| As an ancient disease, diabetes mellitus has long been known, butmodern medicine still struggles with effective treatment. With the number ofpeople with diabetes rising exponentially, the disease represents one of thegreatest medical and socioeconomic challenges worldwide. It is a complexmetabolic disease that can have devastating effects on multiple organs in thebody. Besides autonomic and peripheral neuropathies, diabetes is alsoassociated with gradually developing end-organ damage in the central nervoussystem. This complication is referred to as "diabetic encephalopathy" andcharacterized by impairment of cognitive functions and electrophysiologicalchanges.The central nervous system (CNS), like the brain, depends on afunctionally intact blood-brain barrier (BBB), which regulates and limits theamount of trans-and para-cellular flux, protects the brain from circulatingneurotoxic substances while maintaining nutrients and ions in the brain atlevels suitable for neuronal function. Failure of the BBB is a critical event inthe development and progression of several diseases that affect the CNS,including multiple sclerosis; hypoxia and ischemia; edema; Parkinson'sdisease and Alzheimer's disease; epilepsy; tumours; glaucoma and lysosomalstorage diseases. However, the specific effects of diabetes on the BBB remaincontroversial.The BBB components include the endothelial cells with their basementmembrane, pericytes and astroglial foot processes. And endothelial cells is themost important for the maintenance of the BBB integrity. The junctionalcomplexes between endothelial cells include adherens junctions (AJs) andtight junctions (TJs). The TJs are responsible for the severe restriction of theparacellular diffusional pathway between the endothelial cells to ions and other polar solutes, and effectively block penetration of macromolecules bythis route. TJs are dynamic structures, with decreased TJ protein expression oralteration of subcellular localization associated with alterations in BBBpermeability.CD146(also referred to as MUC18, MCAM, Mel-CAM, S-Endo-1,P1H12antigen), which was initially identified as a marker of tumorprogression and metastasis formation in human melanoma, belongs to theimmunoglobulin superfamily containing five extracellular immuno-globulin-like domains, a single transmembrane domain and a shortcytoplasmic domain. It is constitutively expressed in all endothelial cells,irrespective of the vessel caliber or anatomical localization. CD146localizesat the endothelial junction, but outside the AJs and colocalizes with the actincytoskeleton. Its expression is upregulated when endothelial cells reachconfluence and transfection of fibroblasts with CD146reduces paracellularpermeability. So we hypothesized that CD146expression changes can alsoaffect BBB permeability. In view of few investigations have done about itsfunction in the nervous system, we characterized the expression anddistribution of CD146in the rat cerebral cortical neurons and also investigatedwhether the expression is influenced by diabetes.Objective: This study investigated the effects of streptozotocin(STZ)-induced diabetes on the integrity of the blood-brain barrier in the rat atdifferent times and the relationship between blood-brain barrier integrity andCD146expression changes. The purpose of this study was also to investigatethe expression and distribution of CD146in the rat cerebral cortical neuronsand examine whether the expression was influenced by diabetes.Methods: Healthy adult male Sprague-Dawley rats were randomlydivided into2groups: Streptozotocin (STZ) induced diabetic group (STZgroup) and the control group (CON group). According to the time after themodel was successfully established, each further divided into4subgroups:4weeks group,7weeks group,10weeks group and13weeks group. In order tounderstand the structure changes of blood-brain barrier, we observed rat cerebral cortical capillary using optical microscope and electron microscope.CD146expression changes of capillary endothelial cells were investigated byimmunohistochemistry. Moreover immunohistochemistry was used to observethe expression and distribution of CD146in the rat cerebral cortical neurons.Results:1Body weight of STZ rats was gradually decreased, when compared tothe4weeks group, significantly decreased weight gain was observed in13weeks group (P<0.05). Body weight of CON rats was gradually increased,when compared to the4weeks group, significantly increased weight gain wasobserved in10weeks group (P<0.05) and in13weeks group (P<0.05). Thebody weight of each subgroup of STZ rats than that of correspondingsubgroup of CON rats was significantly reduced (P<0.05).2The level of blood glucose of each subgroup of STZ rats than that ofcorresponding subgroup of CON rats was significantly increased (P<0.05).The level of blood glucose of STZ rats was gradually increased, whencompared to the4weeks group, significantly increased blood glucose wasobserved in10weeks group (P<0.05). No significant change was observed inCON rats.3No obvious abnormalities of cerebral cortical capillaries wereobserved in CON rats using optical and electron microscope. In STZ rats,optical microscope studies showed that ambiguity of the cerebral corticalcapillary, the infiltration of homogeneous materials outside the blood vessel,leading to widened basal lacunar. Cerebral cortical capillary showedultrastructural features suggesting general swelling of glial cells, as well asperivascular space.4No expression of CD146was found in cerebral capillary endothelialcells in this study. Moreover, we found that CD146was expressed in the ratcerebral cortical neurons, but no significantly change of the expression ofCD146was observed in all groups studied.Conclusion: With the progression of diabetes, changes of theblood-brain barrier was observed in this rat model, suggesting that diabetes can damage the structure of blood-brain barrier. The expression of CD146isnot found in endothelial cells, but in the rat cerebral cortical neurons. |
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