Huperzine A, reduces brain iron overload and alleviates cognitive deficit in mice exposed to chronic intermittent hypoxia

Life Sci. 2020 Jun 1:250:117573. doi: 10.1016/j.lfs.2020.117573. Epub 2020 Mar 21.


Chronic intermittent hypoxia (CIH) is a consequence of obstructive sleep apnea (OSA), which increases reactive oxygen species (ROS) generation, resulting in oxidative damage and neurocognitive impairment. This study was designed to determine whether abnormal iron metabolism occurs in the brain under conditions of CIH and whether Huperzine A (HuA) could improve abnormal iron metabolism and neurological damage. The mouse model of CIH was established by reducing the percentage of inspired O2 (FiO2) from 21% to 9% 20 times/h for 8 h/day, and Huperzine A (HuA, 0.1 mg/kg, i.p.) was administered during CIH exposure for 21 days. HuA significantly improved cognitive impairment and neuronal damage in the hippocampus of CIH mice via increasing the ratio of Bcl-2/Bax and inhibiting caspase-3 cleavage. HuA considerably decreased ROS levels by downregulating the high levels of NADPH oxidase (NOX 2, NOX 4) mediated by CIH. There was an overload of iron, which was characterized by high levels of ferritin (FTL and FTH) and transferrin receptor 1 (TfR1) and low levels of ferroportin 1 (FPN1) in the hippocampus of CIH mice. Decreased levels of TfR1 and FTL proteins observed in HuA treated CIH group, could reduce iron overload in hippocampus. HuA increased PSD 95 protein expression, CREB activation and BDNF protein expression to protect against synaptic plasticity impairment induced by CIH. HuA acts as an effective iron chelator to attenuate apoptosis, oxidative stress and synaptic plasticity mediated by CIH.

Keywords: Brain iron; Chronic intermittent hypoxia; Huperzine A; Oxidative stress; Synaptic plasticity.

MeSH terms

  • Alkaloids / therapeutic use*
  • Animals
  • Apoptosis
  • Behavior, Animal
  • Caspase 3 / metabolism
  • Cation Transport Proteins / metabolism
  • Cognition Disorders / drug therapy*
  • Disease Models, Animal
  • Ferritins / metabolism
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hypoxia / pathology*
  • Iron Overload / drug therapy*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuronal Plasticity
  • Neuroprotective Agents / therapeutic use
  • Oxidative Stress
  • Oxygen / metabolism
  • Reactive Oxygen Species
  • Receptors, Transferrin / metabolism
  • Sesquiterpenes / therapeutic use*


  • Alkaloids
  • Cation Transport Proteins
  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Receptors, Transferrin
  • Sesquiterpenes
  • Tfrc protein, mouse
  • metal transporting protein 1
  • huperzine A
  • Ferritins
  • Casp3 protein, mouse
  • Caspase 3
  • Oxygen