Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
Molecules. 2023 Jan 2;28(1):390. doi: 10.3390/molecules28010390.
Diabetes mellitus (DM) is a major risk factor for stroke and exacerbates white-matter damage in focal cerebral ischemia. Our previous study showed that the sigma-1 receptor agonist PRE084 ameliorates bilateral common-carotid-artery occlusion-induced brain damage in mice. However, whether this protective effect can extend to white matter remains unclear. In this study, C57BL/6 mice were treated with high-fat diets (HFDs) combined with streptozotocin (STZ) injection to mimic type 2 diabetes mellitus (T2DM). Focal cerebral ischemia in T2DM mice was established via injection of the vasoconstrictor peptide endothelin-1 (ET-1) into the hippocampus. Three different treatment plans were used in this study. In one plan, 1 mg/kg of PRE084 (intraperitoneally) was administered for 7 d before ET-1 injection; the mice were sacrificed 24 h after ET-1 injection. In another plan, PRE084 treatment was initiated 24 h after ET-1 injection and lasted for 7 d. In the third plan, PRE084 treatment was initiated 24 h after ET-1 injection and lasted for 21 d. The Y-maze, novel object recognition, and passive avoidance tests were used to assess neurobehavioral outcomes. We found no cognitive dysfunction or white-matter damage 24 h after ET-1 injection. However, 7 and 21 d after ET-1 injection, the mice showed significant cognitive impairment and white-matter damage. Only PRE084 treatment for 21 d could improve this white-matter injury; increase axon and myelin density; decrease demyelination; and increase the expressions of myelin regulator 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNpase) and myelin oligodendrocyte protein (MOG) (which was expressed by mature oligodendrocytes), the number of nerve/glial-antigen 2 (NG2)-positive cells, and the expression of platelet-derived growth factor receptor-alpha (PDGFRα), all of which were expressed by oligodendrocyte progenitor cells in mice with diabetes and focal cerebral ischemia. These results indicate that maybe there was more severe white-matter damage in the focal cerebral ischemia of the diabetic mice than in the mice with normal blood glucose levels. Long-term sigma-1 receptor activation may promote oligodendrogenesis and white-matter functional recovery in patients with stroke and with diabetes.
糖尿病（DM）是中风的一个主要危险因素，并加重局灶性脑缺血中的白质损伤。我们之前的研究表明，sigma-1 受体激动剂 PRE084 可改善小鼠双侧颈总动脉闭塞引起的脑损伤。然而，这种保护作用是否可以扩展到白质尚不清楚。在这项研究中，C57BL/6 小鼠接受高脂肪饮食（HFDs）联合链脲佐菌素（STZ）注射，模拟 2 型糖尿病（T2DM）。通过向海马内注射血管收缩肽内皮素-1（ET-1），在 T2DM 小鼠中建立局灶性脑缺血。在这项研究中使用了三种不同的治疗方案。在一个方案中，在 ET-1 注射前 7 天，给予 1mg/kg 的 PRE084（腹腔内）；在 ET-1 注射后 24 小时处死小鼠。在另一个方案中，在 ET-1 注射后 24 小时开始 PRE084 治疗，持续 7 天。在第三个方案中，在 ET-1 注射后 24 小时开始 PRE084 治疗，持续 21 天。Y 迷宫、新物体识别和被动回避测试用于评估神经行为结果。我们发现 ET-1 注射后 24 小时没有认知功能障碍或白质损伤。然而，在 ET-1 注射后 7 和 21 天，小鼠表现出明显的认知障碍和白质损伤。只有 PRE084 治疗 21 天才能改善这种白质损伤；增加轴突和髓鞘密度；减少脱髓鞘；并增加少突胶质细胞髓鞘调节因子 2'-3'-环核苷酸 3'-磷酸二酯酶（CNpase）和髓鞘少突胶质细胞糖蛋白（MOG）（由成熟少突胶质细胞表达）、神经胶质抗原 2（NG2）阳性细胞的数量以及血小板衍生生长因子受体-α（PDGFRα）的表达，这些都在糖尿病和局灶性脑缺血的小鼠中由少突胶质细胞前体细胞表达。这些结果表明，在糖尿病小鼠的局灶性脑缺血中，可能存在比血糖正常的小鼠更严重的白质损伤。长期 sigma-1 受体激活可能促进中风和糖尿病患者的少突胶质细胞发生和白质功能恢复。
