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The Mechanism of Protection of Edaravone on the Rat of EAE

Author: JiaZhen
Tutor: GuoLi
School: Hebei Medical University
Course: Neurology
Keywords: multiple sclerosis experimental autoimmune encephalomyelitis edaravone oxidative stress iron metabolism superoxide dismutase transferrin receptor
CLC: R96
Type: Master's thesis
Year: 2010
Downloads: 51
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Abstract


Objective: Multiple sclerosis (MS) is neuropathologically characterized by infiltration of in?ammatory cells in the central nervous system (CNS). It is characterized by chronic progressive and eventually disabling clinical course. Middle-aged and youth women are the main groups suffering from the disease, and it is a serious threat to human health. Until now the exact mechanisms underling the disease are still less clear. It is considered to be a variety of pathogenic factors, such as: immune disorders, geographic difference, oxidative stress, iron metabolism imbalance, inflammation and other comprehensive effects. In the past few years, evidence has been emerging that oxidative stress induced damage and iron metabolism imbalance contribute to the pathogenesis of MS lesions, and it has been found that they play an important role in the occurrence and development of MS. Oxidative damage and iron metabolic disorder become the hot point of the research.Oxidative stress is due to oxygen metabolism and antioxidant defense system leading to imbalance in the process of tissue damage. Iron overload may promote the highly toxic oxygen free radicals and thus damage the nerve cells. There are a series of oxidative stress-related enzymes, such as Superoxide dismutase (SOD1) who plays protective effects of the tissues. Iron-related proteins are involved in iron metabolism, such as transferrin, transferrin receptor, and ferritin and so on.In this study, the currently accepted animal model of MS we applied is experimental autoimmune encephalomyelitis(EAE)model. Edaravone were administrated to the animals through the incidence of animals, behavioral changes, pathological changes as well as the expression of SOD1 and TfR in the brain tissue to evaluate and analyze edaravone’s effect.Method: Animal grouping: The 72 6-8 week-old healthy female Wistar rats weighing 180-200g, were randomly divided into four groups : normal control group, EAE model group, dexamethasone (DXM) group, and edaravone group (10 mg·kg-1·d-1), and each group has 18 rats. Then each group was randomly divided into 7 days, 16 days, 23 days three sub-groups, and each sub-group has 6 rats. Fresh guinea pig spinal cord homogenate was made, together with complete Freund’s adjuvant (CFA), adjuvant contained in the Mycobacterium tuberculosis dose 6mg/ml, then made them to be emulsion. Each rat was injected 0.5ml emulsion at four foot pads and back.Homologous drug were given to the treatment groups through peritoneal injection on the first day,then daily administration of the drug were given to the animals until they were killed. EAE group, DXM group, edaravone group were injected respectively NS 0.5ml/d, DXM 5mg·kg-1·d-1, edaravone 10mg·kg-1·d-1. Animals were weighted each day, and mental state, activities, nerve function score were also evaluated. Scores were assigned on the basis of the following symptoms: 1, tail weakness; 2, tail weakness plus limb asthenia; 3, mild limb paralysis; 4, severe limb paralysis; 5, moribund or dead. During the experiment, the mean maximal score of animals at different time point and the incidence of disease were observed as results.Histopathology: Rats were sacrificed after anesthesia with intraperitoneal injection.Tissues of the brain and spinal cord were fixed with 4% formalin less than 7 days,then the tissues were embedded in paraffin and sectioned at 5μm thickness.These sections were stained with HE to assess lymphocyte infiltration and inflammation level.Superoxide dismutase (SOD1) and the transferrin receptor (TfR) determination: Brain tissues were fixed with routine paraffin embedding,and then appllied SP’s method to detect the expression level of TfR and SOD1 by immunohistochemical staining in the different parts of the brain tissue (cortical, subcortical, periventricular) .Results:1 The incidence of disease in different groups The incidence of edaravone group and DXM group were significantly lower than that of EAE group (p<0.05).2 Clinical profile of EAE in different groups Neurological deficits scores of edaravonegroup and DXM group were significantly lower than those of EAE group (p<0.05).3 Histopathological observationIn the pre-clinical (the 7th day after immunization) EAE rats, there were inflammatory cells infiltration within the brain tissues, and which is consistent with the clinical manifestations. At the peak of the clinical course (the sixteenth day after immunization),the extent of inflammatory cells infiltration within edaravone group and DXM rat brain tissues was significantly lower than that of EAE group (p<0.05); Ther was no significant difference in the degree of infiltration between edaravone group and DXM group(p>0.05). During clinical remission (the 23th day after immunization) There was no significant difference among these groups (p>0.05).4 The expression level of SOD1 and TfR in the brainsuperoxide dismutase (SOD1): At each time point, the expression level of SOD1 in different tissues of EAE group was significantly lower than that of normal control group, edaravone group and DXM group.There are significant difference between three time points of the EAE subgroup(p<0.05). The expression level of SOD1 between daravone group and DXM group had shown no statistical difference. Only at the peak point (the 16th day), compared with the normal control group, the expression level of SOD1 in edaravone group and DXM group significantly decreased (p<0.05).Transferrin receptor (TfR): With the development of the disease, TfR expression level in the EAE group elevated gradually, and there were significant difference among the different time points. Tfr expression level of the DXM group showed a different change in the trend compared with EAE group, and there are statistically significant among defferent time point. Tfr expression level of Edaravone group, with the development of the disease the change shown decreased trend.Conclusion:1 The expression level of SOD1 and Tfr in EAE rats’brain tissues are related with disease pathogenesis. 2 In the different tissues of the EAE rats’brain (cortical, subcortical, periventricular), the level of SOD1 and TfR showed resemblance changing trend. Pathological changes also happened in cortical not only in subcortical and periventricular.3 Edaravone on EAE rats can play a protective effect, showing to be able to reduce the incidence of EAE in rats, reducing the severity of the disease and alleviating the severity of the inflammatory cells infiltration in the brain tissues.4 Edaravone can protect brain tissue by free radical scavenging in superoxide dismutase (SOD1) to enhance the antioxidant capacity, and have amoderating effect on TfR.5 Compared with dexamethasone, edaravone has less protective effect on reducing the morbidity and improving fuctional scores of EAE rats. But because of less adverse reaction, and long-time administration, edaravone showed a greater advantage.

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