Urolithin a Alleviates Schizophrenia-Like Cognitive Impairments in Male Rats Following Maternal Separation

Abstract

Background: Cognitive impairment in schizophrenia emerges early in the disease. The lack of new and effective preventive and therapeutic medications presents significant challenges in alleviating this impairment. Urolithin A (UA), a gut microbial metabolite of ellagic acid, has shown neuroprotective effects in various neurological disease models. However, its neuromodulatory effects in the schizophrenia remain unclear. In this study, we investigated the behavioral and molecular effects of UA in a stable schizophrenia rat model.Methods: Firstly, Wistar rat pups at postnatal day 9 were subjected to 24 hours of maternal separation to establish a model of cognitive impairment in schizophrenia. The regulatory mechanisms of UA on neuronal function at different administration times and concentrations were explored. The improvement in cognitive function by UA was evaluated through behavioral tests. Immunofluorescence staining was used to detect hippocampal neurogenesis and glial cell proliferation. Western blot analysis was employed to measure the expression levels of brain-derived neurotrophic factor (BDNF) and the phosphorylation levels of extracellular signal-regulated kinase (ERK).Results: Male maternal separation offspring rats exhibit increased susceptibility to schizophrenia-like behavioral and cognitive dysfunctions, accompanied by severe neuroinflammation and impaired neurogenesis. UA attenuates maternal separation induced schizophrenia-like behavioral and cognitive impairments in a dose-dependent manner and restores hippocampal neurogenesis. UA treatment exerts anti-inflammatory effects by inhibiting microglial activation and the expression of proinflammatory cytokines TNF-α, IL-6, and IL-1β. The potential mechanism involves upregulation of BDNF protein expression and activation of the ERK signaling pathway.Conclusions: This is the first preclinical evaluation of the effects of UA on cognitive function in a schizophrenia model. Our results suggest that neuroinflammation, neurogenesis, and synaptic plasticity collectively contribute to cognitive changes in schizophrenia and that UA can reverse these processes. These insights open up new avenues for developing drugs to prevent and treat schizophrenia.

Note:
Funding declaration: This study was supported by the National Natural Science Foundation of China (No.31770381) and Wu Jieping Medical Foundation of China (No.320.6750.2023-25- 6).

Conflict of Interests: There are no conflicts of interest.

Ethical Approval: All animal experiments comply with the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines and were approved by the Institutional Animal Care Committee of Renmin Hospital of Wuhan University. The approved protocol number is WDRM20230310D.

Keywords: schizophrenia, cognitive function, urolithin A