title: Protein Kinase C β: a New Target Therapy to Prevent the Long-Term Atypical Antipsychotic-Induced Weight Gain.
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 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 PKCβ 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 PKCβ knockout mice to investigate the contribution of endogenous PKCβ 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 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.
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Alessandro
authors.identifier: http://orcid.org/0000-0001-7091-5765
authors.initials: A
authors.lastname: Rimessi
authors.affiliation: Unit of Psychiatry, Department of Neurosciences NPSRR, University of Padua, Padua, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pavan
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Elli
authors.initials: E
authors.lastname: Ioannidi
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Nigro
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Morganti
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, Neuroscience Center and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Brugnoli
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, Neuroscience Center and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Longo
authors.affiliation: Department of Biomedical Sciences, University of Padua, Padua, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Gardin
authors.affiliation: Department of Biomedical Sciences, University of Padua, Padua, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Ferroni
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, Neuroscience Center and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
authors.affiliation: Unit of Plastic Surgery, Department of Neurosciences NPSRR, University of Padua, Padua, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Vindigni
authors.affiliation: Department of Biomedical Sciences, University of Padua, Padua, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Zavan
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000633:toxicity; D002478:Cells, Cultured; D003024:Clozapine / Q000008:administration & dosage* / Q000633:toxicity; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008301:Maleimides / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors* / Q000172:deficiency*; D013997:Time Factors; D015430:Weight Gain / Q000187:drug effects* / Q000502:physiology
chemical_list: D014150:Antipsychotic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D064546:Protein Kinase C beta; D003024:Clozapine