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

Radwa S Raafat; Mohamed Z Habib; Amany A AbdElfattah; Nouran K Olama; Sahar M Abdelraouf; Nevien Hendawy; Khaled A Kamal; Salwa A Nawishy; Sawsan Aboul-Fotouh

doi:10.1016/j.intimp.2023.110945

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

Int Immunopharmacol. 2023 Nov;124(Pt A):110945. doi: 10.1016/j.intimp.2023.110945. Epub 2023 Sep 14.

Authors

Radwa S Raafat¹, Mohamed Z Habib², Amany A AbdElfattah³, Nouran K Olama⁴, Sahar M Abdelraouf⁵, Nevien Hendawy⁶, Khaled A Kamal⁷, Salwa A Nawishy¹, Sawsan Aboul-Fotouh¹

Affiliations

¹ Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
² Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Faculty of Medicine, King Salman International University, El-Tor, South Sinai, Egypt. Electronic address: Mohamed.habib@med.asu.edu.eg.
³ Department of Medical Histology and Cell Biology, Faculty of Medicine, Mansoura University, El-Mansoura, Egypt; Faculty of Medicine, King Salman International University, El-Tor, South Sinai, Egypt.
⁴ Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
⁵ Department of Biochemistry, Faculty of Pharmacy, Misr International University, Cairo, Egypt.
⁶ Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Faculty of Medicine, Galala University, Suez, Egypt.
⁷ Department of Clinical Oncology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

PMID: 37716161
DOI: 10.1016/j.intimp.2023.110945

Abstract

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.

Keywords: 5-Fluorouracil; Amisulpride; BDNF; Cognitive Dysfunction; Neuroinflammation; Wnt/β catenin pathway.

MeSH terms

Amisulpride / pharmacology
Animals
Brain-Derived Neurotrophic Factor* / metabolism
Cognition
Cognitive Dysfunction* / chemically induced
Cognitive Dysfunction* / drug therapy
Cognitive Dysfunction* / metabolism
Fluorouracil / pharmacology
Glycogen Synthase Kinase 3 beta / metabolism
Hippocampus
Humans
Rats
Rats, Wistar
Wnt Signaling Pathway
beta Catenin / metabolism

Substances

Glycogen Synthase Kinase 3 beta
Brain-Derived Neurotrophic Factor
Amisulpride
Fluorouracil
beta Catenin