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

Abstract

Studies demonstrated that the iron chelating antioxidant restores brain dysfunction induced by iron toxicity in animals. Earlier, we found that iron overload-induced cerebral cortex apoptosis correlated with oxidative stress could be protected by naringenin (NGEN). In this respect, the present study is focused on the mechanisms associated with the protective efficacy of NGEN, natural flavonoid compound abundant in the peels of citrus fruit, on iron induced impairment of the anxiogenic-like behaviour, purinergic and cholinergic dysfunctions with oxidative stress related disorders on mitochondrial function in the rat hippocampus. Results showed that administration of NGEN (50 mg/kg/day) by gavage significantly ameliorated anxiogenic-like behaviour impairment induced by the exposure to 50 mg of Fe-dextran/kg/day intraperitoneally for 28 days in rats, decreased iron-induced reactive oxygen species formation and restored the iron-induced decrease of the acetylcholinesterase expression level, mitochondrial membrane potential and mitochondrial complexes activities in the hippocampus of rats. Moreover, NGEN was able to restore the alteration on the activity and expression of ectonucleotidases such as adenosine triphosphate diphosphohydrolase and 5'-nucleotidase, enzymes which hydrolyze and therefore control extracellular ATP and adenosine concentrations in the synaptic cleft. These results may contribute to a better understanding of the neuroprotective role of NGEN, emphasizing the influence of including this flavonoid in the diet for human health, possibly preventing brain injury associated with iron overload.

Beneficial effects of naringenin in liver diseases: Molecular mechanisms

“…Co-administration with naringenin blocked the development of oxidative stress and improved antioxidant enzyme activities in the cerebral cortex[ 169 ]. In another work, the effect of naringenin on iron-induced hippocampus damage was investigated: iron administration for 28 d induced an impairment of the anxiogenic-like behavior and induced purinergic and cholinergic dysfunctions with oxidative stress-related disorders on mitochondrial function in the rat hippocampus, but naringenin was able to restore those parameters[ 170 ] (Figure 8 ).…”

Mitoferrin-1 is required for brain energy metabolism and hippocampus-dependent memory

“…Only a general association between iron and hippocampus had so far been described in the literature. The majority of these reports were dedicated to hippocampal damage in situations of iron overload [7,10,23,30], which may occur in the setting of rare diseases, but does not shed much light on the role of physiological iron levels in brain function. More relevant with regard to a reduction of the metal were a few studies of IDA rats (neonatal Fe-deficiency anemia) exhibiting memory deficits and corresponding CA1 micromorphological alternations.…”

“…A larger number of reports were dedicated to the opposite phenomenon, i.e. hampering of hippocampal function by iron overload, including the potential benefit of Fe-chelators for improvement of hippocampal function [7,10,23,30]. Effects of iron overload may also involve mitochondrial mechanisms [20].…”

Antidepressant Flavonoids and Their Relationship with Oxidative Stress

“…It has also been reported to decrease the levels of isoflurane-induced cytosolic calcium and reactive oxygen species [ 121 ]. Likewise, cellular ROS production induced by several oxidative damaging agents was attenuated by pretreatment with chrysin (2) [ 122 ], naringenin (3) [ 123 ], astilbin (4) [ 53 ], icariin (5) [ 124 ], 7,8-dihydroxyflavone (6) [ 125 ], hyperoside (7) [ 126 ], baicalein (8) [ 127 ], rutin (11) [ 128 ], luteolin (12) [ 129 ], fisetin (15) [ 130 ], nobiletin (16) [ 131 ], kaempferitrin (10) [ 132 ], and quercetin (17) [ 133 ].…”

“…Then, these natural compounds enabled metals to chelate or binds to metal ions in humans and animals to block them being accessible to oxidation [ 116 ]. Now, hesperidin (1) [ 36 ], naringenin (3) [ 123 ], astilbin (4) [ 134 ], luteolin (12) [ 135 ], and quercetin (17) [ 136 ] appeared to chelate metal ions such as iron, copper, and zinc in showing their antiradical properties. Notwithstanding free radicals scavenging and chelating of metal ions, several flavonoids, including hesperidin (1), astilbin (4), luteolin (12), baicalein (8), and quercetin (17), played key roles in inhibiting free radical generating enzymes such as myeloperoxidase, xanthine oxidase, lipoxygenase, microsomal monooxygenase, and NADPH oxidase [ 137 – 143 ].…”