化疗引起的认知功能障碍（Chemotherapy-induced cognitive impairment，CICI）是指在化疗药物治疗期间或治疗后出现的认知功能障碍。CICI由于其不断增加的发病率以及缺乏强有力的治疗方法而成为一个重大的医学问题。本研究旨在探究慢性氨硫地平（每日5mg/kg）治疗5-氟尿嘧啶（5-FU）引起的Wistar大鼠认知缺陷的效果。大鼠接受5次腹腔注射5-FU（每3天25mg/kg）。5-FU治疗导致空间学习（物体位置辨别比）和非空间学习（新奇物体识别辨别比）的损害。此外，5-FU引起了Wnt/GSK-3β/β-连环蛋白通路活性的降低，并伴有海马区脑源性神经营养因子（BDNF）水平降低。这些变化与炎症细胞因子肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）的表达增加、海马区有核细胞增殖能力减少、Nissl小体光密度减少（表示神经细胞退行性变）、活性完整神经元数量减少伴随β-淀粉样和半胱氨酸天冬酶-3的表达增加相联系。氨硫地平增强了Wnt/GSK-3β/β-连环蛋白信号传导，增加了BDNF水平，并取消了5-FU引起的神经炎症、细胞凋亡、β-淀粉样沉积和神经退行性变，改善了认知功能。该研究引起了对氨硫地平在5-FU暴露大鼠中的促认知效应的关注，这可能是通过增强海马Wnt/GSK-3β/β-连环蛋白信号传导途径实现的，这为CICI患者提供了一种有前景的治疗选择。 Copyright © 2023 Elsevier B.V. All rights reserved.

Chemotherapy-induced cognitive impairment (CICI) is a general term describing cognitive dysfunction during/after treatment with chemotherapeutic agents. CICI represents a significant medical problem due to its increasing prevalence with the lack of robust therapeutic approaches. This study aimed at investigating the effects of chronic treatment with amisulpride (5 mg/kg/day) in the management of 5-fluorouracil (5-FU)-induced cognitive deficits in Wistar rats. Rats received 5 intraperitoneal injections of 5-FU (25 mg/kg every 3 days). 5-FU treatment induced impairments in spatial learning (reduction in object location discrimination ratio) and non-spatial learning (reduction in novel object recognition discrimination ratio). Moreover, 5-FU induced a decrease in the activity of the Wnt/GSK-3β/β-catenin pathway with a decrease in brain-derived neurotrophic factor (BDNF) level in the hippocampus. These changes were associated with an increase in the expression of the pro-inflammatory cytokines; tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), in hippocampal tissue sections accompanied by a decrease in the number of Ki-67 positive cells (indicating a decrease in proliferative capacity), a decrease in the Nissl's granules optical density (denoting neurodegeneration), a decrease in the number of viable intact neurons with an increase in the expression of β-amyloid and caspase-3. Amisulpride enhanced Wnt/GSK-3β/β-catenin signaling, increased BDNF levels, and abrogated 5-FU-induced neuroinflammation, apoptosis, β-amyloid accumulation, and neurodegenerative changes with an improvement of cognitive performance. This study draws attention to the pro-cognitive effects of amisulpride in 5-FU-exposed rats that could be attributed to enhancing hippocampal Wnt/GSK-3β/β-catenin signaling pathway, and this could offer a promising therapeutic option for subjects with CICI.Copyright © 2023 Elsevier B.V. All rights reserved.