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Research Iron Metabolic Disturbance as the Mechanism of Cerebral Ischemia and Supplementing Qi and Activating Blood Circulation Method Intervention

Author: LiaoJun
Tutor: GeJinWen
School: Hunan University of Traditional Chinese Medicine
Course: Chinese and Western Medicine
Keywords: cerebral ischemia Naotaifang extract (NTE) the irontransmembrane protein hippocampal neuron oxygen glucosedeprivation(OGD)
CLC: R743.3
Type: PhD thesis
Year: 2014
Downloads: 8
Quote: 0
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Abstract


Cerebral ischemia is a reduction of blood flow caused by brain artery spasm or embolism. Recent studies show that cerebral ischemia triggers a cascade of pathophysiological events including glutamate-dependent excitotoxicity, calcium overload, apoptosis, inflamamation, free radical, nitric oxide and mitochondrial damage which lead to death of neurons. Iron is a kind of essential microelement in human body, it participates in synthesis of the myelin sheath protein and neurotransmitter. Iron is also a kind of catalyst increasing concentration of reactive oxygen species. The increased production of reactive oxygen species and lipid peroxidation will damage neurons in cerebral ischemia. Whether iron accumulation and overload in neurons after cerebral ischemic injury is a new mechanism needs to be studied.NaoTaiFang Extract (NTE) is extracts of traditional Chinese medicine compound with the effect of Supplementing Qi and activating blood circulation. Astragalus is monarch drug in NTE. Astragalus effect on the whole body, it can nourish spleen and stomach vigour, promote Qi to improve blood circulation, then elimilate the stasis and cure the root of disease. The rhizome of chuanxiong is ministerial drug; the active ingredients contain ligustrazine and ferulic acid. Earthworm and stiff silkworm are both adjuvant drugs. Earthworm includes earthworm peptides, and stiff silkworm have effective constituent of protein, sterol and uranidin etc. The two adjuvant drugs have effect of clearing and activating the collaterals, and it also can eliminate phlegm and calm wind. All the drugs cooperate to benefit Qi and activating blood circulation, remove meridian obstruction, dispel the wind and reduce phlegm. Preliminary study showed that transferrin(TF) of serum and cerebrospinal fluid increased within24hours after cerebral ischemia, which detected by protein chip technology. concentration of human heme oxygenase-1(HO-1) increased significantly, which treated with Naotaifang extract through intragastric administration. So it is important to reveal new mechanisms of NTE,whether it can protect the neuron by Regulating the iron metabolism.Object:1. In order to Study on the change of the iron transmembrane protein at different time points after cerebral ischemia, reveal that the disregulation of intracellular iron perhaps is the new mechanism of cerebral ischemia injury.2. In order to prove that NTE can protect the neuron in cerebral ischemia by disregulate the intracellular iron.3. The vitro experiments reveal NTE can regulate the iron metabolism imbalance through PI3K/Akt and p38MAPK signal pathway.Method: Sprague Dawley rats were provided. The regional cerebral ischemia model was reproduced by middle cerebral artery occlusion (MCAO) with suture method.1. The iron particles of neurons were observed by Electron microscopic. mRNA and protein level of Fpn were detected by immunohistochemistry and RT-PCR at different time points;2. The iron particles of neurons were observed by Electron microscopic. Neurological behavior of rats was detected by neurobehavioral testing. The protective effect of NTE on neurons is detected by HE staining. TTC staining and Nissl staining. TFR. DMT1、Fpn、FLVCR and BCRP were measured by immunohistochemical method and western-blot, and mRNA were detected by RT-PCR;3. Primary culture of hippocampal neurons used18d SD embryonic rat.The survival rate of neurons was detected with MTT method after Oxygen-glucose deprivation treated with NTE. FLVCR and Fpn was measured by Immunofluorescence method after PI3K and p38MAPK inhibitors intervention.Result:1.Dynamic expression of the iron transport protein after cerebral ischemia:(1) iron particles are showed in neuron through the electron microscope scanning after cerebral ischemia.(2) Expression of non heme iron transport protein:TFR expression significantly increased at12h, and maintain a high level at24h and72h(P<0.05).Expression of Fpn reaches the highest point at12h after operation (P<0.05);(3) Expression of heme iron transport protein:FLVCR expression significantly increased at2h、6h、12h and24h, and decreased at72h (P<0.05). Expression of BCRP decreased at12h after operation,24h and72h maintain low level (P<0.05);2. NTE intervention effects on the iron transport proteins:(1) each dose group of NTE showed less iron particles of neuron in the electron microscope scanning.(2) Expression of non heme iron transport:compared with model group, the large dose group of NTE displayed a lower neurological behavior score (P<0.05);compared with model group,the large dose group of NTE have less infarct size, and have more Nissl body, the nucleus are more clearly show(P<0.05). TFR and TFR-mRNA expression in the ischemic hippocampal CA2region decreased significantly, the expression of Fpn and Fpn-mRNA significantly increased.(3) Expression of heme iron transport protein:expression of the FLVCR andFLVCR-mRNA increased in each NTE dose group (P<0.05), the expression of BCRP had no obvious change.3. The vitro experiments reveal NTE can protect the neuron and regulate the iron metabolism imbalance:(1)Compared with OGD group, the each dosage groups of NTE have higher Neuronal activity after OGD(P<0.05).(2)After Oxygen-glucose deprivation, the neurons treated with the large dose group of NTE. PI3K inhibitors intervention be revealed that can decrease the expression of Fpn and FLVCR, p38MAPK inhibitors intervention can decrease the expression of the Fpn.Conclusion:1. Iron metabolism imbalance is a new mechanism of cerebral ischemic, the iron cross membrane transport protein TFR. DMT1、FPn、FLVCR and BCRP completed the iron transmembrane transport after cerebral ischemia.2. NTE can protect the neuron by adjusting the neuronal iron metabolism in cerebral ischemia.3. we revealed that the expression of Fpn be regulated by PI3K and p38MAPK signal pathway after cerebral ischemia treated with NTE, and FLVCR be regulated by PI3K signal pathway.

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CLC: > Medicine, health > Neurology and psychiatry > Neurology > Cerebrovascular disease > Acute cerebrovascular disease ( stroke)
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