Zhang Wen-Yuan, Zhao Cui-Mei, Wang Chang-Shui, Xie Xin, Li Yu-Qi, Chen Bei-Bei, Feng Lei, Jiang Pei
Department of Pharmacy, Zhongshan City People's Hospital, Zhongshan, 528403, China; School of Pharmaceutical Sciences, Zunyi Medical University, Zunyi, 510006, China.
Translational Pharmaceutical Laboratory, Jining First People's Hospital, Shandong First Medical University, Jining, 272000, China.
Free Radic Biol Med. 2024 Jan;210:108-119. doi: 10.1016/j.freeradbiomed.2023.11.012. Epub 2023 Nov 18.
While it is well-acknowledged that neurovascular dysfunction in hypertension is tightly associated with accelerated brain aging, we contend that the deleterious effects of hypertension may extend beyond affecting only the arteries. Methylglyoxal (MG) derived from glycolysis, is involved in the accumulation of advanced glycated end products (AGEs), which are the hallmarks of neurodegenerative disorders. Therefore, the present study aims to firstly investigate the role of MG metabolism in the hypertension-accelerated brain aging process. The results of our study indicate that the levels of MG increase with age in both the plasma and hippocampus of SHRs at 12, 16, and 30 weeks old. AGE methylglyoxal-hydro imidazoline-1 (MG-H1) is primarily localized in astrocytes, while its presence was not observed in neurons and microglia within the hypertensive hippocampus. Our observations also suggest that angiotensin II (Ang II) enhances glucose uptake and glycolysis while reducing the expression of Glo1 in cultured astrocytes. N-acetylcysteine (NAC) was found to counteract the increase in escape latency and inhibit the activation of the AGEs-RAGE axis in 30-week-old SHRs. NAC decreased Iba-1 immunofluorescence intensity, inhibited the levels of pro-inflammatory markers, and enhanced the abundance of anti-inflammatory markers in the hippocampus of SHRs. Moreover, NAC reduced the immunofluorescence signal of 4HNE and increased the content of GSH and SOD in SHRs. Finally, NAC was observed to inhibit apoptosis in the hippocampus of SHRs. Collectively, we firstly showed the enhanced accumulation of MG in the hypertensive brain, whereas the clearance of MG by NAC treatment mitigated the aging process and attenuated AGEs generation, neuroinflammation, and oxidative damage.
虽然人们普遍认为高血压中的神经血管功能障碍与脑加速老化密切相关，但我们认为高血压的有害影响可能不仅限于影响动脉。糖酵解产生的甲基乙二醛（MG）参与晚期糖基化终产物（AGEs）的积累，而AGEs是神经退行性疾病的标志。因此，本研究旨在首先探讨MG代谢在高血压加速脑老化过程中的作用。我们的研究结果表明，在12周、16周和30周龄的SHR（自发性高血压大鼠）的血浆和海马中，MG水平随年龄增加。AGE甲基乙二醛 - 氢咪唑啉 - 1（MG - H1）主要定位于星形胶质细胞，而在高血压海马中的神经元和小胶质细胞中未观察到其存在。我们的观察结果还表明，血管紧张素II（Ang II）增强葡萄糖摄取和糖酵解，同时降低培养的星形胶质细胞中Glo1的表达。发现N - 乙酰半胱氨酸（NAC）可抵消30周龄SHR逃避潜伏期的增加，并抑制AGEs - RAGE轴的激活。NAC降低了Iba - 1免疫荧光强度，抑制了促炎标志物的水平，并增强了SHR海马中抗炎标志物的丰度。此外，NAC降低了4 - 羟基壬烯醛（4HNE）的免疫荧光信号，并增加了SHR中谷胱甘肽（GSH）和超氧化物歧化酶（SOD）的含量。最后，观察到NAC抑制SHR海马中的细胞凋亡。总体而言，我们首先表明高血压脑中MG的积累增强，而NAC治疗清除MG可减轻老化过程并减弱AGEs生成、神经炎症和氧化损伤。
