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: Alessandro Rimessi, Chiara Pavan, Elli Ioannidi, Federica Nigro, Claudia Morganti, Alberto Brugnoli, Francesco Longo, Chiara Gardin, Letizia Ferroni, Michele Morari, Vincenzo Vindigni, Barbara Zavan, Paolo Pinton
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 42 Issue 7 Pg. 1491-1501 (Jun 2017) ISSN: 1740-634X [Electronic] England
• PMID: 28128334 (Publication Type: Journal Article)

Chemical References

• Antipsychotic Agents
• Enzyme Inhibitors
• Indoles
• Maleimides
• ruboxistaurin
• Protein Kinase C beta
• Clozapine

Topics

• Animals
• Antipsychotic Agents (administration & dosage, toxicity)
• Cells, Cultured
• Clozapine (administration & dosage, toxicity)
• Drug Delivery Systems
• Enzyme Inhibitors (administration & dosage)
• Indoles (administration & dosage)
• Male
• Maleimides (administration & dosage)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Protein Kinase C beta (antagonists & inhibitors, deficiency)
• Time Factors
• Weight Gain (drug effects, physiology)