Citicoline sodium salt is the water-soluble form of citicoline, which is a natural intermediate in the biosynthesis of phosphatidylcholine. Citicoline sodium salt serves as a precursor to acetylcholine and phosphatidylcholine in the brain and has biological functions that include inhibiting the production of reactive oxygen species (ROS) and apoptosis[1]. Citicoline promotes the synthesis of phosphatidylcholine, a major component of cell membranes, thereby supporting the integrity and function of neuronal membranes[2]. Additionally, citicoline enhances the release of neurotransmitters such as dopamine and norepinephrine, which helps improve cognitive function and provides neuroprotection[3]. Citicoline has also been shown to increase cerebral blood flow and glucose metabolism, both of which are crucial for maintaining brain health and cognitive performance[4].
In vitro, pre-treatment of auditory hair cell-like HEI-OC-1 cells with Citicoline sodium salt (10µM) for 12 hours, followed by co-treatment with 10mM neomycin for 24 hours and subsequent recovery in culture medium containing Citicoline sodium salt for 12 hours, significantly reduced neomycin-induced apoptosis, decreased ROS levels, inhibited the decline in mitochondrial membrane potential (MMP), and upregulated the expression of antioxidant genes (Gsr, Sod1, and Glrx) while downregulating the expression of the pro-oxidant gene Alox15. These effects protected the cells from neomycin-induced damage[5]. In a primary retinal cell neurotoxicity model exposed to glutamate and high glucose, combined treatment with Citicoline sodium salt (100µM) and homotaurine significantly reduced apoptosis induced by glutamate and high glucose and synergistically enhanced cell survival, demonstrating stronger neuroprotective effects than either compound alone[6].
In vivo, oral administration of Citicoline sodium salt (200mg/kg, 500mg/kg, and 1000mg/kg) to mice exposed to sodium arsenite (NaAsO₂, 50ppm) for 2 weeks significantly reduced ALT and AST levels in mice, decreased ROS and TBARS levels, and increased the activities of CAT, SOD, and GPx. Additionally, Citicoline sodium salt lowered pro-inflammatory cytokine levels (TNF-α and IL-6), improved insulin secretion function, and alleviated sodium arsenite-induced hepatotoxicity and impaired glucose tolerance[7]. In a mice model of intracerebral hemorrhage (ICH), intraperitoneal injection of Citicoline sodium salt (500mg/kg) three times before and at 24 and 48 hours after ICH induction significantly improved neurological function scores and reduced the volume of ischemic injury surrounding the hemorrhagic area[8].
References:
[1] Bermejo PE, Dorado R, Zea-Sevilla MA. Role of Citicoline in Patients With Mild Cognitive Impairment. Neurosci Insights. 2023 Feb 16;18:26331055231152496.
[2] Gareri P, Castagna A, Cotroneo AM, et al. The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives. Clin Interv Aging. 2015 Sep 3;10:1421-9.
[3] Saver JL. Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair. Rev Neurol Dis. 2008 Fall;5(4):167-77.
[4] Mulè S, Ferrari S, Rosso G, et al. The Combined Effect of Green Tea, Saffron, Resveratrol, and Citicoline against Neurodegeneration Induced by Oxidative Stress in an In Vitro Model of Cognitive Decline. Oxid Med Cell Longev. 2024 Oct 1;2024:7465045.
[5] Zhong Z, Fu X, Li H, et al. Citicoline Protects Auditory Hair Cells Against Neomycin-Induced Damage. Front Cell Dev Biol. 2020 Aug 31;8:712.
[6] Davinelli S, Chiosi F, Di Marco R, et al. Cytoprotective Effects of Citicoline and Homotaurine against Glutamate and High Glucose Neurotoxicity in Primary Cultured Retinal Cells. Oxid Med Cell Longev. 2017;2017:2825703.
[7] Meyer N, Brodowski L, Richter K, et al. Pravastatin Promotes Endothelial Colony-Forming Cell Function, Angiogenic Signaling and Protein Expression In Vitro. J Clin Med. 2021 Jan 6;10(2):183.
[8] Clark W, Gunion-Rinker L, Lessov N, et al. Citicoline treatment for experimental intracerebral hemorrhage in mice. Stroke. 1998 Oct;29(10):2136-40.
Citicoline sodium salt是胞磷胆碱的水溶性形式，胞磷胆碱是磷脂酰胆碱合成过程中的天然中间体，作为乙酰胆碱和磷脂酰胆碱在大脑中的前体，具有抑制活性氧（ROS）产生和细胞凋亡的生物学功能[1]。胞磷胆碱可促进磷脂酰胆碱的合成，磷脂酰胆碱是细胞膜的主要成分，支持神经细胞膜的完整性和功能[2]。胞磷胆碱还增强多巴胺和去甲肾上腺素等神经递质的释放，有助于改善认知功能和神经保护[3]。胞磷胆碱已被证明可以增加脑血流和葡萄糖代谢，这对于维持大脑健康和认知表现至关重要[4]。
在体外，Citicoline sodium salt（10µM）预处理听觉毛细胞样HEI-OC-1细胞12小时后，再与10mM新霉素共处理24小时，随后在含有Citicoline sodium salt的培养基中恢复培养12小时。Citicoline sodium salt显著降低了新霉素诱导的细胞凋亡率，减少了活性氧（ROS）水平，抑制了线粒体膜电位（MMP）的下降，并上调了抗氧化基因（Gsr、Sod1和Glrx）的表达，同时下调了促氧化基因Alox15的表达，从而保护细胞免受新霉素诱导的损伤[5]。Citicoline sodium salt（100µM）与同型牛磺酸（Homotaurine）联合处理原代视网膜细胞神经毒性模型（暴露于谷氨酸和高浓度葡萄糖），Citicoline sodium salt与同型牛磺酸的联合处理显著降低了谷氨酸和高葡萄糖诱导的视网膜细胞凋亡率，并协同增强了细胞的存活率，表现出比单独使用任一化合物更强的神经保护效果[6]。
在体内，Citicoline sodium salt（200mg/kg，500mg/kg和1000mg/kg）通过口服给药处理暴露于亚砷酸钠（NaAsO₂，50ppm）的小鼠，持续2周，Citicoline sodium salt显著降低了小鼠的ALT和AST水平，减少了ROS和TBARS水平，并提升了CAT、SOD和GPx的活性。此外，Citicoline sodium salt还降低了促炎细胞因子（TNF-α和IL-6）水平，改善了胰岛素分泌功能，减轻了亚砷酸钠诱导的肝毒性及血糖耐受不良反应[7]。Citicoline sodium salt（500mg/kg）通过腹腔注射治疗用于诱导脑出血（ICH）的小鼠，分别在诱导ICH前及ICH发生后24小时和48小时给予3次给药，Citicoline sodium salt显著改善了小鼠的神经功能评分，降低了脑出血周围缺血损伤的体积[8]。