• 한국약용작물학회:학술대회논문집
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• 2007.05a
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• pp.255-256
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• 2007

• Journal of Korean Neurosurgical Society
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• v.30 no.6
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• pp.688-698
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• 2001

Objectives : Parkinson's disease is a well-known neurodegenerative disease characterized by dopaminergic cell death in the substantia nigra. The reactive gliosis by activated astrocytes and microglias is no more regarded as a simple sequel of neuronal cell death. Microglial activation takes place in a stereotypic pattern with graded morphologic and functional(resting, activated and phagocytic) changes. In Parkinson's disease animal model, the degree of microglial activation along the nigro-striatal dopaminergic tract has not been studied intensively. The purpose of this study was to elucidate the characteristics of microglial reaction and to grade its degree of activation at substantia nigra and corpus striatum using 6-hydroxydopamine induced rat model of Parkinson's disease. Methods : Using Sprague-Dawley rat, parkinsonian model was made by 6-hydroxydopamine(OHDA) induced destruction of medial and lateral substantia nigra(SN). The rat was sacrificed 3-, 5-, 7-, 14- and 21-day-after operation. For control group, we injected saline with same manner and sacrificed 3-day after operation. With immunohistochemistry, we examined dopaminergic neuronal cells and microglial expression using tyrosine hydroxylase (TH) and OX-42 antibodies, respectively. Also we performed in situ hybridization for osteopontin, a possible marker of subset in activated microglia. Results : 1) In lesioned side of substantia nigra and corpus striatum, the TH immunoreactivity was markedly decreased in whole experimental groups. 2) Using optical densitometry, microglia induced immunoreactivity of OX-42 was counted at SN and corpus striatum. At SN, it was increased significantly on the lesioned side in control and all time-dependent experimental groups. At striatum, it was increased significantly in post lesion 3-day group only(p <0.05). Compared to control group, immunoreactivity of OX-42 on lesioned side was increased in groups, except post lesion 21-day group, at SN. Only post lesion 3-day group showed significance at striatum(p <0.05). Compared to SN region, immunoreactivity of OX-42 was much weaker in striatum. 3) Microscopically, the microglias showed typically different activation pattern. At SN, numerous phagocytic microglias were found at pars compacta and reticularis of lesion side. At striatum, no phagocytic form was found and the intensity of staining was much weaker. 4) At SN, the immunoreactivity of osteopontin showed definite laterality and it was markedly increased at pars compacta of lesion side with relatively short duration time. At striatum, however, it was not detected by in situ hybridization technique. Conclusion : The nigral 6-OHDA induced rat model of Parkinson's disease revealed several characteristic patterns of microglial reaction. At SN, microglias was activated shortly after direct neuronal damage and maintained for about three weeks. In contrast, despite of sufficient dopaminergic insufficiency at striatum, activation of microglias was trivial, and distinguished 3 day later. Antegrade slow neuronal degeneration is major pathophysiology in striatal dopaminergic deficiency. So, the acuteness of neuronal damage and consequential degree of neuronal degeneration may be important factor for microglial activation in neurodegenerative diseases such as Parkinson's disease. Additionally, osteopontin may be a possible marker for several subsets of activated microglia, possibly the phagocytic form.

• Development and Reproduction
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• v.13 no.4
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• pp.257-264
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• 2009

A neurotoxin, 6-hydroxydopamine (6-OHDA) has been widely used to create animal model for Parkinson's disease (PD) due to its specific toxicity against dopaminergic (DA) neurons. Since DA signals modulate a broad spectrum of CNS physiology, one can expect profound alterations in neuroendocrine activities of both PD patients and 6-OHDA treated animals. Limited applications of 6-OHDA injection model, however, have been made on the studies of hypothalamuspituitary neuroendocrine circuits. The present study was performed to examine whether blockade of brain catecholamine (CA) biosynthesis with 6-OHDA can make any alteration in the transcriptional activities of hypothalamus-pituitary hormone genes in adult male rats. Three-month-old male rats (SD strain) were received 6-OHDA ($200{\mu}g$ in $10{\mu}\ell$ of saline/animal) by intracerebroventricular (icv) injection, and sacrificed after two weeks. To determine the mRNA levels of hypothalamuspituitary hormone genes, total RNAs were extracted and applied to the semi-quantitative RT-PCRs. The mRNA levels of tyrosine hydroxylase (TH), the rate-limiting enzyme for the catecholamine biosynthesis, were significantly lower than those from the control group (control:6-OHDA=1:0.72${\pm}$0.02AU, p<0.001), confirming the efficacy of 6-OHDA injection. The mRNA levels of gonadotropin-releasing hormone (GnRH) and corticotropin releasing hormone (CRH) in the hypothalami from 6-OHDA group were significantly lower than those from the control group (GnRH, control:6-OHDA=1:0.39${\pm}$0.03AU, p<0.001; CRH, control:6-OHDA=1:0.76${\pm}$0.07AU, p<0.01). There were significant decreases in the mRNA levels of common alpha subunit of glycoprotein homones (Cg$\alpha$), LH beta subunit (LH-$\beta$), and FSH beta subunit (FSH-$\beta$) in pituitaries from 6-OHDA group compared to control values (Cg$\alpha$, control:6-OHDA=1:0.81${\pm}$0.02AU, p<0.001; LH-$\beta$, control:6-OHDA=1:0.68${\pm}$0.04AU, p<0.001; FSH-$\beta$, control:6-OHDA=1:0.84${\pm}$0.05AU, p<0.001). Similarly, the level of adrenocorticotrophic hormone (ACTH) transcripts from 6-OHDA group was significantly lower than that from the control group (control: 6-OHDA=1:0.86${\pm}$0.04AU, p<0.01). The present study demonstrated that centrally injected DA neurotoxin could downregulate the transcriptional activities of the two hypothalamus-pituitary neuroendocrine circuits, i.e., GnRH-gonadotropins and CRH-ACTH systems. These results suggested that hypothalamic CA input might affect on the activities of gonad and adrenal through modulation of hypothalamus-pituitary function, providing plausible explanation for frequent occurrence of sexual dysfunction and poor stress-response in PD patients.

• Molecules and Cells
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• v.41 no.8
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• pp.742-752
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• 2018

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive degeneration of dopaminergic (DAergic) neurons, particularly in the substantia nigra (SN). Although circadian dysfunction has been suggested as one of the pathophysiological risk factors for PD, the exact molecular link between the circadian clock and PD remains largely unclear. We have recently demonstrated that $REV-ERB{\alpha}$, a circadian nuclear receptor, serves as a key molecular link between the circadian and DAergic systems. It competitively cooperates with NURR1, another nuclear receptor required for the optimal development and function of DA neurons, to control DAergic gene transcription. Considering our previous findings, we hypothesize that $REV-ERB{\alpha}$ may have a role in the onset and/or progression of PD. In the present study, we therefore aimed to elucidate whether genetic abrogation of $REV-ERB{\alpha}$ affects PD-related phenotypes in a mouse model of PD produced by a unilateral injection of 6-hydroxydopamine (6-OHDA) into the dorsal striatum. $REV-ERB{\alpha}$ deficiency significantly exacerbated 6-OHDA-induced motor deficits as well as DAergic neuronal loss in the vertebral midbrain including the SN and the ventral tegmental area. The exacerbated DAergic degeneration likely involves neuroinflammation-mediated neurotoxicity. The $REV-erb{\alpha}$ knockout mice showed prolonged microglial activation in the SN along with the over-production of interleukin $1{\beta}$, a pro-inflammatory cytokine, in response to 6-OHDA. In conclusion, the present study demonstrates for the first time that genetic abrogation of $REV-ERB{\alpha}$ can increase vulnerability of DAergic neurons to neurotoxic insults, such as 6-OHDA, thereby implying that its normal function may be beneficial for maintaining DAergic neuron populations during PD progression.

• Korean Journal of Oriental Medicine
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• v.5 no.1
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• pp.119-131
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• 1999

The effect of herbal medicine on 1-methyl-4-phenylpyridinium ion $(MPP^+)$ and 6-hydroxydopamine (6-OHDA) mediated neurotoxicity was studied in the rat phaeochromocytoma cell line PC12. The present study was designed to test the hypothesis that herbal medicine can protect cells from neurotoxiciy caused by $MPP^+$ and 6-OHDA. Exposure of PC12 cells to 0.2 mM $MPP^+$ and $50\;{\mu}M$ 6-OHDA for 24h resulted in a 50% cell death with respect to the control cells. $MPP^+$ induced cell death was reduced by Yollyounggobondan (延齡固本丹), Sagunjatang (四君子湯), Palmihwan (八味丸), and Palmultang (八物湯)(P<0.05). However, herbal medicines did not protect cells from degeneration caused by the 6-OHDA. Yollyounggobondan, Yungmijihwangwon (六味地黃元), Palmihwan, and Samultang (四物湯) were effective in protecting against $MPP^+$-induced ATP loss in PC12 cells (P<0.05). Yollyounggobondan and Palmultang were effect in neurite protection against 6-OHDA treatment in differentiated PC12 cells with NGF.

• Journal of Ginseng Research
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• v.21 no.1
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• pp.61-67
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• 1997

The present study examined the characteristics of behavior Induced by dopamine agonists following treatment with 6-hydroxydopamine(6-OHDA) unilaterally into left striatum in rats. 6-OHDA was administered at doses of 8,16 and 24 $\mu\textrm{g}$/$\mu\textrm{l}$(in 0.1% ascorbic acid) into dopaminergic neurons in left striatum of 7 weeks old rat under anesthetic. Locomotor activity was significantly decreased at 1 week following 6-OHDA-administration in 7 weeks old rats. The contralateral circling behavior was induced by apomorphine(5 mg/kg, i.v.) after 1 week following 6-OHDA(24$\mu\textrm{g}$/$\mu\textrm{l}$) treatment, and was further increased by repeated administration of apomorphine at 2, 3 and 4 weeks. The contralateral circling behavior was also induced by lisuride and 1-dopa in a dose dependent manner, but not by SK & F 82526 in 7 weeks old rats treated with 6-OHDA. The contralateral circling behavior was significantly higher in 21 weeks old rats but significantly lower In 35 weeks old rats when compared with 7 weeks old rats. The contralateral circling behavior induced by apomorphlne did not differ significantly in 7 and 35 weeks old male and female rats. These results suggest that 6-OHDA treatment into left striatum causes remarkable destrurtion of intrastriatal dopaminergic netcons leading to dopaminergic receptor supersensitivity. Thus, the contralateral circling behavior in duces by apomorphine may be used as indicator for neurodegenerative diseases.

• Proceedings of the PSK Conference
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• 2003.10a
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• pp.108-111
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• 2003

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra. While its precise etiology is unknown, such factors as oxidative stress, impairment of mitochondrial respiration, excitotoxicity and inflammation may play roles in its pathogenesis. Although the role of apoptosis in the process of dopaminergic neuronal death has been highlighted in studies using postmortem brains and experimental models of PD, other evidence implicates both apoptosis and non-apoptotic death in PD. (omitted)

• Journal of Ginseng Research
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• v.19 no.3
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• pp.197-201
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• 1995

The present study was undertaken to elucidate the behavioral characteristics of nootropic candidates, entrophenoxine, N-methyl-D-glucamine, piracetam and red ginseng saponin components on stereotyped sniffing behavior induced by apomorphine in rats. Apomorphine, a direct dopaminergic receptor agonist, induced stereotyped behaviors including sniffing licking growing and biting in a dosedependent manner, and that behaviors were completely inhibited when measured at 1 week after 6-ydroxydopamine(6-HDA) treatment. Centrophenoxine, N-methyl-D-glucamine, red ginseng total saponin(TS), panaxatriol (PT), and Rg1 enhanced but panaxadiol (PD) inhibited, whereas piracetam and Rb1 were not effective of the sterotyped sniffing behavior induced by apomorphine(1mg/kg). The enhanced stereotyped behavior by centrophenoxine, N-methyl-D-glucamine, red ginseng total saponin, panaxatriol(PT), and Rg1 seems to have a similarity to entrophenoxine, N-methyl-D-glucamate in modulating of dopaminergic neuroal activity and also my be useful for the nootropic candidates.

• Development and Reproduction
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• v.15 no.2
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• pp.143-150
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• 2011

The objective of this study was to determine the effect of exercise on a hemiparkinsonian rat model. Nigrostriatal dopamine cell lesions were produced by injecting 6-hydroxydopamine at the left medial forebrain bundle of rats. In this study, the rats were divided into the following 4 groups: the control group without any exercise, experimental group I with aqua-exercise (Exp I), experimental group II with balance exercise (Exp II) and experimental group III with complex exercise (aqua-exercise+balance exercise; (Exp III)). Exercises were applied to all the experimental groups after the operation. In order to observe the dopaminergic cell loss, we assessed the level of tyrosine hydroxylase (TH) expression in the midbrain of rats, and performed the apomorphine-induced rotation test at postoperative days (PDs) 7, 14, and 21. Experimental groups had significantly higher TH-immunoreactivity and behavioral performance than the control group. However, there was no difference in TH-immunoreactivity and behavioral performance across the experimental groups. These results suggest that the application of aqua-exercise and balance exercise could suppress dopaminergic cell loss in the substantia nigra of rat brains and could increase behavioral recovery in hemiparkinsonian rats.

• The Journal of Korean Physical Therapy
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• v.22 no.2
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• pp.47-53
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• 2010

Purpose: This study investigated the effect of electroacupuncture stimulation on changes in blood biochemistry in spinal cord injury (SCI) rats whose cords were damaged by 6-hydroxydopamine (6-OHDA). Methods: Twenty-one Sprague-Dawley adult male rats were assigned to one of three groups: normal (n=7), control (n=7) and experimental group (n=7). The experimental group received electroacupuncture (Es-160, ITO, Japan) for 15 minutes in the form of low frequency (2 Hz) stimulation to the zusanli point. After treatment, we observed motor behavior recovery using the inclined plane test. We also measured serum and CNS concentrations and activities of enzymes including creatine kinase (CK), alkaline phosphatase (ALP), and Immunoglobulin G (IgG). Statistical analysis was done using one-way analysis of variance (ANOVA). Results: Concentrations of CK, ALP and IgG were lower in the experimental group than in the control group. Functional recovery was evaluated by the maximal angle of the inclined board on which rats could maintain their initial position. This allowed us to monitor progressive locomotor recovery. The maximal angles of the inclined plane test were higher in the experimental group than in the control group (p<0.05). Conclusion: The results of this study showed that electroacupuncture to the zusanli point has a therapeutic effect on functional recovery after SCI.