Department of Biochemistry, Basic Medical Science Building, Panjab University, Chandigarh, India.
Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA; Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC, USA.
Neurochem Int. 2018 Sep;118:205-216. doi: 10.1016/j.neuint.2018.05.009. Epub 2018 May 21.
Diabetes is associated with increased blood brain barrier (BBB) permeability resulting in neurological deficits. The present study investigated the role of S-nitrosoglutathione (GSNO) on tight junction proteins and cell adhesion molecules in streptozotocin-induced diabetic mice. Diabetes was induced by intraperitoneal injection of streptozotocin (40 mg/kg body weight) for 5 days in mice. GSNO was administered daily (100 μg/kg body weight, orally) for 8 weeks after the induction of diabetes. A significant decline was observed in the cognitive ability of diabetic animals assessed using radial arm maze test. A significant increase was observed in nitrotyrosine levels in cortex and hippocampus of diabetic mice. Relative mRNA and protein expression of tight junction proteins viz; zona occludens-1 (ZO-1) and occludin were significantly lower in the microvessels isolated from cortex and hippocampus of diabetic animals, whereas expression of claudin-5 was unaltered. Immunofluorescence of tight junction proteins confirmed loss of ZO-1 and occludin in the diabetic brain. Furthermore, significant increase in interstitial cell adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 mRNA and protein levels was observed in diabetic animals. Ultrastructure of microvessels from diabetic brain was also altered thereby confirming BBB disruption. GSNO administration to diabetic animals, on the other hand, was able to ameliorate loss of ZO-1 and occludin as well as normalize ICAM-1 and VCAM-1 expression, restore BBB integrity, and improve cognitive deficits. The findings clearly suggest that GSNO is a therapeutic molecule with potential to protect BBB and prevent diabetes induced neurological deficits.
糖尿病与血脑屏障（BBB）通透性增加有关，导致神经功能缺损。本研究探讨了 S-亚硝基谷胱甘肽（GSNO）在链脲佐菌素诱导的糖尿病小鼠中对紧密连接蛋白和细胞黏附分子的作用。糖尿病通过腹腔注射链脲佐菌素（40mg/kg 体重）5 天诱导小鼠发生。糖尿病诱导后，GSNO 每日（100μg/kg 体重，口服）给药 8 周。使用放射臂迷宫试验评估，糖尿病动物的认知能力显著下降。糖尿病小鼠皮质和海马中的硝基酪氨酸水平显著升高。从糖尿病动物皮质和海马分离的微血管中，紧密连接蛋白（ZO-1 和闭合蛋白）的相对 mRNA 和蛋白表达显著降低，而 Claudin-5 的表达没有改变。紧密连接蛋白的免疫荧光证实了糖尿病大脑中 ZO-1 和闭合蛋白的丢失。此外，糖尿病动物中细胞间黏附分子（ICAM-1）和血管细胞黏附分子（VCAM-1）的 mRNA 和蛋白水平显著增加。糖尿病大脑微血管的超微结构也发生改变，从而证实了 BBB 破坏。另一方面，GSNO 给药可改善 ZO-1 和闭合蛋白的丢失，并使 ICAM-1 和 VCAM-1 的表达正常化，恢复 BBB 的完整性，改善认知缺陷。这些发现清楚地表明，GSNO 是一种具有保护 BBB 和预防糖尿病引起的神经功能缺损的治疗分子。
