Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Pain Research Center, Neuroscience Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.
Drug Dev Res. 2024 Nov;85(7):e70001. doi: 10.1002/ddr.70001.
Dementia develops as a result of multiple factors, including cerebrovascular disease which is called vascular dementia (VD). Histone-3 lysine-9 dimethylation (H3K9me2) broadly increases during VD and inhibits neuroprotective gene expressions. So, we aimed to determine how H3K9me2 inhibitor (BIX01294) affects neuronal damage in VD. An in vivo model of VD was used followed by BIX01294 treatment. Behavioral tests, hematoxylin, and eosin (H&E), Congo red, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were carried out. Hippocampal phosphorylated cyclic-AMP responsive element binding protein (p-CREB), c-fos, brain-derived neurotrophic factor (BDNF), and H3K9me2, were detected by western blot analysis technique. Neurological deficit and anxiety-related behavior significantly reduced in the treatment group compared to the VD group (p < 0.05). BIX01294 improved spatial and passive avoidance memory (p < 0.01 and p < 0.05, respectively) compared to the VD group. Treatment with BIX01294 restored the level of p-CREB/CREB ratio (p < 0.05), cfos (p < 0.01), BDNF (p < 0.01), and suppressed H3K9me2 (p < 0.001) when compared to the VD group. BIX01294 microinjection reduced the apoptosis level in TUNEL staining (p < 0.05), and raised neural cell count in H&E staining (p < 0.01); amyloid beta accumulation significantly decreased in the treatment group (p < 0.05) compared to the VD group. In conclusion, long-term treatment with a low dose of BIX01294 can prevent the progression of neuronal loss in VD model by raising the expression of neurotrophic factors, and reducing the apoptosis level.
痴呆是由多种因素引起的，包括称为血管性痴呆（VD）的脑血管疾病。在 VD 期间，组蛋白-3 赖氨酸-9 二甲基化（H3K9me2）广泛增加，并抑制神经保护基因的表达。因此，我们旨在确定 H3K9me2 抑制剂（BIX01294）如何影响 VD 中的神经元损伤。使用 VD 的体内模型，然后进行 BIX01294 治疗。进行行为测试、苏木精和伊红（H&E）、刚果红和末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）染色。通过 Western blot 分析技术检测海马磷酸化环 AMP 反应元件结合蛋白（p-CREB）、c-fos、脑源性神经营养因子（BDNF）和 H3K9me2。与 VD 组相比，治疗组的神经功能缺损和焦虑相关行为显著减少（p<0.05）。与 VD 组相比，BIX01294 改善了空间和被动回避记忆（p<0.01 和 p<0.05）。与 VD 组相比，BIX01294 恢复了 p-CREB/CREB 比值（p<0.05）、cfos（p<0.01）、BDNF（p<0.01）的水平，并抑制了 H3K9me2（p<0.001）。与 VD 组相比，BIX01294 微注射减少了 TUNEL 染色中的凋亡水平（p<0.05），并增加了 H&E 染色中的神经细胞计数（p<0.01）；与 VD 组相比，治疗组的淀粉样β积累显著减少（p<0.05）。总之，长期低剂量 BIX01294 治疗可以通过提高神经营养因子的表达和降低凋亡水平来防止 VD 模型中神经元丢失的进展。
