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. (22nd September 2016)

• Record Type: Journal Article
• Authors: Sripetchwandee, Jirapas; Wongjaikam, Suwakon; Krintratun, Warunsorn; Chattipakorn, Nipon; Chattipakorn, Siriporn C.
• Is Part Of: Neuroscience. Volume 332(2016)
• Page Start: 191
• Page End: 202
• Publication Date: 2016-09-22
• Subjects: AD Alzheimer's disease -- APP amyloid precursor protein -- Aβ amyloid-β -- BBB blood–brain barrier -- DFO deferoxamine -- DFP deferiprone -- DFX deferasirox -- Drp1 dynamin-related protein 1 -- HFe high-iron diet -- Mfn2 mitofusin2 -- NAC n-acetyl cysteine -- ND normal diet -- NTBI non-transferrin bound iron -- ROS reactive oxygen species; iron-overload -- iron chelator -- combined therapy -- dendritic spine -- mitochondrial dynamic; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2016.07.003
• Languages: English
• ISSNs: 0306-4522

Abstract

Graphical abstract: Highlights: Iron overload causes brain iron toxicity: increased amyloid plaque and disrupted brain mitochondrial dynamics. Iron chelators attenuate brain iron toxicity. Combined iron chelator with NAC exerted better brain protection in iron-overload condition. Combined therapy could provide the best therapeutic approach for treatment of neurodegeneration caused by 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 4 months. 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.