The Combination of Citicoline and Nicotinamide Mononucleotide Induces Neurite Outgrowth and Mitigates Vascular Cognitive Impairment via SIRT1/CREB Pathway.

IF 3.6 4区 医学 Q3 CELL BIOLOGY
Cellular and Molecular Neurobiology Pub Date : 2023-11-01 Epub Date: 2023-10-09 DOI:10.1007/s10571-023-01416-7
Ning Zhao, Xiaofeng Zhu, Luyang Xie, Xin Guan, Leilei Tang, Guojun Jiang, Tao Pang
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Abstract

Vascular dementia (VD) is characterized with vascular cognitive impairment (VCI), which currently has few effective therapies in clinic. Neuronal damage and white matter injury are involved in the pathogenesis of VCI. Citicoline has been demonstrated to exhibit neuroprotection and neurorepair to improve cognition in cerebrovascular diseases. Nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin (SIRT) signaling pathway constitutes a strong intrinsic defense system against various stresses including neuroinflammation in VCI. Our hypothesis is that the combined use of citicoline and the precursor of NAD+, nicotinamide mononucleotide (NMN), could enhance action on cognitive function in VCI. We investigated the synergistic effect of these two drugs in the rat model of VCI by bilateral common carotid artery occlusion (BCCAO). Citicoline significantly enhanced neurite outgrowth in Neuro-2a cells, and the combination of citicoline and NMN remarkably induced neurite outgrowth in Neuro-2a cells and primary cortical neuronal cells with an optimal proportion of 4:1. In the rat model of BCCAO, when two drugs in combination of 160 mg/kg citicoline and 40 mg/kg NMN, this combination administrated at 7 days post-BCCAO significantly improved the cognitive impairment in BCCAO rats compared with vehicle group by the analysis of the Morris water maze and the novel object recognition test. This combination also decreased microglial activation and neuroinflammation, and protected white matter integrity indicated by the increased myelin basic protein (MBP) expression through activation of SIRT1/TORC1/CREB signaling pathway. Our results suggest that the combination of citicoline and NMN has a synergistic effect for the treatment of VD associated with VCI.

Abstract Image

Citicoline和烟酰胺单核苷酸的组合通过SIRT1/CREB途径诱导Neurite生长并减轻血管认知障碍。
血管性痴呆(VD)以血管性认知障碍(VCI)为特征,目前临床上尚无有效的治疗方法。神经元损伤和白质损伤参与了VCI的发病机制。胞磷胆碱已被证明具有神经保护和神经修复作用,可改善脑血管疾病的认知能力。烟酰胺腺嘌呤二核苷酸(NAD+)依赖性SIRT信号通路构成了一个强大的内在防御系统,可抵御包括VCI神经炎症在内的各种应激。我们的假设是,胞磷胆碱和NAD+的前体烟酰胺单核苷酸(NMN)的联合使用可以增强VCI对认知功能的作用。我们在双侧颈总动脉闭塞大鼠VCI模型中研究了这两种药物的协同作用。胞磷胆碱显著增强了Neuro-2a细胞中的轴突生长,并且胞磷胆碱和NMN的组合以4:1的最佳比例显著诱导了Neuro-2 a细胞和原代皮层神经元细胞中的突起生长。在BCAO大鼠模型中,通过Morris水迷宫和新型物体识别测试的分析,当两种药物联合160mg/kg胞磷胆碱和40mg/kg NMN时,在BCAO后7天给药,与载体组相比,该联合用药显著改善了BCCO大鼠的认知障碍。这种组合还降低了小胶质细胞的激活和神经炎症,并通过激活SIRT1/TORC1/CREB信号通路来保护髓鞘碱性蛋白(MBP)表达增加所表明的白质完整性。我们的结果表明,胞磷胆碱和NMN联合治疗VD伴VCI具有协同作用。
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来源期刊
CiteScore
7.70
自引率
0.00%
发文量
137
审稿时长
4-8 weeks
期刊介绍: Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.
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