Antipsychotic drugs are currently used in clinical practice for a variety of mental disorders. Among them, clozapine is the most effective medication for treatment-resistant schizophrenia and is most helpful in controlling aggression and the suicidal behavior in schizophrenia and schizoaffective disorder. Although clozapine is associated with a low likelihood of extrapyramidal symptoms and other neurological side effects, it is well-known for the weight gain and metabolic side effects, which expose the patient to a greater risk of cardiovascular disorders, premature death, as well as psychosocial issues leading to non-adherence to therapy. The mechanisms underlying these iatrogenic metabolic disorders are still controversial. We have therefore investigated the in vivo effects of the selective PKCβ inhibitor, Ruboxistaurin (LY-333531), in a pre-clinical model of long-term clozapine-induced weight gain. Cell biology, biochemistry and behavioral tests have been performed in wild type and PKCβ knockout mice to investigate the contribution of endogenous PKCβ and its pharmacological inhibition to the psychomotor effects of clozapine. Lastly, we also shed light on a novel aspect of the mechanism underlying the clozapine-induced weight gain, demonstrating that the clozapine-dependent PKCβ activation promotes the inhibition of the lipid droplet-selective autophagy process. This paves the way to new therapeutic approaches to this serious complication of clozapine therapy.

Protein Kinase C β: a New Target Therapy to Prevent the Long-Term Atypical Antipsychotics-Induced Weight-Gain.

RIMESSI, Alessandro;MORGANTI, Claudia;BRUGNOLI, Alberto;LONGO, Francesco;FERRONI, Letizia;MORARI, Michele;Zavan, B;PINTON, Paolo
2017

Abstract

Antipsychotic drugs are currently used in clinical practice for a variety of mental disorders. Among them, clozapine is the most effective medication for treatment-resistant schizophrenia and is most helpful in controlling aggression and the suicidal behavior in schizophrenia and schizoaffective disorder. Although clozapine is associated with a low likelihood of extrapyramidal symptoms and other neurological side effects, it is well-known for the weight gain and metabolic side effects, which expose the patient to a greater risk of cardiovascular disorders, premature death, as well as psychosocial issues leading to non-adherence to therapy. The mechanisms underlying these iatrogenic metabolic disorders are still controversial. We have therefore investigated the in vivo effects of the selective PKCβ inhibitor, Ruboxistaurin (LY-333531), in a pre-clinical model of long-term clozapine-induced weight gain. Cell biology, biochemistry and behavioral tests have been performed in wild type and PKCβ knockout mice to investigate the contribution of endogenous PKCβ and its pharmacological inhibition to the psychomotor effects of clozapine. Lastly, we also shed light on a novel aspect of the mechanism underlying the clozapine-induced weight gain, demonstrating that the clozapine-dependent PKCβ activation promotes the inhibition of the lipid droplet-selective autophagy process. This paves the way to new therapeutic approaches to this serious complication of clozapine therapy.
Rimessi, Alessandro; Pavan, C; Ioannidi, E; Nigro, F; Morganti, Claudia; Brugnoli, Alberto; Longo, Francesco; Gardin, C; Ferroni, Letizia; Morari, Michele; Vindigni, V; Zavan, B; Pinton, Paolo
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11392/2363641
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