| Hydrocephalus is a central nervous system disease characterized by brain atrophy and abnormal cerebrospinal fluid flow. Many factors are related with the development of hydrocephalus, such as abnormality, infection and subarachnoid hemorrhage, etc.Transforming growth factorβ1 is an important growth factor involved in individual development. Previous studies indicate that TGF-β1 overexpressing mice can develop hydrocephalus spontaneously, by regulating the expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in the brain. Besides, the expression of TGF-β1 is also found to be up-regulated in the brain of hydrocephalic mice.During our research of the artherosclerosis mouse model--apoE/LDLR double knockout mice, we find that approximately 5%-10% of them manifest abnormal brain development at different age or of different sex. The lateral ventricle were hydrocephalic. In order to investigate the mechnism of this disease, we use this double knockout mice to study the role of TGF-β1/Smad pathway as well as MMP-9 and TIMP-1 during hydrocephalus. RT-PCR, qRT-PCR, Western blot had been used to detect the expression characters of TGF-β1/Smad signaling pathway as well as MMP-9 and TIMP-1. We aim at investigating the mechnism of abnormal brain development and hydrocephalus of the key lipid metabolism gene knockout mice. Moreover, for the detection of blood brain barrier permeability of the hydrocephalic mice, peritoneal injection of Evans blue was practiced and the the content of Evans blue in the brain tissue was determined. To find whether these hydrocephalic mice differ electrophysiologically from non-hydrocephalic mice, electrocorticographics of the hydrocephalic as well as the control mice were recorded.Our research revealed that:1. AL mice of different age and diets are inclined to develop abnormal brain and the ratio is approximately 5%-10%. There are brain atrophy, enlarged brain lateral, thinned cortex in the diseased mice, and the disease is classified as hydrocephalus due to the hydrocephalic brain.2. Assays of mRNA expression levels of TGF-β1/Smad signal pathway revealed that the expression level of hydrocephalic mice was different from that of control mice, while the tendency was different between different groups.3. Assays of mRNA expression levels of MMP-9 and TIMP-1 revealed that the MMP-9 expression was down-regulated in the hydrocephalic mice on the whole, while the expression of TIMP-1 was up-regulated in the hydrocephalic mice.4. Assays of blood-brain barrier permeability of two different groups revealed that no significant difference of permeability existed between the hydrocephalic mice and the control mice.5. Electroencephalography assays revealed that abnormal electroencephalography signs appeared in the mice with hydrocephalus. The EEG wave amplitude of the hydrocephalic mice was significantly increased.The results implied that,(1) AL as well as apoE-/- mice are inclined to develop hydrocephalus frequently, and there are brain atrophy, enlarged brain lateral, thinned cortex in the diseased mice. (2) TGF-β1/Smad signal pathway took part in the development of hydrocephalus, while the mechnism by which this occurs remains obscure. It is estimated that the pathway exerts different roles during different stage of hydrocephalus. (3) The imbalance of MMP-9/TIMP-1 regulation of the hydrocephalic mice might participate in the develoment of this disease by promoting the accumulation of extracellular matrix. (4) The development of hydrocephalus is not directly related to abnormality of blood-brain-barrier permeability. (5) The electroencephalography signs in the hydrocephalic mice revealed abnormal electric activity of the brain cells. It is probably that the accumulation of cerebrospinal fluid induced ischemia in certain area of brain and insecondary atrophy of pericerebral white matter, which lead to the increased electric excitability of the brain cells.
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