Amisulpride attenuates 5-fluorouracil-induced cognitive deficits via modulating hippocampal Wnt/GSK-3β/β-catenin signaling in Wistar rats

• Published in: International immunopharmacology Vol. 124; no. Pt A; p. 110945
• Main Authors: Raafat, Radwa S., Habib, Mohamed Z., AbdElfattah, Amany A., Olama, Nouran K., Abdelraouf, Sahar M., Hendawy, Nevien, Kamal, Khaled A., Nawishy, Salwa A., Aboul-Fotouh, Sawsan
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.11.2023
• Subjects: 5-Fluorouracil; Amisulpride; BDNF; Cognitive Dysfunction; Neuroinflammation; Wnt/β catenin pathway; Cognitive Dysfunction; Amisulpride; Neuroinflammation; 5-Fluorouracil; Wnt/β catenin pathway; BDNF
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2023.110945

[Display omitted] •5-FU induced impairments in spatial and non-spatial learning in rats.•5-FU decreased Wnt/GSK-3β/β-catenin activity and BDNF level in the hippocampus.•5-FU increased hippocampal TNF-α, IL-1β, β-amyloid, and caspase-3 expression.•AMI enhanced hippocampal Wnt/GSK-3β/β-catenin signaling and increased BDNF levels.•AMI abrogated 5-FU-induced cellular changes and improved cognitive performance. 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.