Journal
NEUROPSYCHOPHARMACOLOGY
Volume 42, Issue 7, Pages 1491-1501Publisher
SPRINGERNATURE
DOI: 10.1038/npp.2017.20
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Funding
- University of Ferrara
- Italian Ministry of Health [GR-2011-02346964]
- Italian Cystic Fibrosis Foundation [20/2015]
- Italian Association for Cancer Research (AIRC) [IG-18624]
- Telethon [GGP15219B]
- Italian Ministry of Health
- Italian Ministry of Education, University and Research [COFIN: 20129JLHSY_ 002, FIRB: RBAP11FXBC_ 002, Futuro in Ricerca: RBFR10EGVP_ 001]
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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 and 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 PKC beta inhibitor, ruboxistaurin (LY-333531), in a preclinical model of long-term clozapine-induced weight gain. Cell biology, biochemistry, and behavioral tests have been performed in wild-type and PKC beta knockout mice to investigate the contribution of endogenous PKC beta and its pharmacological inhibition to the psychomotor effects of clozapine. Finally, we also shed light on a novel aspect of the mechanism underlying the clozapine-induced weight gain, demonstrating that the clozapine-dependent PKC beta 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.
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