Cannabidiol Normalizes Caspase 3, Synaptophysin, and Mitochondrial Fission Protein DNM1L Expression Levels in Rats with Brain Iron Overload: Implications for Neuroprotection

Abstract

We have recently shown that chronic treatment with cannabidiol (CBD) was able to recover memory deficits induced by brain iron loading in a dose-dependent manner in rats. Brain iron accumulation is implicated in the pathogenesis of neurodegenerative diseases, including Parkinson's and Alzheimer's, and has been related to cognitive deficits in animals and human subjects. Deficits in synaptic energy supply have been linked to neurodegenerative diseases, evidencing the key role played by mitochondria in maintaining viable neural cells and functional circuits. It has also been shown that brains of patients suffering from neurodegenerative diseases have increased expression of apoptosisrelated proteins and specific DNA fragmentation. Here, we have analyzed the expression level of brain proteins involved with mitochondrial fusion and fission mechanisms (DNM1L and OPA1), the main integral transmembrane protein of synaptic vesicles (synaptophysin), and caspase 3, an apoptosis-related protein, to gain a better understanding of the potential of CBD in restoring the damage caused by iron loading in rats. We found that CBD rescued iron-induced effects, bringing hippocampal DNM1L, caspase 3, and synaptophysin levels back to values comparable to the control group. Our results suggest that iron affects mitochondrial dynamics, possibly trigging synaptic loss and apoptotic cell death and indicate that CBD should be considered as a potential molecule with memory-rescuing and neuroprotective properties to be used in the treatment of cognitive deficits observed in neurodegenerative disorders.

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

“…We have previously described that iron overload induces severe and persistent long-term impairments in spatial, recognition, and emotional memories 5–11 . In molecular analyses, we found lipid peroxidation and oxidative damage associated with iron excess 6 , increased apoptotic markers, Par4 12 and Caspase 3 13 , accumulation of ubiquitinated proteins 14 , and reactive gliosis 15 . Moreover, iron treatment in the neonatal period decreased acetylcholinesterase activity in the striatum 8 and affected the regulation of iron homeostasis proteins in the hippocampus, cortex, and striatum of aged rats 16 .…”

“…Moreover, iron treatment in the neonatal period decreased acetylcholinesterase activity in the striatum 8 and affected the regulation of iron homeostasis proteins in the hippocampus, cortex, and striatum of aged rats 16 . In addition, there was a decrease in synaptophysin levels, a marker of synaptic viability, and changes in DNM1L levels, a protein critically involved in mitochondrial dynamics in the hippocampus of iron-treated rats 13 . We have also 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 .…”

Fear Memory

“…This led to further investigations on the anticonvulsant action first of extracts and then of isolated compounds of the plant (111, 212,275,276,280) and almost simultaneously to effects of Cannabis and its compounds on fear learning (212,275,288,467) in the laboratory of E. A. Carlini in São Paulo. Concerning the anticonvulsant effects, the nonpsychotropic natural cannabinoid cannabidiol is now beginning to draw generalized attention through a variety of effects aside from the anticonvulsant one: anxiolytic (67) and perhaps neuroprotective (161,600). Concerning the anxiolytic effect, recent studies show that cannabidiol acting on the PL vmPFC via 5HT 1A receptor-mediated mechanisms can be anxiolytic or anxiogenic in an elevated plus maze depending on the previous record of the animals in terms of stressful experiences (174,387).…”

Naringenin Mitigates Iron-Induced Anxiety-Like Behavioral Impairment, Mitochondrial Dysfunctions, Ectonucleotidases and Acetylcholinesterase Alteration Activities in Rat Hippocampus

“…Previous studies in rodents have shown that oral administration of iron during the period of rapid brain development produces iron accumulation in the hippocampus. Da Silva et al [12] observed that iron-induced oxidative stress may be related to mitochondrial dysfunction, resulting in an alteration in the expression of fusion and fission proteins, which might ultimately lead to unbalanced mitochondrial dynamics and impaired energy production reducing the ATP levels in the brain of rats [12]. The impairment of mitochondrial function and reduction of ATP levels and extracellular adenosine accumulation are pathological conditions found in neurodegenerative diseases such as Alzheimer's disease (AD), which is closely linked to the decline of cognitive processes [13].…”