Investigating the therapeutic potential of naringin in MK-801-induced schizophrenia model: focus on cognitive impairment and miR-25-3p-regulated pathways.

Abstract

Aim: The aim of this study was to assess the ameliorative effects of naringin (NR) on cognitive impairment in schizophrenia(SZ) from multiple perspectives using behavioral, histopathological and molecular biological approaches.

Materials and methods: SZ models were established in rats via acute intraperitoneal injection of MK-801 in all groups except the control group, which received saline. Cognitive function was assessed using the Morris water maze test 21 days after prophylactic NR administration. Subsequently, Serum interleukin-6 (IL-6) and homocysteine (HCY) levels were quantified using enzyme-linked immunosorbent assay (ELISA), and hippocampal neuronal and synaptic structures were observed via microscopy. Molecular detection was performed using real-time reverse transcription polymerase chain reaction (RT-qPCR) and western blotting (WB) to assess the expression levels of molecules related to the microRNA-25-3p/salt inducible kinase 1/CREB regulated transcription coactivator 2/cAMP responsive element binding protein 1 (miR-25-3p/SIK1/CRTC2/CREB1) pathway, thereby elucidating the mechanism by which NR ameliorates cognitive impairment in SZ.

Results: NR was found to mitigate cognitive decline in learning and memory induced by MK-801. It lowered serum levels of IL-6 and HCY, reduced neuronal damage in the CA1 region of the hippocampus, increased the thickness of postsynaptic dense material, decreased the distance between synaptic gaps, decreased the expression of SIK1, and elevated the expression of miR-25-3p, CRTC2 and CREB1 in the hippocampus.

Conclusion: NR may protect neurons in the CA1 region of the hippocampus and enhance synaptic plasticity by regulating the miR-25-3p/SIK1/CRTC2/CREB1 signaling pathway, thereby promoting cognitive improvement.