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Targeting hepcidin improves cognitive impairment and reduces iron deposition in a diabetic rat model.

ABSTRACT: Cognitive impairment is a common complication of type 2 diabetes mellitus (T2DM) that may be related to iron deposition in the brain. Hepcidin is expressed in the brain and has the ability to regulate iron. Therefore, this study explored the role of hepcidin in hippocampal iron deposition and cognitive impairment in T2DM. The effects of a recombinant adeno-associated virus targeting hepcidin (AAV-hepcidin) for hippocampal iron content and cognitive function were investigated in a T2DM rat model induced by streptozotocin and a high-fat diet. Adult male rats (n = 32) were categorized as either C-saline (normal control), M-saline (T2DM), M-blank (AAV-blank + T2DM), or M-hepcidin (AAV-hepcidin + T2DM). Hippocampal iron content was assessed using quantitative susceptibility mapping. Morris water maze (MWM) testing was used to assess the cognitive function. Magnetic resonance imaging indicated that hippocampal susceptibility values were significantly increased bilaterally in T2DM rats compared with controls (P = 0.044, P = 0.043). Compared with the M-blank group, the M-hepcidin group exhibited significantly decreased hippocampal susceptibility values bilaterally (P = 0.007, P = 0.030). Compared with the M-saline group, susceptibility values from left hippocampus in the M-hepcidin group were significantly reduced (P = 0.002). MWM results showed that the performance of T2DM rats was significantly decreased from that of control rats. Compared with the M-saline and M-blank groups, the performance of the M-hepcidin group was significantly increased. These studies demonstrate that T2DM rats developed cognitive impairment and iron deposits in the hippocampus, both of which were improved by AAV-hepcidin administration.

SUBMITTER: Liu J

PROVIDER: S-EPMC7476126 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Targeting hepcidin improves cognitive impairment and reduces iron deposition in a diabetic rat model.

Liu Juan J Hu Xiaofei X Xue Yuan Y Liu Chen C Liu Daihong D Shang Yongning Y Shi Yanshu Y Cheng Lin L Zhang Jiqiang J Chen Antao A Wang Jian J

American journal of translational research 20200815 8

Cognitive impairment is a common complication of type 2 diabetes mellitus (T2DM) that may be related to iron deposition in the brain. Hepcidin is expressed in the brain and has the ability to regulate iron. Therefore, this study explored the role of hepcidin in hippocampal iron deposition and cognitive impairment in T2DM. The effects of a recombinant adeno-associated virus targeting hepcidin (AAV-hepcidin) for hippocampal iron content and cognitive function were investigated in a T2DM rat model ...[more]

PMID: 32913554

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Project description:PurposeExcessive brain iron accumulation contributes to cognitive impairments in hepatitis B virus (HBV)-related cirrhotic patients. The underlying mechanism remains unclear. Hepcidin, a liver-produced, 25-aminoacid peptide, is the major regulator of systemic iron metabolism. Abnormal hepcidin level is a key factor in some body iron accumulation or deficiency disorders, especially in those associated with liver diseases. Our study was aimed to explore the relationship between brain iron content in patients with HBV-related cirrhosis and serum hepcidin level.MethodsSeventy HBV-related cirrhotic patients and forty age- sex-matched healthy controls were enrolled. Brain iron content was quantified by susceptibility weighted phase imaging technique. Serum hepcidin as well as serum iron, serum transferrin, ferritin, soluble transferrin receptor, total iron binding capacity, and transferrin saturation were tested in thirty cirrhotic patients and nineteen healthy controls. Pearson correlation analysis was performed to investigate correlation between brain iron concentrations and serum hepcidin, or other iron parameters.ResultsCirrhotic patients had increased brain iron accumulation compared to controls in the left red nuclear, the bilateral substantia nigra, the bilateral thalamus, the right caudate, and the right putamen. Cirrhotic patients had significantly decreased serum hepcidin concentration, as well as lower serum transferring level, lower total iron binding capacity and higher transferrin saturation, compared to controls. Serum hepcidin level negatively correlated with the iron content in the right caudate, while serum ferritin level positively correlated with the iron content in the bilateral putamen in cirrhotic patients.ConclusionsDecreased serum hepcidin level correlated with excessive iron accumulation in the basal ganglia in HBV-related cirrhotic patients. Our results indicated that systemic iron overload underlined regional brain iron repletion. Serum hepcidin may be a clinical biomarker for brain iron deposition in cirrhotic patients, which may have therapeutic potential.

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Project description:BACKGROUND:Prenatal alcohol exposure (PAE) causes neurodevelopmental disability. Clinical and animal studies show gestational iron deficiency (ID) exacerbates PAE's behavioral and growth deficits. In rat, PAE manifests an inability to establish iron homeostasis, increasing hepcidin (maternal and fetal), and fetal liver iron while decreasing brain iron and promoting anemia. Here, we hypothesize dietary iron fortification during pregnancy may mitigate alcohol's disruption of fetal iron homeostasis. METHODS:Pregnant Long-Evans rats, fed iron-sufficient (100 ppm iron) or iron-fortified (IF; 500 ppm iron) diets, received either 5 g/kg alcohol (PAE) or isocaloric maltodextrin daily on gestational days (GD) 13.5 through 19.5. Maternal and fetal outcomes were evaluated on GD20.5. RESULTS:PAE reduced mean fetal weight (p < 0.001) regardless of maternal iron status, suggesting iron fortification did not improve fetal growth. Both PAE (p < 0.01) and IF (p = 0.035) increased fetal liver iron. In fetal brain, PAE (p = 0.015) affected total (p < 0.001) and nonheme iron (p < 0.001) such that iron fortification normalized (p = 0.99) the alcohol-mediated reductions in brain iron and nonheme iron. Iron fortification also improved fetal hematologic indices in PAE including hemoglobin, hematocrit, and mean cell volume (ps<0.001). Iron fortification also normalized hepcidin expression in alcohol-exposed maternal and fetal liver. Neither diet nor PAE affected transferrin (Tf) and ferritin (FTN) content in fetal liver, nor Tf or transferrin receptor in fetal brain. However, IF-PAE fetal brains trended to less FTN content (p = 0.074), suggesting greater availability of nonstorage iron. In PAE, hepcidin levels were linearly related to increased liver iron stores and decreased red blood cell count and brain iron. CONCLUSIONS:Maternal oral iron fortification mitigated PAE's disruption of fetal iron homeostasis and improved brain iron content, hematologic indices, and hepcidin production in this rat PAE model. Clinical studies show maternal ID substantially enhances fetal vulnerability to PAE, and our work supports increased maternal dietary iron intake may improve fetal iron status in alcohol-exposed pregnancies.

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Targeting hepcidin improves cognitive impairment and reduces iron deposition in a diabetic rat model.

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Targeting hepcidin improves cognitive impairment and reduces iron deposition in a diabetic rat model.

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