Study on ceramide modulates EAAT-2 participation in the immunoinflammatory response in schizophrenia

W.-M. Ling, M.-C. Chen, Y.-C. Zhang, M.-M. Ou, L.-Z. Gu

Department of Laboratory Medicine, The Affiliated Wuxi Mental Health Center of Nanjing Medical University, Wuxi, P. R. China. mayamaha@163.com

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• Pharmacology

OBJECTIVE: Abnormal immunoinflammatory responses play important roles in the pathogenesis of schizophrenia, but the underlying molecular mechanisms are still unclear.

MATERIALS AND METHODS: In this study, the ceramide agonist daunorubicin (DNR) was injected into the lateral ventricles to induce ceramide accumulation. The behavioral tests were used to observe schizophrenia-like behavioral changes. Changes in the mRNA levels of the proinflammatory cytokines and the protein levels of the glutamate transporter excitatory amino acid transporter-2 (EAAT-2) were detected. After inhibition of nuclear factor-κB (NF-κB), the above indices were detected again. Nissl staining was used to assess neuronal damage.

RESULTS: After intracerebroventricular injection of DNR, ceramide significantly accumulated in the hippocampus, and behavioral tests revealed negative schizophrenia symptoms accompanied by induced learning and memory dysfunction. Furthermore, the hippocampus demonstrated increased mRNA levels of the proinflammatory cytokines including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) and significantly decreased EAAT-2 protein levels. Nissl staining revealed neuronal damage after ceramide accumulation. The NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) reduced the behavioral abnormalities caused by ceramide accumulation, downregulated

CONCLUSIONS: The experimental results suggest that ceramide reduces EAAT-2 expression through the NF-κB/TNF-α pathway and causes neuronal excitotoxicity in the pathogenesis of schizophrenia, leading to neuronal damage.

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