Clozapine attenuates mitochondrial burdens and abnormal behaviors elicited by phencyclidine in mice via inhibition of p47^phox; Possible involvements of phosphoinositide 3-kinase/Akt signaling

Abstract

Our results suggest that p47 gene mediates phencyclidine-induced mitochondrial burdens and abnormal behaviors, and that the interactive modulation between p47 and phosphoinositide 3-kinase/Akt is important for the understanding on the pharmacological mechanism of clozapine.

Akt+ IKKα/β+ Rab5+ Signalosome Mediate the Endosomal Recruitment of Sec61 and Contribute to Cross-Presentation in Bone Marrow Precursor Cells

“…X-linked inhibitor-of-apoptosis protein (XIAP), a physiological substrate of Akt, interact with phosphorylated Akt at serine 87 [ 29 ]. These effects reduce XIAP degradation and decrease cisplatin-stimulated Caspase 3 activity [ 30 , 31 ]. Moreover, Akt phosphorylate Ataxin1 and modulate neurodegeneration 14-3-3 protein, thereby slowing its normal degradation [ 32 ].…”

Clozapine's Multiple Cellular Mechanisms: What Do We Know after More than Fifty Years? a Systematic Review and Critical Assessment of Translational Mechanisms Relevant for Innovative Strategies in Treatment-Resistant Schizophrenia

“…Oxidative stress, as measured by lipid peroxidation, was found elevated in TRS patients compared to antipsychotic-responsive patients, but its relevance for DSP has not yet been investigated (Medina-Hernández, et al, 2007). Although with conflicting evidence (Elmorsy, Al-Ghafari, Aggour, Khan, & Amer, 2017b;Elmorsy, et al, 2017a;Elmorsy, Elzalabany, Elsheikha, & Smith, 2014;Elmorsy & Smith, 2015), clozapine has shown the ability to counter oxidative stress (Sadowska-Bartosz, et al, 2016;Sommer, et al, 2018), protecting cells against DNA damage (Topak, Ozdel, Dodurga, & Secme, 2018), mitochondrial dysfunction (Tran, et al, 2018), death induced by oxygen radicals (Magliaro & Saldanha, 2009), as well as to correct cortico-striatal redox disturbances in SCZ (Möller, et al, 2013). These preclinical observations suggest that antioxidant properties of clozapine may contribute to its peculiar effectiveness in treating re-emergent unresponsive psychotic symptoms in the event of DSP.…”