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

Neuroscience. 2016 Sep 22;332:191-202. doi: 10.1016/j.neuroscience.2016.07.003. Epub 2016 Jul 9.


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.

Keywords: combined therapy; dendritic spine; iron chelator; iron-overload; mitochondrial dynamic.

MeSH terms

  • Acetylcysteine / pharmacology
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Antioxidants / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Benzoates / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Deferasirox
  • Deferoxamine / pharmacology
  • Dendrites / drug effects
  • Dendrites / metabolism
  • Dendrites / pathology
  • Diet
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Iron / toxicity
  • Iron Chelating Agents / pharmacology*
  • Iron Overload / drug therapy*
  • Iron Overload / metabolism
  • Iron Overload / pathology
  • Male
  • Mitochondrial Dynamics / drug effects
  • Mitochondrial Dynamics / physiology
  • Neurodegenerative Diseases / drug therapy*
  • Neurodegenerative Diseases / etiology
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Phosphorylation / drug effects
  • Phosphorylation / physiology
  • Random Allocation
  • Rats, Wistar
  • Triazoles / pharmacology
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • Antioxidants
  • Benzoates
  • Iron Chelating Agents
  • Mapt protein, rat
  • Triazoles
  • tau Proteins
  • Iron
  • Deferoxamine
  • Deferasirox
  • Acetylcysteine