Jean Kim

Ajou University, Seoul, Seoul, South Korea

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Publications (5)23.34 Total impact

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    ABSTRACT: We have investigated the effectiveness of transplantation of human neural stem cells into adult rat striatum prior to induction of striatal damage with the mitochondrial toxin 3-nitropropionic acid (3-NP). Systemic 3-NP administration caused widespread neuropathological deficits similar to ones found in Huntington disease (HD) including impairment in motor function (rotarod balance test) and extensive degeneration of neuron-specific nuclear antigen (NeuN)(+) neurons, calbindin(+) neurons and glutamic acid decarboxylase (GAD)(+) striatal neurons. Animals receiving intrastriatal implantation of human neural stem cells (hNSCs) 1 week before 3-NP treatments exhibited significantly improved motor performance and reduced damage to striatal neurons compared with control sham injections. In contrast, transplantation of hNSCs at 12 h after the initial 3-NP administration did not lead to any improvement in motor performance or protect striatal neurons from the 3-NP-induced toxicity. These results indicate that the presence of grafted hNSCs before 3-NP treatment is required for host striatal neuronal protection and enhanced motor function. Immunoreactivity of brain-derived neurotrophic factor (BDNF) was found in vitro in cultured hNSCs and in vivo in grafted NSCs with expression and secretion of BDNF demonstrated by RT-PCR, immunocytochemistry, dot-blot, and ELISA analyses. Thus, protective effects of proactive transplantation of hNSCs may be due, in part, to effects mediated by BDNF. The findings in this work have particular relevance to a rat model of HD in that proactive transplanted hNSCs protect host striatal neurons against neuronal injury and improve motor impairment induced by 3-NP toxicity.
    Neurobiology of Disease 07/2004; 16(1):68-77. · 5.62 Impact Factor
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    ABSTRACT: One week after intranigral injection of thrombin resulted in a dose-dependent loss of dopaminergic neurons (20-78%) in the rat substantia nigra (SN), as evidenced by tyrosine hydroxylase (TH) immunohistochemistry. This cell death was accompanied by localization of terminal deoxynucleotidyl transferase-mediated fluorecein UTP nick end labeling (TUNEL) staining within dopaminergic neurons, activation of caspase-3 and attenuation of dopaminergic neuronal cell death in the SN by the caspase inhibitor (zVAD-fmk), indicative of apoptosis. Furthermore, Western blot analyses and double-immunofluorescent staining showed activation of c-Jun N-terminal kinase (JNK) and p53, and a localization of p53 in the dopaminergic neurons in the SN after thrombin, respectively. Intriguingly, Western blot analyses demonstrated significant down-regulation of Bcl-2 protein, but no alteration in Bax protein expression in the SN after thrombin. Consistent with in vivo data, degeneration of dopaminergic neurons and colocalization of TUNEL and TH were observed in mesencephalic cultures, following treatment with thrombin. Cell death was almost completely abolished by the thrombin-specific inhibitor, hirudin. Thrombin receptor-activating peptides (TRAP-6 and-14) did not mimic the effects of thrombin, even at much higher (1,000 to 2,000-fold) concentrations, although expression of protease-activated receptor-1 (PAR-1) mRNA was detected using RT-PCR. Morphological evidence and molecular events in vivo and in vitro collectively suggest that thrombin induces apoptosis in dopaminergic neurons via non-PAR-1 receptors.
    Neurobiology of Disease 11/2003; 14(2):181-93. · 5.62 Impact Factor
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    ABSTRACT: Metabolic impairment of neurons has been implicated in several neurological disorders, but it is not at present known whether such metabolic impairment has deleterious effects on microglia, the phagocytic cells of the central nervous system (CNS). In the present study, we examined whether metabolic impairment induced by 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, affects the function and viability of microglia in vitro and in vivo. Treatment of HMO6 human microglia cell line with 3-NP induced the elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)) and activation of microglia with production of reactive oxygen species (ROS). Exposure of HMO6 cells to 3-NP also induced cell death as indicated by nuclear fragmentation in a dose- and time-dependent manner. Trolox, an antioxidant agent, was effective in reduction in ROS production and cell death caused by 3-NP. Consistent with in vitro findings, intrastriatal injection of 3-NP in adult rats resulted in an increase in ROS production in microglia in vivo, as evidenced by the oxidation of the reduced MitoTracker probe. ROS production induced by 3-NP was inhibited when trolox was coinjected with 3-NP. Caspase-3 immunoreactivity was demonstrated in OX-42+ microglia in the core and penumbra area of the 3-NP-injected striatum. Apoptotic cell death of microglia was also demonstrated by terminal deoxynucleotidyl- transferase-mediated biotin-dUTP nick end labeling reaction in the 3-NP-induced lesion area. The present results indicate that metabolic impairment in the CNS could involve both activation and cell death of microglia and contribute to pathology in neurodegenerative diseases.
    Neurobiology of Disease 04/2003; 12(2):121-32. · 5.62 Impact Factor
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    ABSTRACT: The present study examined the effects of ATP on the striatum of Sprague-Dawley rats. Intrastriatal administration of ATP produced dose-dependent striatal lesions as confirmed by cresyl violet staining. Additional immunostaining using neuronal nuclear protein (NeuN), OX-42 and GFAP antibodies revealed that ATP caused death of both neurons and glial cells. The nonmetabolizable ATP analogue ATPgammaS and P2X receptor agonist alpha,beta-methylene ATP (alpha,beta-MeATP) mimicked ATP effects, whereas either P2Y receptor agonist ADP or P1 receptor agonist adenosine did not. The P2 receptor antagonist reactive blue 2, but not pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) attenuated ATP-induced striatal injury. These results suggest that intrastriatal administration of ATP causes P2X receptor-mediated cell death in the striatum and support the hypothesis that extracellular ATP can be an important mediator of neuropathological events of brain injuries.
    Neuroreport 10/2002; 13(13):1611-5. · 1.40 Impact Factor
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    ABSTRACT: We recently showed that trisialoganglioside (GT1b) induces cell death of dopaminergic neurons in rat mesencephalic cultures (Chung et al., Neuroreport 12:611-614, 2001). The present study examines the in vivo neurotoxic effects of GT1b on dopaminergic neurons in the substantia nigra (SN) of Sprague-Dawley rats. Seven days after GT1b injection into the SN, immunocytochemical staining of SN tissue revealed death of nigral neurons, including dopaminergic neurons. Additional immunostaining using OX-42 and OX-6 antibodies showed that GT1b-activated microglia were present in the SN where degeneration of nigral neurons was found. Western blot analysis and double-labeled immunohistochemistry showed that inducible nitric oxide synthase (iNOS) was expressed in the SN, where its levels were maximal at 8 h post-GT1b injection, and that iNOS was localized exclusively within microglia. GT1b-induced loss of dopaminergic neurons in the SN was partially inhibited by N(G)-nitro-L-arginine methyl ester hydrochloride, an NOS inhibitor. Our results indicate that in vivo neurotoxicity of GT1b against nigral dopaminergic neurons is at least in part mediated by nitric oxide released from activated microglia. Because GT1b exists abundantly in central nervous system neuronal membranes, our data support the hypothesis that immune-mediated events triggered by endogenous compounds such as GT1b could contribute to the initiation and/or the progression of dopaminergic neuronal cell death that occurs in Parkinson's disease.
    Glia 05/2002; 38(1):15-23. · 5.07 Impact Factor