糖尿病性中风模型中的脑毛细血管组织型纤溶酶原激活剂

Brain capillary tissue plasminogen activator in a diabetes stroke model.

作者信息

Kittaka M, Wang L, Sun N, Schreiber S S, Seeds N W, Fisher M, Zlokovic B V

机构信息

Department of Neurosurgery, Children's Hospital, University of Southern California School of Medicine, Los Angeles, USA.

出版信息

Stroke. 1996 Apr;27(4):712-9. doi: 10.1161/01.str.27.4.712.

DOI:10.1161/01.str.27.4.712

PMID:8614937

Abstract

BACKGROUND AND PURPOSE

Tissue plasminogen activator (TPA) is normally expressed in rat brain capillaries. This study examines the expression of TPA in brain capillaries of diabetic rats in relation to focal ischemic brain injury.

METHODS

Diabetes type 1 was induced by streptozotocin for 7 days. Acute hyperglycemia was induced by 50% dextrose. Expression of TPA in brain capillaries was determined by Western blot and reverse transcription-polymerase chain reaction analyses. Focal stroke was produced by 1 hour of reversible middle cerebral artery occlusion. Physiological variables and cerebral blood flow were monitored during occlusion and within 1 hour of reperfusion. Neurological and neuropathologic examinations were performed after 24 hours of reperfusion.

RESULTS

All rats developed comparable hyperglycemia (approximately 15 mmol/L). A complete depletion of TPA protein and 6.5-fold decrease in TPA mRNA were found in brain capillaries of diabetic rats, in contrast to normal TPA capillary levels in hyperglycemic rats. The blood flow in the periphery of the ischemic core was significantly reduced during reperfusion by 52% to 62% (P<.001) in diabetic rats and by 23% to 25% (P<.05) in hyperglycemic rats. The neurological score was worsened by 3.2-fold (P<.0003) by diabetes and by 24% by hyperglycemia only. Significant 41% (P<.007) and 29% (P<.05) increases in infarct volume and 163% (P<.007) and 60% increases in edema volume were found in diabetic rats relative to control and hyperglycemic rats, respectively.

CONCLUSIONS

Diabetes type 1, but not acute hyperglycemia, produces downregulation of TPA in rat brain capillaries. This TPA reduction is associated with impaired restoration of blood flow after an ischemic insult, poor neurological outcome, and enhanced ischemic brain injury.

摘要

背景与目的

组织型纤溶酶原激活剂（TPA）通常在大鼠脑毛细血管中表达。本研究检测糖尿病大鼠脑毛细血管中TPA的表达及其与局灶性缺血性脑损伤的关系。

方法

用链脲佐菌素诱导1型糖尿病7天。用50%葡萄糖诱导急性高血糖。通过蛋白质印迹法和逆转录-聚合酶链反应分析测定脑毛细血管中TPA的表达。通过1小时的可逆性大脑中动脉闭塞制造局灶性中风。在闭塞期间和再灌注1小时内监测生理变量和脑血流量。再灌注24小时后进行神经学和神经病理学检查。

结果

所有大鼠均出现相似程度的高血糖（约15 mmol/L）。与高血糖大鼠正常的TPA毛细血管水平相比，糖尿病大鼠脑毛细血管中TPA蛋白完全缺失，TPA mRNA减少6.5倍。再灌注期间，糖尿病大鼠缺血核心周边的血流量显著减少52%至62%（P<0.001），高血糖大鼠减少23%至25%（P<0.05）。糖尿病使神经学评分恶化3.2倍（P<0.0003），高血糖仅使其恶化24%。与对照组和高血糖大鼠相比，糖尿病大鼠梗死体积分别显著增加41%（P<0.007）和29%（P<0.05），水肿体积分别增加163%（P<0.007）和60%。