Li Jiang, Xu Shaofeng, Wang Ling, Wang Xiaoliang
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Antioxidants (Basel). 2024 May 10;13(5):585. doi: 10.3390/antiox13050585.
Hypertension reduces the bioavailability of vascular nitric oxide (NO) and contributes to the onset of vascular dementia (VaD). A loss of NO bioavailability increases inflammation and oxidative stress. 2-(4-Methylthiazol-5-yl) ethyl nitrate hydrochloride (W1302) is a novel nitric oxide donor (NOD) which is undergoing phase I clinical trials in China for the treatment of VaD. In this study, we investigated the protective effects of W1302 in VaD rats induced by the permanent occlusion of a bilateral common carotid arteries model related to spontaneous hypertension (SHR-2VO), and we further explored the underlying mechanisms. Nimodipine was used as a positive control. Our results showed that W1302 treatment for 4 weeks (10 mg/Kg/day) exhibited stronger improvement in the spatial learning and memory deficits in SHR-2VO rats compared with nimodipine with slightly lower systolic blood pressure (SBP). Meanwhile, W1302 treatment significantly increased NO and cGMP production, restored mitochondrial membrane potential and attenuated oxidative stress as evidenced by increasing ATP production and reducing malondialdehyde (MDA) levels in the brain. Furthermore, W1302 treatment markedly inhibited the iNOS activity and decreased TNF-α expression via inhibiting the nuclear factor kappa B (NF-κB) signaling pathway. Nimodipine treatment also restored these aberrant changes, but its ATP production was weaker than that of W1302, and there was no significant effect on NO release. Taken together, W1302 exhibited beneficial effects on complications in VaD with hypertension, which is involved in suppressing oxidative damage, and the inflammatory reaction might be mediated by an increase in NO release. Therefore, W1302 has therapeutic potential for the treatment of VaD caused by chronic cerebral hypoperfusion-associated spontaneous hypertension.
高血压会降低血管一氧化氮（NO）的生物利用度，并导致血管性痴呆（VaD）的发生。NO生物利用度的丧失会增加炎症和氧化应激。2-（4-甲基噻唑-5-基）乙基硝酸盐酸盐（W1302）是一种新型一氧化氮供体（NOD），正在中国进行治疗VaD的I期临床试验。在本研究中，我们研究了W1302对与自发性高血压（SHR-2VO）相关的双侧颈总动脉永久闭塞模型诱导的VaD大鼠的保护作用，并进一步探讨了其潜在机制。尼莫地平用作阳性对照。我们的结果表明，与尼莫地平相比，W1302治疗4周（10mg/Kg/天）对SHR-2VO大鼠的空间学习和记忆缺陷有更强的改善作用，且收缩压（SBP）略低。同时，W1302治疗显著增加了NO和cGMP的产生，恢复了线粒体膜电位，并减轻了氧化应激，这可通过增加大脑中的ATP产生和降低丙二醛（MDA）水平来证明。此外，W1302治疗通过抑制核因子κB（NF-κB）信号通路显著抑制诱导型一氧化氮合酶（iNOS）活性并降低肿瘤坏死因子-α（TNF-α）表达。尼莫地平治疗也恢复了这些异常变化，但其ATP产生比W1302弱，并且对NO释放没有显著影响。综上所述，W1302对高血压性VaD的并发症具有有益作用，其涉及抑制氧化损伤，并且炎症反应可能由NO释放增加介导。因此，W1302具有治疗慢性脑灌注不足相关自发性高血压所致VaD的治疗潜力。
