Methamphetamine-induced dopaminergic neurotoxicity as a model of Parkinson’s disease

Eun-Joo Shin,정지훈,Yeonggwang Hwang,Naveen Sharma,Duy-Khanh Dang,Bao-Trong Nguyen,나승열,Choon-Gon Jang,Guoying Bing,Toshitaka Nabeshima,Hyoung-Chun Kim 대한약학회 2021 Archives of Pharmacal Research Vol.44 No.7

Parkinson’s disease (PD) is a progressive neurodegenerativedisease with a high prevalence, approximately1 % in the elderly population. Numerous studies have demonstratedthat methamphetamine (MA) intoxication causedthe neurological defi cits and nigrostriatal damage seen inParkinsonian conditions, and subsequent rodent studies havefound that neurotoxic binge administration of MA reproducedPD-like features, in terms of its symptomatology andpathology. Several anti-Parkinsonian medications have beenshown to attenuate the motor impairments and dopaminergicdamage induced by MA. In addition, it has been recognized that mitochondrial dysfunction, oxidative stress, pro-apoptosis,proteasomal/autophagic impairment, and neuroinfl ammationplay important roles in inducing MA neurotoxicity. Importantly, MA neurotoxicity has been shown to share acommon mechanism of dopaminergic toxicity with that ofPD pathogenesis. This review describes the major fi ndingson the neuropathological features and underlying neurotoxicmechanisms induced by MA and compares them with Parkinsonianpathogenesis. Taken together, it is suggested thatneurotoxic binge-type administration of MA in rodents is avalid animal model for PD that may provide knowledge onthe neuropathogenesis of PD.

Microglia Activation Induces Parkinsonism : a New animal Model for Parkinson`s Disease

Bing, Guoying,Kim, Hyoung-Chun 한림대학교 환경·생명과학연구소 2002 [일송 국제심포지엄] 노화와 만성퇴행성 신경질환 Vol.- No.4

Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of dopamine-containing neurons in the substantia nigra pars compacta(SNpc). Although the cause of neuronal death remains unclear, increasing evidence points to the role of inflammatory processes. In this study, we have injected lipopolysaccharide(LPS) into the SNpc to induce local inflammatory changes and have observed dopaminergic neuronal cell loss. Using immunocytochemistry, Western blot analysis, RNAse protection assay(RPA), electron microscopy, DNA fragmentation detection, and locomotor activity analysis we have found that intranigral, intrastriatal or intrapallidal injection of LPS produced a marked microglial activation and a dose-dependent, selective cell loss in the SNpc that is mediated by apoptosis. LPS also induced up-regulation of the mRNA of the cytokines IL-1α, IL-6, IL-10, and TNF-α, as well as activation of nuclear factor-κB(NFκB) detected by nuclear translocation, and increased expression of the apoptosis-related gene Bax in the SNpc. In addition, SNpc neurons were shown to be more susceptible to LPS toxicity than the cells in the adjacent ventral tegmental area(VTA). Moreover, infusion of IL-10 mitigated the LPS-induced loss of dopaminergic neurons in the SNpc. These results demonstrate that LPS-induced activation of microglia and the concomitant increase in pro-inflammatory cytokines may be responsible for the selective cell death observed in the SN and provide a new animal model for the study of Parkinson's disease.

Long-term expression of proenkephalin and prodynorphin in the rat brain after systemic administration of kainic acid - an iin situ hybridization study

Bing.Guoying 강원대학교 종합약학연구소 1996 약학연구 Vol.9 No.-

Long-Term expression of the 35,000 mol. wt fos-related antigen in rat brain after kainic acid treatment

Bing.Guoying Ph.D. 강원대학교 종합약학연구소 1998 약학연구 Vol.10 No.-

Role of microsomal epoxide hydrolase in methamphetamine-induced drug dependence in mice

Shin, Eun-Joo,Bing, Guoying,Chae, Jong Seok,Kim, Tae Woo,Bach, Jae-Hyung,Park, Dae Hun,Yamada, Kiyofumi,Nabeshima, Toshitaka,Kim, Hyoung-Chun Wiley Subscription Services, Inc., A Wiley Company 2009 Journal of neuroscience research Vol.87 No.16

<P>Microsomal epoxide hydrolase (mEH) and cytochrome P-450 (CYP) ensure the rapid detoxification of epoxides generated during the oxidative metabolism of xenobiotics. Although CYP has been demonstrated to modulate methamphetamine (METH)-induced behavioral effects, little is known about the role of the mEH gene on these effects. We examined the role of mEH gene expression in METH-induced conditioned place preference and behavioral sensitization by using mEH<SUP>–/–</SUP> and wild-type (WT) mice. Extracellular dopamine (DA) levels and DA uptake into synaptosomes were assessed by using an in vivo microdialysis and [<SUP>3</SUP>H]DA uptake assay. We applied double-label immunocytochemistry to characterize mEH-positive cellular types. METH-induced behavioral responses paralleled striatal c-Fos-like immunoreactivity. METH treatment resulted in increased extracellular DA levels in the nucleus accumbens but decreased synaptosomal DA uptake in the striatum. These behavioral and neurochemical changes were more pronounced in the mEH<SUP>–/–</SUP> mice than in WT mice. In WT mice, mEH-like immunoreactivity was expressed in astrocytes labeled by GFAP or S100B after METH treatment. The results suggest that epoxide intermediates mediate METH drug dependence and that astrocytic reactions of mEH protein are important in the endogenous modulation in response to METH drug dependence. © 2009 Wiley-Liss, Inc.</P>

Effects of prodynorphin deletion on striatal dopamine in mice during normal aging and in response to MPTP

Nguyen, Xuan V.,Liu, Mei,Kim, Hyoung-Chun,Bing, Guoying Elsevier 2009 Experimental neurology Vol.219 No.1

<P><B>Abstract</B></P><P>Dynorphins, endogenous neuropeptides found in striatonigral neurons, have been observed to exhibit dopamine-inhibitory actions and under some circumstances possess intrinsic neurotoxic activity. To test the hypothesis that dynorphin suppression mitigates effects of aging on the striatal dopaminergic system, HPLC quantitation of dopamine and related amines was performed on striatal homogenates of wild-type (WT) mice and mice lacking the prodynorphin (<I>Pdyn</I>) gene at varying ages. <I>Pdyn</I> knockout (KO) mice at 10 and 20?months show significant elevations in striatal dopamine compared to 3-month mice. Differences in tyrosine hydroxylase (TH) immunoreactivity could not account for these findings, but phosphorylation of TH at Ser40, but not Ser31, was enhanced in aged <I>Pdyn</I> KO mice. Systemic administration of MPTP produced significant dopamine depletion in an age-dependent manner, but <I>Pdyn</I> deletion conferred no protection against MPTP-induced dopamine loss, arguing against a mechanism by which <I>Pdyn</I> deletion enhances dopaminergic neuron survival. The above findings demonstrate an age-dependent inhibitory effect of dynorphins on striatal dopamine synthesis via modulation of TH activity.</P>

Trichloroethylene induces dopaminergic neurodegeneration in Fisher 344 rats

Liu, Mei,Choi, Dong-Young,Hunter, Randy L.,Pandya, Jignesh D.,Cass, Wayne A.,Sullivan, Patrick G.,Kim, Hyoung-Chun,Gash, Don M.,Bing, Guoying Blackwell Publishing Ltd 2010 Journal of Neurochemistry Vol.112 No.3

<P><I>J. Neurochem.</I> (2010) <B>112</B>, 773–783.</P><P>Abstract</P><P>Trichloroethylene, a chlorinated solvent widely used as a degreasing agent, is a common environmental contaminant. Emerging evidence suggests that chronic exposure to trichloroethylene may contribute to the development of Parkinson’s disease. The purpose of this study was to determine if selective loss of nigrostriatal dopaminergic neurons could be reproduced by systemic exposure of adult Fisher 344 rats to trichloroethylene. In our experiments, oral administration of trichloroethylene induced a significant loss of dopaminergic neurons in the substantia nigra pars compacta in a dose-dependent manner, whereas the number of both cholinergic and GABAergic neurons were not decreased in the striatum. There was a robust decline in striatal levels of 3, 4-dihydroxyphenylacetic acid without a significant depletion of striatal dopamine. Rats treated with trichloroethylene showed defects in rotarod behavior test. We also found a significantly reduced mitochondrial complex I activity with elevated oxidative stress markers and activated microglia in the nigral area. In addition, we observed intracellular &agr;-synuclein accumulation in the dorsal motor nucleus of the vagus nerve, with some in nigral neurons, but little in neurons of cerebral cortex. Overall, our animal model exhibits some important features of Parkinsonism, and further supports that trichloroethylene may be an environmental risk factors for Parkinson’s disease.</P>

Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system

Hunter, Randy L.,Dragicevic, Natasa,Seifert, Kristen,Choi, Dong Young,Liu, Mei,Kim, Hyoung‐,Chun,Cass, Wayne A.,Sullivan, Patrick G.,Bing, Guoying Blackwell Publishing Ltd 2007 Journal of Neurochemistry Vol.100 No.5

<P><B>Abstract</B></P><P>Evidence suggests that chronic inflammation, mitochondrial dysfunction, and oxidative stress play significant and perhaps synergistic roles in Parkinson’s disease (PD), where the primary pathology is significant loss of the dopaminergic neurons in the substantia nigra. The use of anti‐inflammatory drugs for PD treatment has been proposed, and inhibition of cyclo‐oxygenase‐2 (COX‐2) or activation of peroxisome proliferator‐activated receptor gamma (PPAR‐γ) yields neuroprotection in MPTP‐induced PD. Lipopolysaccharide (LPS) induces inflammation‐driven dopaminergic neurodegeneration. We tested the hypothesis that celecoxib (Celebrex, COX‐2 inhibitor) or pioglitazone (Actos, PPAR‐γ agonist) will reduce the LPS‐induced inflammatory response, spare mitochondrial bioenergetics, and improve nigral dopaminergic neuronal survival. Rats were treated with vehicle, celecoxib, or pioglitazone and were intrastriatally injected with LPS. Inflammation, mitochondrial dysfunction, oxidative stress, decreased dopamine, and nigral dopaminergic neuronal loss were observed post‐LPS. Celecoxib and pioglitazone provided neuroprotective properties by decreasing inflammation and restoring mitochondrial function. Pioglitazone also attenuated oxidative stress and partially restored striatal dopamine as well as demonstrated dopaminergic neuroprotection and reduced nigral microglial activation. In summary, intrastriatal LPS served as a model for inflammation‐induced dopaminergic neurodegeneration, anti‐inflammatory drugs provided protective properties, and pioglitazone or celecoxib may have therapeutic potential for the treatment of neuro‐inflammation and PD.</P>

Trichloroethylene and Parkinson’s Disease: Risk Assessment

Liu, Mei,Shin, Eun-Joo,Dang, Duy-Khanh,Jin, Chun-Hui,Lee, Phil Ho,Jeong, Ji Hoon,Park, Seok-Joo,Kim, Yong-Sun,Xing, Bin,Xin, Tao,Bing, Guoying,Kim, Hyoung-Chun Springer-Verlag 2018 Molecular neurobiology Vol.55 No.7

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>