title: A combination of an iron chelator with an antioxidant effectively diminishes the dendritic loss, tau-hyperphosphorylation, amyloids-β accumulation and brain mitochondrial dynamic disruption in rats with chronic iron-overload.
abstract: Iron-overload can cause cognitive impairment due to blood-brain barrier (BBB) breakdown and brain mitochondrial dysfunction. Although deferiprone (DFP) has been shown to exert neuroprotection, the head-to-head comparison among iron chelators used clinically on brain iron-overload has not been investigated. Moreover, since antioxidant has been shown to be beneficial in iron-overload condition, its combined effect with iron chelator has not been tested. Therefore, the hypothesis is that all chelators provide neuroprotection under iron-overload condition, and that a combination of an iron chelator with an antioxidant has greater efficacy than monotherapy. Male Wistar rats (n=42) were assigned to receive a normal diet (ND) or a high-iron diet (HFe) for 4months. At the 2nd month, HFe-fed rats were treated with a vehicle, deferoxamine (DFO), DFP, deferasirox (DFX), n-acetyl cysteine (NAC) or a combination of DFP with NAC, while ND-fed rats received vehicle. At the end of the experiment, rats were decapitated and brains were removed to determine brain iron level and deposition, brain mitochondrial function, BBB protein expression, brain mitochondrial dynamic, brain apoptosis, tau-hyperphosphorylation, amyloid-β (Aβ) accumulation and dendritic spine density. The results showed that iron-overload induced BBB breakdown, brain iron accumulation, brain mitochondrial dysfunction, impaired brain mitochondrial dynamics, tau-hyperphosphorylation, Aβ accumulation and dendritic spine reduction. All treatments, except DFX, attenuated these impairments. Moreover, combined therapy provided a greater efficacy than monotherapy. These findings suggested that iron-overload induced brain iron toxicity and a combination of an iron chelator with an antioxidant provided a greatest efficacy for neuroprotection than monotherapy.
authors.affiliation: Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Jirapas
authors.initials: J
authors.lastname: Sripetchwandee
authors.affiliation: Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Suwakon
authors.initials: S
authors.lastname: Wongjaikam
authors.affiliation: Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Warunsorn
authors.initials: W
authors.lastname: Krintratun
authors.affiliation: Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Nipon
authors.initials: N
authors.lastname: Chattipakorn
authors.affiliation: Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address: scchattipakorn@gmail.com.
authors.forename: Siriporn C
authors.initials: SC
authors.lastname: Chattipakorn
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001565:Benzoates / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077588:Deferasirox; D003676:Deferoxamine / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004032:Diet; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D007501:Iron / Q000633:toxicity; D007502:Iron Chelating Agents / Q000494:pharmacology*; D019190:Iron Overload / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D017208:Rats, Wistar; D014230:Triazoles / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D001565:Benzoates; D007502:Iron Chelating Agents; C489131:Mapt protein, rat; D014230:Triazoles; D016875:tau Proteins; D007501:Iron; D003676:Deferoxamine; D000077588:Deferasirox; D000111:Acetylcysteine
keywords: combined therapy; dendritic spine; iron chelator; iron-overload; mitochondrial dynamic