Clozapine influences cytoskeleton structure and calcium homeostasis in rat cerebral cortex and has a different proteomic profile than risperidone.

Abstract

For over the last 50years, the molecular mechanism of anti-psychotic drugs' action has been far from clear. While risperidone is very often used in clinical practice, the most efficient known anti-psychotic drug is clozapine (CLO). However, the biochemical background of CLO's action still remains elusive. In this study, we performed comparative proteomic analysis of rat cerebral cortex following chronic administration of these two drugs. We observed significant changes in the expression of cytoskeletal, synaptic, and regulatory proteins caused by both antipsychotics. Among other proteins, alterations in collapsin response mediator proteins, CRMP2 and CRMP4, were the most spectacular consequences of treatment with both drugs. Moreover, risperidone increased the level of proteins involved in cell proliferation such as fatty acid-binding protein-7 and translin-associated factor X. CLO significantly up-regulated the expression of visinin-like protein 1, neurocalcin δ and mitochondrial, stomatin-like protein 2, the calcium-binding proteins regulating calcium homeostasis, and the functioning of ion channels and receptors. Using two-dimensional differential electrophoresis, we demonstrate that chronic treatment the healthy rats with anti-psychotics, clozapine and risperidone, induce changes in expression of cytoskeletal, synaptic, and regulatory proteins in the cerebral cortex. While risperidone increases the level of proteins regulating cell proliferation, namely, fatty acid-binding protein-7 and translin-associated factor X, the clozapine significantly up-regulates calcium sensors, i.e., visinin-like protein 1 and neurocalcin δ. 2D DIGE, Differential in Gel Electrophoresis; Cy2, Cy3, and Cy5 are cyanine dyes.