¹Yangzhou University Medical College, Jiangsu Key Laboratory of Experimental and Translational Non-Coding RNA Research, Yangzhou, China, ²Yangzhou University Medical College, Department of Pharmacy, Yangzhou, China

Background: Schizophrenia (SCZ) is a devastating mental disorder. Development or discovery of new drugs or compounds to treat SCZ is of great importance. A nanozyme-based artificial peroxisome (FeN pero-nanozysome) was reported to be effective in ameliorating neurological diseases, previously.

Aims & Objectives: In this study, the in vivo effects and underlying mechanism of FeN pero-nanozysome on alleviating SCZ-like abnormalities were explored.

Method: MTT assay and Calcein/PI staining with PC12 cells treated with MK-801 were first carried out to assess the neuroprotective effects of FeN pero-nanozysome. A developmental SCZ mouse model employing 3-week repeated MK-801 administration and 1-week follow-up FeN pero-nanozysome administration was then established. Open-field, novel object recognition, forced swimming, rotarod, Y-maze tests were performed to examine the therapeutic effects of FeN pero-nanozysome on behavioural abnormalities. Furthermore, transcriptomics and metabolomics with the hippocampal tissue were employed to explore its underlying mechanism.

Results: The in vitro experiments showed a neuroprotective effect of FeN pero-nanozysome on the PC12 cells against MK-801. Behavioural experiments indicated that FeN pero-nanozysome was able to alleviate various MK-801-induced SCZ-like behavioural abnormalities. Transcriptomics data revealed 166 differentially-expressed genes caused by FeN pero-nanozysome. Additionally, 145 differentially-expressed metabolites (DEMs) were found after the FeN pero-nanozysome administration. An integrated analysis of metabolomics and transcriptomics further revealed that Pla2g4f- and Cyp3a13-correlated phosphatidylcholine and phosphatidylethanolamine pathways might be involved in the pharmacological mechanism of FeN pero-nanozysome.

Discussion & Conclusions: Our findings together showed the alleviating effects of FeN pero-nanozysome on SCZ-like abnormalities and investigated its underlying mechanism, suggesting the potential clinical application of FeN pero-nanozysome for treating schizophrenia.