Data_Sheet_1_Neuroprotective Effects of Ceftriaxone Involve the Reduction of Aβ Burden and Neuroinflammatory Response in a Mouse Model of Alzheimer’s Disease.docx

Ceftriaxone (CEF) is a safe and multipotent antimicrobial agent that possesses neuroprotective properties. Earlier, we revealed the restoration of cognitive function in OXYS rats with signs of Alzheimer’s disease (AD)-like pathology by CEF along with its modulating the expression of genes related to the system of amyloid beta (Aβ) metabolism in the brain. The aim of this study was to determine the effects of CEF on behavior, Aβ deposition, and associated neuroinflammation using another model of an early AD-like pathology induced by Aβ. Mice were injected bilaterally i.c.v. with Aβ fragment 25–35 to produce the AD model, while the CEF treatment (100 mg/kg/day, i.p., 36 days) started the next day after the surgery. The open field test, T-maze, Barnes test, IntelliCage, and passive avoidance test were used for behavioral phenotyping. Neuronal density, amyloid accumulation, and the expression of neuroinflammatory markers were measured in the frontal cortex and hippocampus. CEF exhibited beneficial effects on some cognitive features impaired by Aβ neurotoxicity including complete restoration of the fear-induced memory and learning in the passive avoidance test and improved place learning in the IntelliCage. CEF significantly attenuated amyloid deposition and neuroinflammatory response. Thus, CEF could be positioned as a potent multipurpose drug as it simultaneously targets proteostasis network and neuroinflammation, as well as glutamate excitotoxicity, oxidative pathways, and neurotrophic function as reported earlier. Together with previous reports on the positive effects of CEF in AD models, the results confirm the potential of CEF as a promising treatment against cognitive decline from the early stages of AD progression.

头孢曲松钠（CEF）是一种安全且多效的抗菌剂，兼具神经保护特性。此前，我们揭示了CEF通过调节大脑中与淀粉样β（Aβ）代谢相关的基因表达，能够恢复OXYS大鼠认知功能，并改善其类似阿尔茨海默病（AD）病理学的症状。本研究旨在通过Aβ诱导的早期AD样病理模型，确定CEF对行为、Aβ沉积和相关神经炎症的影响。将Aβ片段25-35通过双侧脑室内注射的方式引入小鼠模型，而CEF治疗（100 mg/kg/天，腹腔注射，持续36天）则从手术次日开始。开放场测试、T迷宫、Barnes测试、IntelliCage和被动回避测试被用于行为表型分析。在额叶皮层和海马体中，测量了神经元密度、淀粉样蛋白积累和神经炎症标志物的表达。CEF在改善由Aβ神经毒性引起的某些认知功能障碍方面表现出益处，包括在被动回避测试中恐惧记忆和学习能力的完全恢复，以及在IntelliCage中空间学习能力的提高。CEF显著减轻了淀粉样蛋白沉积和神经炎症反应。因此，CEF作为一种能够同时靶向蛋白稳态网络、神经炎症、以及如先前报道的谷氨酸兴奋毒性、氧化途径和神经营养功能的强大多效药物，具有其独特的地位。结合先前关于CEF在AD模型中积极效果的报道，这些结果进一步证实了CEF作为对抗AD早期阶段认知能力下降的潜在治疗药物的潜力。