The-Vinh Tran

Protective Potential of the Glutathione Peroxidase-1 Gene in Abnormal Behaviors Induced by Phencyclidine in Mice

Escalating evidence suggests that the impairment of glutathione (GSH)-dependent systems is one of the etiologic factors of schizophrenia. GSH is an important substrate of glutathione peroxidase (GPx). Among GPx isozymes, selenium-dependent GPx (GPx-1) is recognized as a major type, and therefore, this study investigates the role of the GPx-1 gene in abnormal behaviors induced by repeated phencyclidine (PCP) treatment using GPx-1 knockout (KO) and overexpressing transgenic (GPx-1 TG) mice. PCP-induced abnormal behaviors were more pronounced in GPx-1 KO mice than abnormal behaviors in wild-type (WT) mice, and the abnormal behaviors were less pronounced in GPx-1 TG mice than abnormal behaviors in non-TG mice. PCP treatment significantly reduced GSH levels and enhanced oxidative burdens in the prefrontal cortex of the test animals. In addition, PCP treatment significantly upregulated the nuclear translocations of nuclear factor erythroid-2-related factor 2 (Nrf2) and nuclear factor kappa-B (NF-κB) p65, as well as their DNA binding activities and γ-glutamylcysteine (GCL) mRNA expression in WT and non-TG mice. However, GPx-1 KO abolished this upregulation system. In contrast, genetic overexpression of GPx-1 further upregulated Nrf2-dependent GSH synthetic system, but downregulated NF-κB p65 activity in the presence of PCP. Clozapine, an antipsychotic, significantly upregulated GPx-1 and Nrf2-dependent GSH synthetic systems in the presence of PCP, but failed to affect NF-κB p65 activity. Our results suggest that interactive modulations between the GPx-1 gene and Nrf2-dependent GSH induction are critical for attenuating PCP-induced abnormal behaviors in mice.

Ceruloplasmin is an endogenous protectant against kainate neurotoxicity.

To determine the role of ceruloplasmin (Cp) in epileptic seizures, we used a kainate (KA) seizure animal model and examined hippocampal samples from epileptic patients. Treatment with KA resulted in a time-dependent decrease in Cp protein expression in the hippocampus of rats. Cp-positive cells were colocalized with neurons or reactive astrocytes in KA-treated rats and epileptic patient samples. KA-induced seizures, initial oxidative stress (i.e., hydroxyl radical formation, lipid peroxidation, protein oxidation, and synaptosomal reactive oxygen species), altered iron status (increasing Fe(2+) accumulation and L-ferritin-positive reactive microglial cells and decreasing H-ferritin-positive neurons), and impaired glutathione homeostasis and neurodegeneration (i.e., Fluoro-Nissl and Fluoro-Jade B staining analyses) were more pronounced in Cp antisense oligonucleotide (ASO)- than in Cp sense oligonucleotide-treated rats. Consistently, Cp ASO facilitated KA-induced lactate dehydrogenase (LDH) release, Fe(2+) accumulation, and glutathione loss in neuron-rich and mixed cultures. However, Cp ASO did not alter KA-induced LDH release or Fe(2+) accumulation in the astroglial culture, but did facilitate impairment in glutathione homeostasis in the same culture. Importantly, treatment with human Cp protein resulted in a significant attenuation against these neurotoxicities induced by Cp ASO. Our results suggest that Cp-mediated neuroprotection occurs via the inhibition of seizure-associated oxidative damage (including impairment in glutathione homeostasis), Fe(2+) accumulation, and alterations in ferritin immunoreactivity. Moreover, interactive modulation between neurons and glia was found to be important for Cp upregulation in the attenuation of epileptic damage in both animals and humans.

Current understanding of methamphetamine-associated dopaminergic neurodegeneration and psychotoxic behaviors

Clinical and preclinical studies have indicated that chronic methamphetamine (MA) use is associated with extensive neurodegeneration, psychosis, and cognitive impairment. Evidence from animal models has suggested a considerable role of excess dopamine or glutamate, oxidative stress, neuroinflammation, and apoptosis in MA-induced neurotoxicity, and that protein kinase Cδ might mediate the interaction among these factors. In addition, the relatively long-lasting and recurrent nature of MA psychosis has been reproduced in animals treated with various dosing regimens of MA, which have shown behavioral sensitization, sociability deficits, and impaired prepulse inhibition. Genetic predisposition as well as dopaminergic and glutamatergic alterations might be important in the development of MA psychosis. Neuroimaging studies have identified functional and morphological changes related to the cognitive dysfunction shown in chronic MA users. Failure in the task-evoked phosphorylation of extracellular signal-related kinase likely underlies MA-induced memory impairment. Recent progress has suggested certain roles of oxidative stress and neuroinflammation in the psychosis and cognitive deficits induced by repeated low doses of MA. This review provides a comprehensive description of pertinent findings from human and animal studies, with an emphasis on the current understanding of the underlying mechanisms of MA neuropsychotoxicity and its relevance to Parkinson’s disease or schizophrenia.

MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced convulsive behavior: Possible involvement of the GluN2B receptor

&NA; Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine‐like opioid. When administered at supra‐antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well‐documented, few studies have examined the effects of high‐dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80 mg/kg), Sprague–Dawley rats showed increased seizure occurrence and intensity. Hippocampal expression levels of N‐methyl‐D‐aspartate (NMDA) receptor subunits (GluN1 < GluN2A < GluN2B), c‐Fos and pro‐apoptotic factors (Bax and cleaved caspase‐3) were upregulated by DM treatment; while levels of anti‐apoptotic factors (Bcl‐2 and Bcl‐xL) were downregulated. Consistently, DM also induced ultrastructural degeneration in the hippocampus. A non‐competitive NMDA receptor antagonist, MK‐801, attenuated these effects of high‐dose DM, whereas an opioid antagonist, naloxone, did not affect DM‐induced neurotoxicity. Moreover, pretreatment with a highly specific GluN2B subunit inhibitor, traxoprodil, was selectively effective in preventing DM‐induced c‐Fos expression and apoptotic changes. These results suggest that high‐dose DM produces convulsive behaviors by activating GluN2B/NMDA signaling that leads to pro‐apoptotic changes. HighlightsHigh‐dose (a supra antitussive dose) DM produces seizure behaviors.Intraperitoneal route (i.p.) is critical for induction of DM neurotoxicity.NMDA receptor antagonist, but not opioid receptor antagonist, attenuates DM seizures.GluN2B/NMDA signaling mediates DM‐induced neurotoxicity.

Ginsenoside Re protects against phencyclidine-induced behavioral changes and mitochondrial dysfunction via interactive modulation of glutathione peroxidase-1 and NADPH oxidase in the dorsolateral cortex of mice

We investigated whether ginsenoside Re (Re) modulates phencyclidine (PCP)-induced sociability deficits and recognition memory impairments to extend our recent finding. We examined the role of GPx-1 gene in the pharmacological activity of Re against mitochondrial dysfunction induced by PCP in the dorsolateral cortex of mice. Since mitochondrial oxidative stress activates NADPH oxidase (PHOX), we applied PHOX inhibitor apocynin for evaluating interactive modulation between GPx-1 and PHOX against PCP neurotoxicity. Sociability deficits and recognition memory impairments induced by PCP were more pronounced in GPx-1 knockout (KO) than in wild type (WT) mice. PCP-induced mitochondrial oxidative stress, mitochondrial dysfunction, and membrane translocation of p47phox were more evident in GPx-1 KO than in WT. Re treatment significantly attenuated PCP-induced neurotoxic changes. Re also significantly attenuated PCP-induced sociability deficits and recognition memory impairments. The attenuation by Re was comparable to that by apocynin. The attenuation was more obvious in GPx-1 KO than in WT. Importantly, apocynin did not show any additional positive effects on the neuroprotective activity of Re, indicating that PHOX is a molecular target for therapeutic activity of Re. Our results suggest that Re requires interactive modulation between GPx activity and PHOX (p47phox) to exhibit neuroprotective potentials against PCP insult.

Blockade of platelet-activating factor receptor attenuates abnormal behaviors induced by phencyclidine in mice through down-regulation of NF-κB

Accumulating evidence suggests that neuroinflammation is one of the important etiologic factors of abusive and neuropsychiatric disorders. Platelet-activating factor (PAF) is potent proinflammatory lipid mediat1or and plays a pivotal role in neuroinflammatory disorders through the specific PAF receptor (PAF-R). Phencyclidine (PCP) induces a psychotomimetic state that closely resembles schizophrenia. Here, we investigated the role of PAF-R in the abnormal behaviors induced by PCP in mice. Repeated treatment with PCP resulted in a significant increase in PAF-R gene expression in the prefrontal cortex (PFC) and in the hippocampus. This increase was more pronounced in the PFC than hippocampus. Treatment with PCP resulted in a significant increase in nuclear translocation of the nuclear factor kappa beta (NF-κB) p65 and DNA binding activity, indicating that the proinflammatory molecule NF-κB was increased through up-regulation of PAF-R. Consistently, NF-κB activation was significantly protected by the PAF-R antagonist, ginkgolide B (Gink B), in PAF-R knockout mice and by the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC). In addition, PCP-induced abnormal behaviors (i.e., reduced sociability, depression, cognitive impairment, and behavioral sensitization) were significantly attenuated by Gink B, in PAF-R knockout mice, and by PDTC. Importantly, PDTC did not significantly alter the attenuations observed in Gink B-treated mice or PAF-R knockout mice, indicating that NF-κB is a critical target for neuropsychotoxic modulation of PAF-R. Therefore, the results suggest that PAF-R mediates PCP-induced neuropsychotoxicity via a NF-κB-dependent mechanism, and that up-regulation of PAF-R may be associated with schizophrenia-like behavior in animal models.

PM377. Role of glutathione peroxidase-1 gene in the phencyclidine-induced schizophrenia-like psychosis in mice

Objective: Many evidences suggested that impairment of glutathione-dependent system is observed in the brain of schizophrenic patients. GSH is an important substrate of glutathione peroxidase (GPx). It is recognized that selenium-dependent GPx (GPx-1) out of GPx isozymes provides a first line of defense against peroxides. Thus, we investigated in the present study a role of GPx-1 gene in schizophrenia-like psychosis induced by phencyclidine (PCP) in mice. Method: GPx-1 knock-out (KO)-, wild-type (WT)-, GPx-1 overexpressing transgenic (Tg)and non-Tg-mice were received PCP (10 mg/kg/day, s.c.) for consecutive 14 days. Novel object recognition-, forced swimming-, and social interaction-tests were performed 7 days after withdrawal from PCP. Behavioral sensitization to an acute challenge of PCP (3 mg/kg, s.c.) was also evaluated. We examined Nrf-2-dependent GSH-synthetic process in the prefrontal cortex and hippocampus. Result: PCP-induced behavioral side effects were more pronounced in the GPx-1 KO than those in WT mice, and they were less pronounced in GPx-1 Tg than those in non-Tg mice. Moreover, PCP treatment significantly reduced GSH level, and increased oxidative burdens in prefrontal cortex as compared to those in hippocampus. Treatment with PCP resulted in a significant increase in nuclear translocation of Nrf2, Nrf2 DNA binding activity, and γ-glutamylcysteine modifier subunit (GCLm) mRNA expression in WT or non-Tg mice. These inductions were not observed in GPx1 KO mice. Further, this Nrf-2 dependent GSH synthetic system was more pronounced in GPx-1 Tg than non-Tg mice. Conclusion: Our results suggest that GPx-1 gene is a potential protective factor in response to schizophrenia-like psychosis induced by PCP in mice [This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea]. PM378 A reduced risk of severe hepatic outcome with paliperidone exposure in schizophrenia patients with viral hepatitis: a population-based retrospective cohort study Running title: Schizophrenia, severe hepatic outcome, and paliperidone Chun-Hung Chang,1,2,3 Shaw-Ji Chen,4,5,6 Chieh-Yu Liu7, Hsien-Yuan Lane1,2 * 1Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan, R.O.C. 2Institute of Clinical Medicine, China Medical University, Taichung, Taiwan, R.O.C.; 3Sunshine Psychiatric Hospital, Taichung, Taiwan, R.O.C. 4Department of Psychiatry, Mackay Memorial Hospital Taitung Branch, Taitung, R.O.C. 5Mackay Junior College of Medicine, Nursing, and Management, Taipei, R.O.C. 6Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan, R.O.C. 7Biostatistical Consulting Lab, Institute of Nursing-Midwifery, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan, R.O.C. *Corresponding author: Hsien-Yuan Lane, Ph.D. 2, Yuh-Der Rd, Taichung 40447, Taiwan Institute of Clinical Medicine, China Medical University Tel: +886-422052121 extension 1073 Fax: +886-4-26202946 E-mail: chang763@ gmail.com E-mail: d21868@mail.cmuh.org.tw Financial Disclosure: The authors have indicated they have no relevant financial relationships to disclose for this article. Conflicts of Interest: The authors declare that there is no conflict of