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

Hai Quyen Tran, Se J. Park, Eun Joo Shin, The Vinh Tran, Naveen Sharma, Yu J. Lee, Ji H. Jeong, Choon Gon Jang, Dae Joong Kim, Toshitaka Nabeshima, Hyoung Chun Kim

Research output: Contribution to journalArticle

Abstract

Background: Oxidative stress and mitochondrial dysfunction have been implicated in the pathophysiology of schizophrenia. Aims: We investigated whether antipsychotic clozapine modulates nicotinamide adenine dinucleotide phosphate oxidase and mitochondrial burdens induced by phencyclidine in mice. Methods: We examined the effect of clozapine on nicotinamide adenine dinucleotide phosphate oxidase activation, mitochondrial burdens (i.e. oxidative stress and mitochondrial dysfunction), and activities of enzymatic antioxidant in the prefrontal cortex, and subsequent abnormal behaviors induced by repeated treatment with phencyclidine. p47 phox Knockout mice and LY294002, a phosphoinositide 3-kinase inhibitor, were employed to elucidate the pharmacological mechanism of clozapine. Results: Phencyclidine treatment resulted in an early increase nicotinamide adenine dinucleotide phosphate oxidase activity, membrane translocation of p47 phox , interaction between p-Akt and p47 phox , and mitochondrial burdens in wild-type mice. Although these increases returned to near control level four days post-phencyclidine, mitochondrial superoxide dismutase and glutathione peroxidase activities were decreased at that time. Clozapine, LY294002, or p47 phox knockout significantly ameliorated social withdrawal and recognition memory deficits produced by phencyclidine. Importantly, LY294002 did not significantly alter the effects of clozapine against abnormal behaviors and the interaction between p-Akt and p47 phox induced by phencyclidine. Furthermore, neither LY294002 nor clozapine exhibited any additive effects to the protection afforded by p47 phox knockout against phencyclidine insult. Conclusion: Our results suggest that p47 phox gene mediates phencyclidine-induced mitochondrial burdens and abnormal behaviors, and that the interactive modulation between p47 phox and phosphoinositide 3-kinase/Akt is important for the understanding on the pharmacological mechanism of clozapine.

Original languageEnglish
Pages (from-to)1233-1251
Number of pages19
JournalJournal of Psychopharmacology
Volume32
Issue number11
DOIs
Publication statusPublished - 01-11-2018

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Phencyclidine
1-Phosphatidylinositol 4-Kinase
Clozapine
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
NADP
Oxidoreductases
Oxidative Stress
Pharmacology
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one
Inhibition (Psychology)
Memory Disorders
Glutathione Peroxidase
Prefrontal Cortex
Knockout Mice
Antipsychotic Agents
Superoxide Dismutase
Schizophrenia
Antioxidants
Membranes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

Tran, Hai Quyen ; Park, Se J. ; Shin, Eun Joo ; Tran, The Vinh ; Sharma, Naveen ; Lee, Yu J. ; Jeong, Ji H. ; Jang, Choon Gon ; Kim, Dae Joong ; Nabeshima, Toshitaka ; Kim, Hyoung Chun. / 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 In: Journal of Psychopharmacology. 2018 ; Vol. 32, No. 11. pp. 1233-1251.
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abstract = "Background: Oxidative stress and mitochondrial dysfunction have been implicated in the pathophysiology of schizophrenia. Aims: We investigated whether antipsychotic clozapine modulates nicotinamide adenine dinucleotide phosphate oxidase and mitochondrial burdens induced by phencyclidine in mice. Methods: We examined the effect of clozapine on nicotinamide adenine dinucleotide phosphate oxidase activation, mitochondrial burdens (i.e. oxidative stress and mitochondrial dysfunction), and activities of enzymatic antioxidant in the prefrontal cortex, and subsequent abnormal behaviors induced by repeated treatment with phencyclidine. p47 phox Knockout mice and LY294002, a phosphoinositide 3-kinase inhibitor, were employed to elucidate the pharmacological mechanism of clozapine. Results: Phencyclidine treatment resulted in an early increase nicotinamide adenine dinucleotide phosphate oxidase activity, membrane translocation of p47 phox , interaction between p-Akt and p47 phox , and mitochondrial burdens in wild-type mice. Although these increases returned to near control level four days post-phencyclidine, mitochondrial superoxide dismutase and glutathione peroxidase activities were decreased at that time. Clozapine, LY294002, or p47 phox knockout significantly ameliorated social withdrawal and recognition memory deficits produced by phencyclidine. Importantly, LY294002 did not significantly alter the effects of clozapine against abnormal behaviors and the interaction between p-Akt and p47 phox induced by phencyclidine. Furthermore, neither LY294002 nor clozapine exhibited any additive effects to the protection afforded by p47 phox knockout against phencyclidine insult. Conclusion: Our results suggest that p47 phox gene mediates phencyclidine-induced mitochondrial burdens and abnormal behaviors, and that the interactive modulation between p47 phox and phosphoinositide 3-kinase/Akt is important for the understanding on the pharmacological mechanism of clozapine.",
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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 . / Tran, Hai Quyen; Park, Se J.; Shin, Eun Joo; Tran, The Vinh; Sharma, Naveen; Lee, Yu J.; Jeong, Ji H.; Jang, Choon Gon; Kim, Dae Joong; Nabeshima, Toshitaka; Kim, Hyoung Chun.

In: Journal of Psychopharmacology, Vol. 32, No. 11, 01.11.2018, p. 1233-1251.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Tran, Hai Quyen

AU - Park, Se J.

AU - Shin, Eun Joo

AU - Tran, The Vinh

AU - Sharma, Naveen

AU - Lee, Yu J.

AU - Jeong, Ji H.

AU - Jang, Choon Gon

AU - Kim, Dae Joong

AU - Nabeshima, Toshitaka

AU - Kim, Hyoung Chun

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Background: Oxidative stress and mitochondrial dysfunction have been implicated in the pathophysiology of schizophrenia. Aims: We investigated whether antipsychotic clozapine modulates nicotinamide adenine dinucleotide phosphate oxidase and mitochondrial burdens induced by phencyclidine in mice. Methods: We examined the effect of clozapine on nicotinamide adenine dinucleotide phosphate oxidase activation, mitochondrial burdens (i.e. oxidative stress and mitochondrial dysfunction), and activities of enzymatic antioxidant in the prefrontal cortex, and subsequent abnormal behaviors induced by repeated treatment with phencyclidine. p47 phox Knockout mice and LY294002, a phosphoinositide 3-kinase inhibitor, were employed to elucidate the pharmacological mechanism of clozapine. Results: Phencyclidine treatment resulted in an early increase nicotinamide adenine dinucleotide phosphate oxidase activity, membrane translocation of p47 phox , interaction between p-Akt and p47 phox , and mitochondrial burdens in wild-type mice. Although these increases returned to near control level four days post-phencyclidine, mitochondrial superoxide dismutase and glutathione peroxidase activities were decreased at that time. Clozapine, LY294002, or p47 phox knockout significantly ameliorated social withdrawal and recognition memory deficits produced by phencyclidine. Importantly, LY294002 did not significantly alter the effects of clozapine against abnormal behaviors and the interaction between p-Akt and p47 phox induced by phencyclidine. Furthermore, neither LY294002 nor clozapine exhibited any additive effects to the protection afforded by p47 phox knockout against phencyclidine insult. Conclusion: Our results suggest that p47 phox gene mediates phencyclidine-induced mitochondrial burdens and abnormal behaviors, and that the interactive modulation between p47 phox and phosphoinositide 3-kinase/Akt is important for the understanding on the pharmacological mechanism of clozapine.

AB - Background: Oxidative stress and mitochondrial dysfunction have been implicated in the pathophysiology of schizophrenia. Aims: We investigated whether antipsychotic clozapine modulates nicotinamide adenine dinucleotide phosphate oxidase and mitochondrial burdens induced by phencyclidine in mice. Methods: We examined the effect of clozapine on nicotinamide adenine dinucleotide phosphate oxidase activation, mitochondrial burdens (i.e. oxidative stress and mitochondrial dysfunction), and activities of enzymatic antioxidant in the prefrontal cortex, and subsequent abnormal behaviors induced by repeated treatment with phencyclidine. p47 phox Knockout mice and LY294002, a phosphoinositide 3-kinase inhibitor, were employed to elucidate the pharmacological mechanism of clozapine. Results: Phencyclidine treatment resulted in an early increase nicotinamide adenine dinucleotide phosphate oxidase activity, membrane translocation of p47 phox , interaction between p-Akt and p47 phox , and mitochondrial burdens in wild-type mice. Although these increases returned to near control level four days post-phencyclidine, mitochondrial superoxide dismutase and glutathione peroxidase activities were decreased at that time. Clozapine, LY294002, or p47 phox knockout significantly ameliorated social withdrawal and recognition memory deficits produced by phencyclidine. Importantly, LY294002 did not significantly alter the effects of clozapine against abnormal behaviors and the interaction between p-Akt and p47 phox induced by phencyclidine. Furthermore, neither LY294002 nor clozapine exhibited any additive effects to the protection afforded by p47 phox knockout against phencyclidine insult. Conclusion: Our results suggest that p47 phox gene mediates phencyclidine-induced mitochondrial burdens and abnormal behaviors, and that the interactive modulation between p47 phox and phosphoinositide 3-kinase/Akt is important for the understanding on the pharmacological mechanism of clozapine.

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