Abstract

Potential Benefits of Melatonergic Treatment in Schizophrenia: Ameliorating Demyelination via Inhibiting CDK5-Mediated Hyper Autophagy

Author(s): Dayun Feng, Gaohua Liu, Baolin Guo, Min Cai, Kai Tao, Han Yao, Rui Lu, Shengxi Wu

 Objective

Impairment of melatonergic activity, including alteration of melatonin secretion and melatonin receptor (MT) modifications, has been linked to the pathophysiology of schizophrenia. However, its definite therapeutic effect on schizophrenia-like symptoms and the biological mechanism are still illusive. The present study aimed to explore the potential benefis of melatonergic treatment in schizophrenia and underlying molecular mechanism.

Methods

A cuprizone (CPZ) -induced schizophrenic mice model was established. Agomelatine, a MT1 and MT2 agonist, was administrated intraperitoneally. Open field, three-chamber and Y-maze tests were performed for evaluation of behavioral and cognitive deficits. The myelination was examined in corpus striatum of mice. In vitro, alterations of cyclin-dependent kinase 5 (CDK5) expression, autophagic flux and apoptotic index were detected in OLN93 oligodendrocytes.

Results

We demonstrate that treatment with agomelatine exerts a significant improvement of the behavioral and cognitive deficits in CPZ-induced schizophrenic mice. Agomelatine also suppresses the excessive autophagy and rescues the myelination in corpus striatum in CPZtreated mice. Notably, all these effects of agomelatine are markedly weakened by an autophagy inducer Rapamycin (RAPA). In vitro, cuprizone dose- and time-dependently induces excessive autophagy and autophagic flux, therefore depresses cell viability in oligodendrocytes. Interestingly, CDK5 exerts positive regulation in CPZ-induced autophagy, revealing that CDK5 overexpression enhances LC3â�?�?¡ level and autophagosome formation in company with cuprizone treatment, while CDK5 knockdown works conversely. Importantly, agomelatine suppresses CDK5 expression and autophagic flux against cuprizone, which to the contrary is blocked by CDK5. Meanwhile, agomelatine also inhibits stress-associated activation of p38 and c-Jun-N-terminal Kinase (JNK) induced by cuprizone in CDK5-dependent manner, as well as reducing cellular apoptosis.

Conclusion

The present findings, for the first time, link autophagy-demyelination in schizophrenia, and strongly suggest that melatinergic treatment possesses potential benefits against schizophrenia through ameliorating demyelination by inhibiting CDK5-mediated autophagy.