Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 52626202, Israel.
Department of Neurology and Neurosurgery, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Int J Mol Sci. 2023 Jan 19;24(3):2021. doi: 10.3390/ijms24032021.
Diabetic encephalopathy (DE) is an inflammation-associated diabetes mellitus (DM) complication. Inflammation and coagulation are linked and are both potentially modulated by inhibiting the thrombin cellular protease-activated receptor 1 (PAR1). Our aim was to study whether coagulation pathway modulation affects DE. Diabetic C57BL/6 mice were treated with PARIN5, a novel PAR1 modulator. Behavioral changes in the open field and novel object recognition tests, serum neurofilament (NfL) levels and thrombin activity in central and peripheral nervous system tissue (CNS and PNS, respectively), brain mRNA expression of tumor necrosis factor α (TNF-α), Factor X (FX), prothrombin, and PAR1 were assessed. Subtle behavioral changes were detected in diabetic mice. These were accompanied by an increase in serum NfL, an increase in central and peripheral neural tissue thrombin activity, and TNF-α, FX, and prothrombin brain intrinsic mRNA expression. Systemic treatment with PARIN5 prevented the appearance of behavioral changes, normalized serum NfL and prevented the increase in peripheral but not central thrombin activity. PARIN5 treatment prevented the elevation of both TNF-α and FX but significantly elevated prothrombin expression. PARIN5 treatment prevents behavioral and neural damage in the DE model, suggesting it for future clinical research.
糖尿病性脑病（DE）是一种与炎症相关的糖尿病（DM）并发症。炎症和凝血是相互关联的，通过抑制凝血酶细胞蛋白酶激活受体 1（PAR1）都可以潜在地调节。我们的目的是研究凝血途径调节是否会影响 DE。用新型 PAR1 调节剂 PARIN5 处理糖尿病 C57BL/6 小鼠。在旷场和新物体识别测试中评估行为变化、血清神经丝（NfL）水平以及中枢和外周神经系统组织（CNS 和 PNS，分别）中的凝血酶活性、脑肿瘤坏死因子α（TNF-α）、因子 X（FX）、凝血酶原和 PAR1 的 mRNA 表达。在糖尿病小鼠中检测到细微的行为变化。这些伴随着血清 NfL 增加、中枢和外周神经组织凝血酶活性增加以及 TNF-α、FX 和凝血酶原脑内固有 mRNA 表达增加。PARIN5 的全身治疗可预防行为变化的出现，使血清 NfL 正常化，并防止外周但不包括中枢凝血酶活性的增加。PARIN5 治疗可预防 TNF-α和 FX 的升高，但显著升高了凝血酶原的表达。PARIN5 治疗可预防 DE 模型中的行为和神经损伤，表明其可用于未来的临床研究。
