PKCδ-dependent p47<i>phox</i> activation mediates methamphetamine-induced dopaminergic neurotoxicity

Dang, Duy-Khanh,Shin, Eun-Joo,Kim, Dae-Joong,Tran, Hai-Quyen,Jeong, Ji Hoon,Jang, Choon-Gon,Ottersen, Ole Petter,Nah, Seung-Yeol,Hong, Jau-Shyong,Nabeshima, Toshitaka,Kim, Hyoung-Chun PERGAMON PRESS 2018 FREE RADICAL BIOLOGY AND MEDICINE Vol.115 No.-

<P><B>Abstract</B></P> <P>Protein kinase C (PKC) has been recognized to activate NADPH oxidase (PHOX). However, the interaction between PKC and PHOX <I>in vivo</I> remains elusive. Treatment with methamphetamine (MA) resulted in a selective increase in PKCδ expression out of PKC isoforms. PKCδ co-immunoprecipitated with p47<I>phox</I>, and facilitated phosphorylation and membrane translocation of p47<I>phox</I>. MA-induced increases in PHOX activity and reactive oxygen species were attenuated by knockout of p47<I>phox</I> or PKCδ. In addition, MA-induced impairments in the Nrf-2-related glutathione synthetic system were also mitigated by knockout of p47<I>phox</I> or PKCδ. Glutathione-immunoreactivity was co-localized in Iba-1-labeled microglial cells and in NeuN-labeled neurons, but not in GFAP-labeled astrocytes, reflecting the necessity for self-protection against oxidative stress by mainly microglia. Buthionine-sulfoximine, an inhibitor of glutathione biosynthesis, potentiated microglial activation and pro-apoptotic changes, leading to dopaminergic losses. These neurotoxic processes were attenuated by rottlerin, a pharmacological inhibitor of PKCδ, genetic inhibitions of PKCδ <B>[</B>i.e., PKCδ knockout mice (KO) and PKCδ antisense oligonucleotide (ASO)<B>]</B>, or genetic inhibition of p47<I>phox</I> (i.e., p47<I>phox</I> KO or p47<I>phox</I> ASO). Rottlerin did not exhibit any additive effects against the protective activity offered by genetic inhibition of p47<I>phox</I>. Therefore, we suggest that PKCδ is a critical regulator for p47<I>phox</I> activation induced by MA, and that Nrf-2-dependent GSH induction via inhibition of PKCδ or p47<I>phox</I>, is important for dopaminergic protection against MA insult.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Interplay between PKC and PHOX <I>in vivo</I> in the neurotoxic condition remains unclear. </LI> <LI> PKCδ co-immunoprecipitated with p47<I>phox</I> and facilitated the potential of p47<I>phox.</I> </LI> <LI> Methamphetamine-induced Nrf-2 system was mitigated by inhibition of p47<I>phox</I> or PKCδ. </LI> <LI> BSO potentiated microgliosis and apoptotic changes, leading to dopaminergic losses. </LI> <LI> PKCδ is a critical regulator for p47<I>phox</I> activation induced by methamphetamine. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Genetic or pharmacological depletion of cannabinoid CB1 receptor protects against dopaminergic neurotoxicity induced by methamphetamine in mice

Dang, Duy-Khanh,Shin, Eun-Joo,Mai, Anh-Thu,Jang, Choon-Gon,Nah, Seung-Yeol,Jeong, Ji Hoon,Ledent, Catherine,Yamamoto, Tsuneyuki,Nabeshima, Toshitaka,Onaivi, Emmanuel S.,Kim, Hyoung-Chun Elsevier 2017 FREE RADICAL BIOLOGY AND MEDICINE Vol.108 No.-

<P><B>Abstract</B></P> <P>Accumulating evidence suggests that cannabinoid ligands play delicate roles in cell survival and apoptosis decisions, and that cannabinoid CB1 receptors (CB1R) modulate dopaminergic function. However, the role of CB1R in methamphetamine (MA)-induced dopaminergic neurotoxicity in vivo remains elusive. Multiple high doses of MA increased phospho-ERK and CB1R mRNA expressions in the striatum of CB1R (+/+) mice. These increases were attenuated by CB1R antagonists (i.e., AM251 and rimonabant), an ERK inhibitor (U0126), or dopamine D2R antagonist (sulpiride). In addition, treatment with MA resulted in dopaminergic impairments, which were attenuated by CB1R knockout or CB1R antagonists (i.e., AM251 and rimonabant). Consistently, MA-induced oxidative stresses (i.e., protein oxidation, lipid peroxidation and reactive oxygen species) and pro-apoptotic changes (i.e., increases in Bax, cleaved PKCδ- and cleaved caspase 3-expression and decrease in Bcl-2 expression) were observed in the striatum of CB1R (+/+) mice. These toxic effects were attenuated by CB1R knockout or CB1R antagonists. Consistently, treatment with four high doses of CB1R agonists (i.e., WIN 55,212-2 36mg/kg and ACEA 16mg/kg) also resulted in significant oxidative stresses, pro-apoptotic changes, and dopaminergic impairments. Since CB1R co-immunoprecipitates PKCδ in the presence of MA or CB1R agonists, we applied PKCδ knockout mice to clarify the role of PKCδ in the neurotoxicity elicited by CB1Rs. CB1R agonist-induced toxic effects were significantly attenuated by CB1R knockout, CB1R antagonists or PKCδ knockout. Therefore, our results suggest that interaction between D2R, ERK and CB1R is critical for MA-induced dopaminergic neurotoxicity and that PKCδ mediates dopaminergic damage induced by high-doses of CB1R agonist.</P> <P><B>Highlights</B></P> <P> <UL> <LI> MA or CB1R agonists increased CB1R mRNA level in the striatum of wild type mice. </LI> <LI> Inhibition of CB1R attenuated dopaminergic degeneration induced by MA. </LI> <LI> CB1R co-immunoprecipitated PKCδ in the presence of MA or CB1R agonists. </LI> <LI> Oxidative burdens contributed to PKCδ cleavage and apoptotic activity. </LI> <LI> CB1R agonists-induced dopaminergic degeneration was protected by PKCδ inhibition. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Inhibition of cannabinoid CB1 receptor attenuates methamphetamine-induced neurotoxicity

DANG Duy-Khanh,SHIN Eun-Joo,NAM Yunsung,JANG Choon-Gon,KIM Hyoung-Chun 한국특수교육학회 2014 한국특수교육학회 학술대회 Vol.2014 No.-

Antisense oligonucleotide against P47phox inhibits dopaminergic neurotoxicity and apoptosis induced by methamphetamine

DANG Duy-Khanh,NAM Yunsung,TRAN The-Vinh,JANG Choon-Gon,SHIN Eun-Joo,KIM Hyoung-Chun 한국특수교육학회 2014 한국특수교육학회 학술대회 Vol.2014 No.-

Golf Green Slope Estimation Using a Cross Laser Structured Light System and an Accelerometer

Duy Duong Pham,Quoc Khanh Dang,Young Soo Suh 대한전기학회 2016 Journal of Electrical Engineering & Technology Vol.11 No.2

In this paper, we propose a method combining an accelerometer with a cross structured light system to estimate the golf green slope. The cross-line laser provides two laser planes whose functions are computed with respect to the camera coordinate frame using a least square optimization. By capturing the projections of the cross-line laser on the golf slope in a static pose using a camera, two 3D curves’ functions are approximated as high order polynomials corresponding to the camera coordinate frame. Curves’ functions are then expressed in the world coordinate frame utilizing a rotation matrix that is estimated based on the accelerometer’s output. The curves provide some important information of the green such as the height and the slope’s angle. The curves estimation accuracy is verified via some experiments which use OptiTrack camera system as a ground-truth reference.

Golf Green Slope Estimation Using a Cross Laser Structured Light System and an Accelerometer

Pham, Duy Duong,Dang, Quoc Khanh,Suh, Young Soo The Korean Institute of Electrical Engineers 2016 Journal of Electrical Engineering & Technology Vol.11 No.2

In this paper, we propose a method combining an accelerometer with a cross structured light system to estimate the golf green slope. The cross-line laser provides two laser planes whose functions are computed with respect to the camera coordinate frame using a least square optimization. By capturing the projections of the cross-line laser on the golf slope in a static pose using a camera, two 3D curves’ functions are approximated as high order polynomials corresponding to the camera coordinate frame. Curves’ functions are then expressed in the world coordinate frame utilizing a rotation matrix that is estimated based on the accelerometer’s output. The curves provide some important information of the green such as the height and the slope’s angle. The curves estimation accuracy is verified via some experiments which use OptiTrack camera system as a ground-truth reference.

Current understanding of methamphetamine-associated dopaminergic neurodegeneration and psychotoxic behaviors

신은주,Duy-Khanh Dang,The-Vinh Tran,Hai-Quyen Tran,정지훈,나승열,장춘곤,Kiyofumi Yamada,Toshitaka Nabeshima,김형천 대한약학회 2017 Archives of Pharmacal Research Vol.40 No.4

Clinical and preclinical studies have indicatedthat chronic methamphetamine (MA) use is associated withextensive neurodegeneration, psychosis, and cognitiveimpairment. Evidence from animal models has suggested aconsiderable role of excess dopamine or glutamate,oxidative stress, neuroinflammation, and apoptosis in MAinducedneurotoxicity, and that protein kinase Cd mightmediate the interaction among these factors. In addition,the relatively long-lasting and recurrent nature of MApsychosis has been reproduced in animals treated withvarious dosing regimens of MA, which have shownbehavioral sensitization, sociability deficits, and impairedprepulse inhibition. Genetic predisposition as well asdopaminergic and glutamatergic alterations might beimportant in the development of MA psychosis. Neuroimagingstudies have identified functional andmorphological changes related to the cognitive dysfunctionshown in chronic MA users. Failure in the task-evokedphosphorylation of extracellular signal-related kinaselikely underlies MA-induced memory impairment. Recentprogress has suggested certain roles of oxidative stress andneuroinflammation in the psychosis and cognitive deficitsinduced by repeated low doses of MA. This review providesa comprehensive description of pertinent findingsfrom human and animal studies, with an emphasis on thecurrent understanding of the underlying mechanisms ofMA neuropsychotoxicity and its relevance to Parkinson’sdisease or schizophrenia.

Orodispersible film incorporating nanoparticulate loratadine for an enhanced oral bioavailability

Van Nguyen Khanh,Dang Thu Kim,Vu Linh Thi Dieu,Ha Nhan Thi,Truong Hieu Duy,Tran Tuan Hiep 한국약제학회 2023 Journal of Pharmaceutical Investigation Vol.53 No.3

Purpose Loratadine (LOR), a commonly prescribed antihistamine, has low water solubility but high permeability. In this study, an orodispersible film incorporating the nanoparticulate loratadine was prepared to enhance the oral bioavailability of a poorly water-soluble drug. Methods Nanoparticulate loratadine was formulated using the antisolvent precipitation method and optimized by a singlefactor design based on the particle size and polydispersity index. The optimal formulation was spray-dried and characterized by powder X-ray diffraction and differential scanning calorimetry. Nanoparticulate loratadine was loaded into an orodispersible film using a solvent casting method. Results In the dissolution tests, the nanoparticulate loratadine-loaded orodispersible film exhibited a 6.5-fold higher dissolution rate than the pure loratadine-loaded film and a similar dissolution rate compared to the commercialized orodispersible tablet, Loratadine SPM. In pharmacokinetic studies conducted on rats, the maximum concentration (Cmax) and area under the curve of the plasma concentration–time profile from 0 to 24 h (AUC 0-24 h) of the nanoparticulate loratadine-loaded orodispersible film significantly increased 1.8-fold and 5.8-fold, respectively. The elimination half-life (t1//2) increased 5.1-fold compared to the loratadine-loaded counterpart. Conclusion These results suggest the potential of orodispersible films to improve the oral bioavailability of poorly watersoluble drugs and promote compliance in pediatric and geriatric patients.

Growth Hormone-Releaser Diet Attenuates Cognitive Dysfunction in Klotho Mutant Mice via Insulin-Like Growth Factor-1 Receptor Activation in a Genetic Aging Model

박석주,정윤희,이정현,Duy-Khanh Dang,남윤성,정지훈,김용선,Toshitaka Nabeshima,신은주,김형춘 대한내분비학회 2014 Endocrinology and metabolism Vol.29 No.3

Background: It has been recognized that a defect in klotho gene expression accelerates the degeneration of multiple age-sensitive traits. Accumulating evidence indicates that aging is associated with declines in cognitive function and the activity of growth hormone (GH)/insulin-like growth factor-1 (IGF-1). Methods: In this study, we examined whether a GH-releaser diet could be effective in protecting against cognitive impairment in klotho mutant mice. Results: The GH-releaser diet significantly induced the expression of IGF-1 and IGF-1 receptors in the hippocampus of klotho mutant mice. Klotho mutant mice showed significant memory impairments as compared with wild-type mice. In addition, the klotho mutation significantly decreased the expression of cell survival/antiapoptotic factors, including phospho-Akt (p-Akt)/phospho-glycogen synthase kinase3β (p-GSK3β), phospho-extracellular signal-related kinase (p-ERK), and Bcl-2, but significantly increased those of cell death/proapoptotic factors, such as phospho-c-jun N-terminal kinase (p-JNK), Bax, and cleaved caspase-3 in the hippocampus. Treatment with GH-releaser diet significantly attenuated both decreases in the expression of cell survival/antiapoptotic factors and increases in the expression of cell death/proapoptotic factors in the hippocampus of klotho mutant mice. In addition, klotho mutation-induced oxidative stress was significantly attenuated by the GH-releaser diet. Consequently, a GH-releaser diet significantly improved memory function in the klotho mutant mice. GH-releaser diet-mediated actions were significantly reversed by JB-1, an IGF-1 receptor antagonist. Conclusion: The results suggest that a GH-releaser diet attenuates oxidative stress, proapoptotic changes and consequent dysfunction in klotho mutant mice by promoting IGF-1 expression and IGF-1 receptor activation.

Methiopropamine, a methamphetamine analogue, produces neurotoxicity via dopamine receptors

Nguyen, Phuong-Tram,Dang, Duy-Khanh,Tran, Hai-Quyen,Shin, Eun-Joo,Jeong, Ji Hoon,Nah, Seung-Yeol,Cho, Min Chang,Lee, Yong Sup,Jang, Choon-Gon,Kim, Hyoung-Chun Elsevier Pub. Co 2019 Chemico-biological interactions Vol.305 No.-

<P><B>Abstract</B></P> <P>Methiopropamine (MPA) is structurally categorized as a thiophene ring-based methamphetamine (MA) derivative. Although abusive potential of MPA was recognized, little is known about the neurotoxic potential of MPA up to now. We investigated whether MPA induces dopaminergic neurotoxicity, and whether MPA activates a specific dopamine receptor. Here, we observed that treatment with MPA resulted in dopaminergic neurotoxicity in a dose-dependent manner. MPA treatment potentiated oxidative parameters (i.e., increases in the level of reactive oxygen species, 4-hydroxynonenal, and protein carbonyl), M1 phenotype-related microglial activity, and pro-apoptotic property (i.e<I>.,</I> increases in Bax- and cleaved caspase-3-expressions, while a decrease in Bcl-2-expression). Moreover, treatment with MPA resulted in significant impairments in dopaminergic parameters [i.e., changes in dopamine level, dopamine turnover rate, tyrosine hydroxylase (TH) levels, dopamine transporter (DAT) expression, and vesicular monoamine transporter-2 (VMAT-2) expression], and in behavioral deficits. Both dopamine D1 receptor antagonist SCH23390 and D2 receptor antagonist sulpiride protected from these neurotoxic consequences. Therefore, our results suggest that dopamine D1 and D2 receptors simultaneously mediate MPA-induced dopaminergic neurodegeneration in mice via oxidative burdens, microgliosis, and pro-apoptosis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> MPA-induced initial oxidative burdens are prerequisite for neurotoxic consequences. </LI> <LI> Dopamine receptors facilitate microglial, and proapoptotic changes induced by MPA. </LI> <LI> Dopamine receptors mediate dopaminergic impairments induced by MPA. </LI> <LI> Microglia, but not astroglia, may be the neurotoxic target against MPA insult. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>