Exposure to far-infrared rays attenuates methamphetamine-induced recognition memory impairment via modulation of the muscarinic M1 receptor, Nrf2, and PKC

Mai, Huynh Nhu,Sharma, Naveen,Shin, Eun-Joo,Nguyen, Bao Trong,Nguyen, Phuong Tram,Jeong, Ji Hoon,Jang, Choon-Gon,Cho, Eun-Hee,Nah, Seung-Yeol,Kim, Nam Hun,Nabeshima, Toshitaka,Kim, Hyoung-Chun Elsevier 2018 Neurochemistry International Vol.116 No.-

<P><B>Abstract</B></P> <P>We demonstrated that activation of protein kinase Cδ (PKCδ) and inactivation of the glutathione peroxidase-1 (GPx-1)-dependent systems are critical for methamphetamine (MA)-induced recognition memory impairment. We also demonstrated that exposure to far-infrared rays (FIR) causes induction of the glutathione (GSH)-dependent system, including induction of the GPx-1 gene. Here, we investigated whether exposure to FIR rays affects MA-induced recognition memory impairment and whether it modulates PKC, cholinergic receptors, and the GSH-dependent system. Because the PKC activator bryostatin-1 mainly induces PKCα, PKCε, and PKCδ, we assessed expression of these proteins after MA treatment. MA treatment selectively increased PKCδ expression and its phosphorylation. Exposure to FIR rays significantly attenuated MA-induced increases in PKCδ phosphorylation. Importantly, bryostatin-1 potentiated MA-induced phosphorylation of PKCδ. MA treatment significantly decreased M1, M3, and M4 muscarinic acetylcholine receptors (mAChRs) and β2 nicotinic acetylcholine receptor expression. Of these, the decrease was most pronounced in M1 mAChR. Exposure to FIR significantly attenuated MA-induced decreases in the M1 mAChR and phospho-ERK<SUB>1/2</SUB>, while it facilitated Nrf2-dependent GSH induction. Dicyclomine, an M1 mAChR antagonist, and <SMALL>L</SMALL>-buthionine-(S, R)-sulfoximine (BSO), an inhibitor of GSH synthesis, counteracted against the protective potentials mediated by FIR. More importantly, the memory-enhancing potential of FIR rays was significantly counteracted by bryostatin-1, dicyclomine, and BSO. Our results suggest that exposure to FIR rays attenuates MA-induced impairment in recognition memory via up-regulation of M1 mAChR, Nrf2-dependent GSH induction, and ERK<SUB>1/2</SUB> phosphorylation by inhibiting PKCδ phosphorylation by bryostatin-1.</P> <P><B>Highlights</B></P> <P> <UL> <LI> FIR attenuated MA-induced memory dysfunction via inhibition of PKCδ phosphorylation. </LI> <LI> FIR potentiated MA-induced compensative induction in Nrf2 and GCLs levels. </LI> <LI> Inhibition of PKCδ phosphorylation activated M1 mAChR/Nrf-2/ERK<SUB>1/2</SUB> signaling. </LI> <LI> Protective activity of FIR was counteracted by PKC activation, dicyclomine, and BSO. </LI> </UL> </P>

P53 knockout mice are protected from cocaine-induced kindling behaviors via inhibiting mitochondrial oxidative burdens, mitochondrial dysfunction, and proapoptotic changes

Mai, Huynh Nhu,Sharma, Naveen,Jeong, Ji Hoon,Shin, Eun-Joo,Pham, Duc Toan,Trinh, Quynh Dieu,Lee, Yu Jeung,Jang, Choon-Gon,Nah, Seung-Yeol,Bing, Guoying,Kim, Hyoung-Chun Elsevier 2019 Neurochemistry International Vol.124 No.-

<P><B>Abstract</B></P> <P>Previously we demonstrated that p53 mediates dopaminergic neurotoxicity via inducing mitochondrial burdens and proapoptotsis. However, little is known about the role of p53 in the excitotoxicity induced by psychostimulant, such as cocaine. Cocaine-induced kindling (convulsive) behaviors significantly increased p53 expression in the brain. Cocaine-induced p53 expression was more pronounced in hippocampus than in striatum or prefrontal cortex. Genetic depletion of p53 significantly attenuated cocaine-induced convulsive behaviors, followed by c-Fos immunoreactivity, and oxidative burdens in the hippocampus of mice. The antioxidant potentials mediated by genetic depletion of p53 were more pronounced in the mitochondrial-than cytosolic-fraction. Depletion of p53 significantly attenuated the changes in mitochondrial transmembrane potential, intramitochondrial Ca<SUP>2+</SUP> level, and mitochondrial oxidative burdens induced by cocaine. Consistently, depletion of p53 significantly inhibited mitochondrial p53 translocation, and cleaved-PKCδ induced by cocaine. In addition, depletion of p53 protected from cytosolic cytochrome c release, and pro-apoptotic changes induced by cocaine. Importantly, the protective/anticonvulsant potentials by genetic depletion of p53 were comparable to those by pifithrin-μ (PFT), a p53 inhibitor. Our results suggest that depletion of p53 offers anticonvulsive and neuroprotective potentials mainly via attenuating mitochondrial oxidative burdens, mitochondrial dysfunction, and pro-apoptotic signalings against cocaine-induced convulsive neurotoxicity.</P> <P><B>Highlights</B></P> <P> <UL> <LI> P53 inhibition protects against cocaine-induced kindling (convulsive) behaviors. </LI> <LI> Cocaine-induced p53 expression is most pronounced in hippocampus. </LI> <LI> Cocaine-induced oxidative stress is more evident in mitochondria than in cytosol. </LI> <LI> P53 depletion attenuates cocaine-induced mitochondrial dysfunction. </LI> <LI> P53 depletion attenuates cocaine-induced pro-apoptotic phenomena. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Protein kinase Cδ knockout mice are protected from cocaine-induced hepatotoxicity

Mai, Huynh Nhu,Lee, Sung Hoon,Sharma, Garima,Kim, Dae-Joong,Sharma, Naveen,Shin, Eun-Joo,Pham, Duc Toan,Trinh, Quynh Dieu,Jang, Choon-Gon,Nah, Seung-Yeol,Jeong, Ji Hoon,Kim, Hyoung-Chun Elsevier 2019 Chemico-biological interactions Vol.297 No.-

<P><B>Abstract</B></P> <P>We investigated whether protein kinase Cδ (PKCδ) mediates cocaine-induced hepatotoxicity in mice. Cocaine treatment (60 mg/kg, i.p.) significantly increased cleaved PKCδ expression in the liver of wild-type (WT) mice, and led to significant increases in oxidative parameters (i.e., reactive oxygen species, 4-hydroxylnonenal and protein carbonyl). These cocaine-induced oxidative burdens were attenuated by pharmacological (i.e., rottlerin) or genetic depletion of PKCδ. We also demonstrated that treatment with cocaine resulted in significant increases in nuclear factor erythroid-2-related factor 2 (Nrf-2) nuclear translocation and increased Nrf-2 DNA-binding activity in wild-type (WT) mice. These increases were more pronounced in the rottlerin-treated WT or PKCδ knockout mice than in the saline-treated WT mice. Although cocaine treatment increased Nrf-2 nuclear translocation, DNA binding activity, and γ-glutamyl cysteine ligases (i.e., GCLc and GCLm) mRNA expressions, while it reduced the glutathione level and GSH/GSSG ratio. These decreases were attenuated by PKCδ depletion. Cocaine treatment significantly increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the serum of WT mice signifying the hepatic damage. These increases were also attenuated by PKCδ depletion. In addition, cocaine-induced hepatic degeneration in WT mice was evident 1 d post-cocaine. At that time, cocaine treatment decreased Bcl-2 and Bcl-xL levels, and increased Bax, cytosolic cytochrome c, and cleaved caspase-3 levels. Pharmacological or genetic depletion of PKCδ significantly ameliorated the pro-apoptotic properties and hepatic degeneration. Therefore, our results suggest that inhibition of PKCδ, as well as activation of Nrf-2, is important for protecting against hepatotoxicity induced by cocaine.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Cocaine induces hepatotoxicity via oxidative stress and activation of PKCδ. </LI> <LI> Depletion of PKCδ protects from cocaine-induced hepatotoxicity. </LI> <LI> Depletion of PKCδ exerts antioxidant activity via Nrf2-related glutathione system. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

IL-6 knockout mice are protected from cocaine-induced kindling behaviors; possible involvement of JAK2/STAT3 and PACAP signalings

Mai, Huynh Nhu,Chung, Yoon Hee,Shin, Eun-Joo,Sharma, Naveen,Jeong, Ji Hoon,Jang, Choon-Gon,Saito, Kuniaki,Nabeshima, Toshitaka,Reglodi, Dora,Kim, Hyoung-Chun Elsevier Science B.V., Amsterdam. 2018 Food and Chemical Toxicology Vol. No.

Glutathione peroxidase-1 overexpressing transgenic mice are protected from cocaine-induced drug dependence

Mai, Huynh Nhu,Chung, Yoon Hee,Shin, Eun-Joo,Kim, Dae-Joong,Sharma, Naveen,Lee, Yu Jeung,Jeong, Ji Hoon,Nah, Seung-Yeol,Jang, Choon-Gon,Kim, Hyoung-Chun Elsevier 2019 Neurochemistry International Vol.124 No.-

<P><B>Abstract</B></P> <P>Converging evidence has demonstrated that oxidative burdens are associated with drug dependence induced by psychostimulants. Here, we investigated whether oxidative stress directly mediates conditioned place preference and behavioral sensitization (drug dependence) induced by cocaine and whether glutathione peroxidase-1 (GPx-1), a major GPx, modulates cocaine-induced psychotoxic changes in mice. Cocaine-induced drug dependence was followed by increases in c-Fos-immunoreactivity (c-Fos-IR) in the nucleus accumbens. Simultaneously, cocaine significantly increased oxidative parameters and nuclear factor κB (NFκB) activity (i.e. nuclear translocation and DNA binding activity) in the striatum (including nucleus accumbens). Genetic depletion of GPx-1 made mice susceptible to drug dependence induced by cocaine in mice, while genetic overexpression of GPx-1 protected the mice from drug dependence. Pyrrolidine dithiocarbamate (PDTC), a NFκB inhibitor, significantly attenuated the sensitivity induced by the genetic depletion of GPx-1 in mice. However, PDTC did not exhibit any additive effects against the protection afforded by the genetic overexpression of GPx-1. Our results suggest that drug dependence induced by cocaine requires oxidative stress and NFκB activation, and that the GPx-1 gene is a potential protective factor against cocaine-induced drug dependence through positive modulation of NFκB.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Treatment with cocaine resulted in a compensative induction of GPx-1. </LI> <LI> GPx-1 gene attenuated cocaine-induced oxidative potentials in the striatum. </LI> <LI> NFkB is a critical target for the GPx-1 activity against cocaine drug dependence. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Genetic depletion of p53 attenuates cocaine-induced hepatotoxicity in mice

Mai, Huynh Nhu,Sharma, Garima,Sharma, Naveen,Shin, Eun-Joo,Kim, Dae-Joong,Pham, Duc Toan,Trinh, Quynh Dieu,Jang, Choon-Gon,Nah, Seung Yeol,Jeong, Ji Hoon,Kim, Hyoung-Chun Elsevier 2019 Biochimie Vol.158 No.-

<P><B>Abstract</B></P> <P>Cocaine, an addictive drug, is known to induce hepatotoxicity via oxidative damage and proapoptosis. Since p53, a tumor suppressor gene, plays a major role in inducing oxidative stress and apoptosis, we examined the role of p53 inhibition against cocaine-induced hepatotoxicity. Cocaine treatment significantly increased oxidative parameters (i.e., reactive oxygen species, 4-hydroxylnonenal, and protein carbonyl) in the liver of wild type (WT) mice. We found that the pharmacological (i.e. pifithrin-α) and genetic (i.e. p53 knockout) inhibition of p53 significantly attenuates cocaine-induced hepatotoxicity. Cocaine treatment increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the serum of mice, signifying hepatic damage. Consistently, these increases were attenuated by inhibition of p53, implying protection against cocaine-induced hepatic damage. In addition, cocaine treatment significantly increased PKCδ, cleaved PKCδ and p53 levels in the liver of WT mice. These increases were followed by the interaction between p53 and PKCδ, and pro-apoptotic consequences (i.e., cytosolic release of cytochrome <I>c</I>, activation of caspase-3, increase in Bax level and decreases in Bcl-2 and Bcl-xL levels). These changes were attenuated by p53 depletion, reflecting that the critical role of PKCδ in p53-mediated apoptotic potentials. Combined, our results suggest that the inhibition of p53 is important for protection against oxidative burdens, pro-apoptotic events, and hepatic degeneration induced by cocaine.</P> <P><B>Highlight</B></P> <P> <UL> <LI> Cocaine induces hepatotoxicity in mice via oxidative stress and p53 activation. </LI> <LI> Interaction of p53 and PKCδ might be important for p53-mediated toxic potentials. </LI> <LI> p53 knockout or PFT-α attenuates hepatotoxic outcomes induced by cocaine in mice. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Astrocytic mobilization of glutathione peroxidase-1 contributes to the protective potential against cocaine kindling behaviors in mice via activation of JAK2/STAT3 signaling

Mai, Huynh Nhu,Nguyen, Lan Thuy Ty,Shin, Eun-Joo,Kim, Dae-Joong,Jeong, Ji Hoon,Chung, Yoon Hee,Lei, Xin Gen,Sharma, Naveen,Jang, Choon-Gon,Nabeshima, Toshitaka,Kim, Hyoung-Chun Elsevier 2019 FREE RADICAL BIOLOGY AND MEDICINE Vol.131 No.-

<P><B>Abstract</B></P> <P>Compelling evidence indicates that oxidative stress contributes to cocaine neurotoxicity. The present study was performed to elucidate the role of the glutathione peroxidase-1 (GPx-1) in cocaine-induced kindling (convulsive) behaviors in mice. Cocaine-induced convulsive behaviors significantly increased <U>GPx-1</U>, p-IkB, and p-JAK2/STAT3 expression, and oxidative burdens in the hippocampus of mice. There was no significant difference in cocaine-induced p-IkB expression between non-transgenic (non-TG) and GPx-1 overexpressing transgenic (GPx-1 TG) mice, but significant differences were observed in cocaine-induced p-JAK2/STAT3 expression and oxidative stress between non-TG and GPx-1 TG mice. Cocaine-induced glial fibrillary acidic protein (GFAP)-labeled astrocytic level was significantly higher in the hippocampus of GPx-1 TG mice. Triple-labeling immunocytochemistry indicated that GPx-1-, p-STAT3-, and GFAP-immunoreactivities were co-localized in the same cells. AG490, a JAK2/STAT3 inhibitor, but not pyrrolidone dithiocarbamate, an NFκB inhibitor, significantly counteracted GPx-1-mediated protective potentials (i.e., anticonvulsant-, antioxidant-, antiapoptotic-effects). Genetic overexpression of GPx-1 significantly attenuated proliferation of Iba-1-labeled microglia induced by cocaine in mice. However, AG490 or astrocytic inhibition (by GFAP antisense oligonucleotide and α-aminoadipate) significantly increased Iba-1-labeled microglial activity and M1 phenotype microglial mRNA levels, reflecting that proinflammatory potentials were mediated by AG490 or astrocytic inhibition. This microglial activation was less pronounced in GPx-1 TG than in non-TG mice. Furthermore, either AG490 or astrocytic inhibition significantly counteracted GPx-1-mediated protective potentials. Therefore, our results suggest that astrocytic modulation between GPx-1 and JAK2/STAT3 might be one of the underlying mechanisms for protecting against convulsive neurotoxicity induced by cocaine.</P> <P><B>Highlights</B></P> <P> <UL> <LI> GPx-1 overexpression protects against oxidative burdens induced by cocaine. </LI> <LI> Anti-convulsive potentials of GPx-1 require JAK2/STAT3/GFAP signaling process. </LI> <LI> The activation of GFAP requires GPx-1 overexpression gene. </LI> <LI> AG490 or astrocytic inhibition increased Iba-1-labeld microglial activity. </LI> <LI> AG490 or astrocytic inhibition counteracted GPx-1-mediated protective potentials. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Exposure to Far Infrared Ray Protects Methamphetamine-Induced Behavioral Sensitization in Glutathione Peroxidase-1 Knockout Mice via Attenuating Mitochondrial Burdens and Dopamine D1 Receptor Activation

Mai, Huynh Nhu,Sharma, Naveen,Shin, Eun-Joo,Nguyen, Bao Trong,Jeong, Ji Hoon,Jang, Choon-Gon,Cho, Eun-Hee,Nah, Seung Yeol,Kim, Nam Hun,Nabeshima, Toshitaka,Kim, Hyoung-Chun Springer-Verlag 2018 Neurochem Res Vol.43 No.5

Jak2/Stat3 signaling pathway, but not NF-kB signaling pathway, is involved in oxidative damage and astroglial dysregulation induced by cocaine; Attenuation by glutathione peroxidase-1

MAI Huynh-Nhu,NAM Yunsung,KIM Dae-Joong,JANG Choon-Gon,SHIN Eun-Joo,KIM Hyoung-Chun 한국특수교육학회 2014 한국특수교육학회 학술대회 Vol.2014 No.-