal period decreased acetylcholinesterase activity in the striatum[8] and affected the regulation of da Silva et al Translational Psychiatry (2018)8:176 iron homeostasis proteins in the hippocampus, cortex, and striatum of aged rats[16]. We have demonstrated that iron chelation prevented memory impairments and oxidative stress in aged rats, supporting the concept that cognitive deficits associated with aging might be related to iron accumulation in the brain[17]
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