Damages and its mechanism of the blood brain barrier in rats with diabetes mellitus with depression

doi:10.13459/j.cnki.cjap.2016.06.016

Abstract

Abstract: Objective: To investigate the expressions of key proteins type IV collagen (CoIV), zonula occludens-1(ZO-1), α-smooth muscle actin(a-SMA) and the mechanisms of the structural injuries of the blood brain barrier in the hippocampus of diabetic rats with depression. Methods: After 14 days of high-fat diet, the rats were treated with streptozotocin (STZ, 38 mg/kg, iv). Then, the animals were randomly divided into 2 groups (n=15):the diabetic group and the diabetes mellitus with depression group. The normal rats were randomly divided into 2 groups(n=15):the control group and the depression group. Diabetic group and control group were kept in normal conditions. The diabetes mellitus with depression group and the depression group were treated with chronic unpredictable stress for 28 days. The levels of blood glucose were detected. The behavior changes of rats were evaluated by open-field test and Morris test. The blood brain barrier morphological changes were observed under the electron microscope. The expressions of CoIV, ZO-1 and a-SMA in rat hippocampal blood-brain barrier were detected by immunocytochemistry. Results: Compared with control group, the level of blood glucose was increased,the number of autonomic activity was decreased, the escape latencies were significantly longer in the Morris water maze test, as well as the space exploration times were shortened in the diabetes mellitus with depression group (P<0.05, P<0.01). The endothelial cells of the hippocampus were blurred, the capillary lumen was narrow, and the peripheral glial cells were edema, the expressions of ZO-1 and a-SMA were decreased(P <0.05), while the expression of CoIV was increased(P <0.05). Compared with diabetic group, the number of autonomic activity in the diabetes mellitus with depression group was significantly decreased (P<0.01), the escape latencies were longer (P<0.05), the blood brain barrier capillary lumen was more narrow and the glial cell terminal edema was more obvious, the expression of a-SMA was decreased(P<0.05). Conclusion: The abnormal expressions of ZO-1, CoIV and -SMA, key proteins in the hippocampal blood brain barrier, may be involved in the mechanisms of structural damages of the blood brain barrier in diabetes mellitus with depression.

Key words: diabetes mellitus with depression, CoIV, ZO-1, a-SMA, rats

CLC Number:

DU Qing, WANG Yu-hong, ZHAO Hong-qing, YANG Hui, MENG Pan, XU Ya-lan. Damages and its mechanism of the blood brain barrier in rats with diabetes mellitus with depression[J]. CJAP, 2016, 32(6): 558-562.

References

[1] 张娟, 毕艳, 沈山梅, 等. 2型糖尿病患者抑郁的患病率及相关危险因素分析[J]. 中华内分泌代谢杂志, 2011, 2(10):796-799.
[2] Schroeter ML, Abdul-Khaliq H, Krebs M, et al. Serum markers support disease-specific glial pathology in major de-pression[J]. J Af f ect Disord, 2008, 111(2):271-280.
[3] 余爱勇, 赵玉武. 糖尿病对血脑屏障影响的研究进展[J]. 国际神经病学神经外科学杂志, 2008, 38(2):150-153.
[4] Willner P. Chronic mild stress (CMS) revisited:consistency and behaviouralneurobio logical concordance in the effects of CMS[J]. Neuropsychobiol, 2005, 52(2):90-110.
[5] Wang YH, Yin LT, Yang H, et al. Hypoglycemic and anti-depressant effects of Zuogui Jiangtang Jieyu formulation in a model of unpredictable chronic mild stress in rats with dia-betes mellitus[J]. Exp Ther Med, 2014, 8(1):281-285.
[6] Aggarwal A, Khera A, Singh I, et al. S-nitrosoglutathione prevents blood-brain barrier disruption associated with in-creased matrix metalloproteinase-9 activity in experimental di-abetes[J]. J Neurochem, 2015, 132(3):595-608.
[7] Najjar S, Pearlman DM, Devinsky O, et al. Neurovascular unit dysfunction with blood-brainbarrier hyperpermeability contributes to major depressive disorder:a review of clinical andexperimental evidence[J]. J Neuroinf lammation, 2013, 10:142.
[8] Hawkins BT, Lundeen TF, Norwood KM, et al. Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat:contribution of hypergly-caemia and matrix metalloproteinases[J]. Diabetol, 2007, 50(1):202-211.
[9] 许庆梅. 糖尿病大鼠侧脑室脉络丛及脑小血管基底膜的观察和脑小血管α-SMA及CD31表达的研究[D]. 石家庄, 河北医科大学:2011.
[10] Howarth AG, Hughes MR, Stevenson BR. Detection of the tight junction-associated protein ZO-1 in astrocytes and other nonepitheli-al cell types[J]. Am J Physiol, 1992, 262(2 Pt1):C461-469.
[11] Fanning AS, Jameson BJ, Jesaitis LA, et al. The tight junc-tion protein ZO-1 establishes a link between the transmem-brane protein occluding and the actin cytoskeleton[J]. J Biol Chem, 1998, 273(45):29745-29753.
[12] Hayashi Y, Makino H, Ota Z. Serum and urinary concentra-tions of type IV collagen and laminin as a marker of microan-giopathy in diabetes[J]. Diabet Med, 1992, 9(4):366-370.
[13] 董小平, 喻斌, 金路, 等. 血脑屏障的细胞组成研究进展[J]. 中国实验方剂学杂志, 2012, 18(8):281-284.
[14] Nishikawa T, Giardino I, Edelstein D, et al. Changes in di-abetic retinal matrix protein mRNA levels in common trans-genic mouse strain[J]. Curr Eye Res, 2000, 21(1):581-587.
[15] Margarti A, Zeng L, Xu Q. Stem cells, vascular smooth muscle cells and atherosclerosis[J]. Histol Histopathol, 2006, 21(9):979-985.