• The Korean Journal of Physiology and Pharmacology
• /
• v.17 no.1
• /
• pp.89-97
• /
• 2013

Developing an animal model for a specific disease is very important in the understanding of the underlying mechanism of the disease and allows testing of newly developed new drugs before human application. However, which of the plethora of experimental animal species to use in model development can be perplexing. Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a very well known method to induce the symptoms of Parkinson's disease in mice. But, there is very limited information about the different sensitivities to MPTP among mouse strains. Here, we tested three different mouse strains (C57BL/6, Balb-C, and ICR) as a Parkinsonian model by repeated MPTP injections. In addition to behavioral analysis, endogenous levels of dopamine and tetrahydrobiopterin in mice brain regions, such as striatum, substantia nigra, and hippocampus were directly quantified by liquid chromatography-tandem mass spectrometry. Repeated administrations of MPTP significantly affected the moving distances and rearing frequencies in all three mouse strains. The endogenous dopamine concentrations and expression levels of tyrosine hydroxylase were significantly decreased after the repeated injections, but tetrahydrobiopterin did not change in analyzed brain regions. However, susceptibilities of the mice to MPTP were differed based on the degree of behavioral change, dopamine concentration in brain regions, and expression levels of tyrosine hydroxylase, with C57BL/6 and Balb-C mice being more sensitive to the dopaminergic neuronal toxicity of MPTP than ICR mice.

• Journal of Ginseng Research
• /
• v.42 no.4
• /
• pp.429-435
• /
• 2018

Background: Recent studies have shown that Korean Red Ginseng (KRG) successfully protects against dopaminergic neuronal death in the nigrostriatal pathway of a Parkinson's disease (PD) mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration; however, the mechanism has yet to be identified. Therefore, in this study we used two-dimensional electrophoresis to investigate the effects of KRG on the changes in protein expression in the substantia nigra (SN) of MPTP-treated mice. Methods: Male C57BL/6 mice (9 wk old) were intraperitoneally administered MPTP (20 mg/kg) four times at 2-h intervals, after which KRG (100 mg/kg) was orally administered once a day for 5 d. Two hours after the fifth KRG administration, a pole test was conducted to evaluate motor function, after which the brains were immediately collected. Survival of dopaminergic neurons was measured by immunohistochemistry, and protein expression was measured by two-dimensional electrophoresis and Western blotting. Results: KRG alleviated MPTP-induced behavioral dysfunction and neuronal toxicity in the SN. Additionally, the expression of eight proteins related to neuronal formation and energy metabolism for survival were shown to have changed significantly in response to MPTP treatment or KRG administration. KRG alleviated the downregulated protein expression following MPTP administration, indicating that it may enhance neuronal development and survival in the SN of MPTP-treated mice. Conclusion: These findings indicate that KRG may have therapeutic potential for the treatment of patients with PD.

• Korean Journal of Acupuncture
• /
• v.39 no.4
• /
• pp.142-151
• /
• 2022

Objectives : Parkinson's disease (PD) is a neurodegenerative disorder threatening the quality of life and highly occurred in over 65 years old. Gastrodia elata Blume (GEB), a traditional medicine used for the treatment of headache and convulsion, has been reported to have neuroprotective effect. This study was designed to investigate the neuroprotective effect of GEB and the proteomic changes in the substantia nigra (SN) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Methods : Male eleven-week-old C57BL/6 mice were intraperitoneally injected with 30 mg/kg of MPTP at 24-h intervals for 5 days. Two hours after the daily MPTP injection, the mice were orally administered 800 mg/kg of GEB extract, which continued for 7 days beyond the MPTP injections, for a total of 12 consecutive days. Two hours after the final GEB administration, the brain samples were collected, and dopaminergic neuronal death and proteomic changes in the SN were evaluated. Results : GEB prevented the MPTP-induced dopaminergic neuronal death and regulated the expression of 11 proteins including thimet oligopeptidase, T-complex protein 1, glycine tRNA ligase, and pyruvate kinase isozymes M1. Conclusions : GEB prevents MPTP-induced dopaminergic neuronal death by regulating the proteins in the SN.

• Journal of Ginseng Research
• /
• v.39 no.2
• /
• pp.148-154
• /
• 2015

Background: Ginseng is known to have antiapoptotic, anti-inflammatory, and antioxidant effects. The present study investigated a possible role of Korean Red Ginseng (KRG) in suppressing dopaminergic neuronal cell death and the cleavage of p35 to p25 in the substantia nigra (SN) and striatum (ST) using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse model. Methods: Ten-week-old male C57BL/6 mice were injected intraperitoneally with 30 mg/kg of MPTP at 24-h intervals for 5 d, and then administered KRG (1 mg/kg, 10 mg/kg, or 100 mg/kg) once a day for 12 consecutive days from the first injection. Pole tests were performed to assess the motor function of the mice, dopaminergic neuronal survival in the SN and ST was evaluated using tyrosine hydroxylase-immunohistochemistry, and the expressions of cyclin-dependent kinase 5 (Cdk5), p35, and p25 in the SN and ST were measured using Western blotting. Results: MPTP administration caused behavioral impairment, dopaminergic neuronal death, increased Cdk5 and p25 expression, and decreased p35 expression in the nigrostriatal system of mice, whereas KRG dose-dependently alleviated these MPTP-induced changes. Conclusion: These results indicate that KRG can inhibit MPTP-induced dopaminergic neuronal death and suppress the cleavage of p35 to p25 in the SN and the ST, suggesting a possible role for KRG in the treatment of Parkinson's disease.

• Journal of Korean Medicine Rehabilitation
• /
• v.19 no.2
• /
• pp.73-88
• /
• 2009

Objectives : Neuronal changes that result from treadmill exercise for patients with Parkinson's disease(PD) have not been well documented, although some clinical and laboratory reports suggest that regular exercise may produce a neuroprotective effect and restore dopaminergic and motor functions. However, it is not clear if the improvements are due to neuronal alterations within the affected nigrostriatal region or result from a more general effect of exercise on affect areas and motivation. In this study, we demonstrate that motorized treadmill exercise improves the neuronal outcomes in rodent models of PD. Methods : We used a chronic mouse model of parkinsonism, which was induced by injecting male C57BL/6 mice with 10 doses(Every 12 hour) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (30 mg/kg) and probenecid (20 mg/kg) over 5 days. These mice were able to sustain an exercise training program on a motorized rodent treadmill at a speed of 18 m/min, $0^{\circ}$ of inclination, 40 min/day, 5 days/week for 4 weeks. At the end of exercise training, we extracted the brain and compared their neuronal and neurochemical changes with the control(saline and sedentary) mice groups. Synphilin protein is the substance that manifestly reacts with ${\alpha}$-synuclein. In this study, we used Synphilin as a manifest sign of recovery from neurodegeneration. We analyze the brain stems of the substantia nigra and striatum region using the western blotting technique. Results : There were no expression of synphilin in the saline-induced groups. The addition of MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) greatly accelerated synphilin expression which meant an aggregation of ${\alpha}$-synuclein. But, the MPTP-induced treadmill exercise group showed significantly lower expression than the MPTP-induced sedentary group. This means treadmill exercise has a definite effect on the decrease of ${\alpha}$-synuclein aggregation. Conclusions : In this study, our results suggest that treadmill exercise promoted the removal of the aggregation of ${\alpha}$-synuclein, resulting in protection against disease development and blocks the apoptotic process in the chronic parkinsonian mice brain with severe neurodegeneration.

• Journal of the Korean Applied Science and Technology
• /
• v.37 no.4
• /
• pp.744-754
• /
• 2020

We investigated the whether endurance exercise and MitoQ intake mediated neuroprotection are associated with mitochondrial function in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine(MPTP) -induced mice model of Parkinson's disease. C57BL/6 male mice were randomly assigned to five groups: Normal Conrol(NC, n=10), MPTP Control(MC, n=10), MPTP +MitoQ(MQ, n=10), MPTP + Exercise(ME, n=10) and MPTP + MitoQ + Exercise(MQE, n=10). Exercise intervention groups performed the treadmill exercise for 5days/week for 5 weeks with gradual increase of intensity. MitoQ intake groups consumed the MitoQ at a concentration of 250μmol by dissolving with water during experiment period. Our data demonstrated that ME and MQE group restored MPTP-induced motor dysfunction. In addition, treatment groups(MQ, ME and MQE) increased tyrosine hydroxylase levels, and suppressed the accumulation of α-synuclein levels. Futhermore, treatment groups modulated the mitochondrial function such as upregulated mitochondrial biogenesis, increased antioxidant enzyme, enhanced a anti-apoptotic protein(e.g., BCL2), and reduced a pro-apoptotic protein(e.g., BAX). Taken together, these results suggested that endurance exercise and MitoQ intake-mediated increase in mitochondrial function contributes to improvement of aggravated dopaminergic neuronal, resulting in attenuation of motor function of Parkinson's disease.

• Journal of Ginseng Research
• /
• v.42 no.3
• /
• pp.379-388
• /
• 2018

Background: Ginsenosides are the main ingredients of Korean Red Ginseng. They have extensively been studied for their beneficial value in neurodegenerative diseases such as Parkinson's disease (PD). However, the multitarget effects of Korean Red Ginseng extract (KRGE) with various components are unclear. Methods: We investigated the multitarget activities of KRGE on neurological dysfunction and neurotoxicity in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. KRGE (37.5 mg/ kg/day, 75 mg/kg/day, or 150 mg/kg/day, per os (p.o.)) was given daily before or after MPTP intoxication. Results: Pretreatment with 150 mg/kg/day KRGE produced the greatest positive effect on motor dysfunction as assessed using rotarod, pole, and nesting tests, and on the survival rate. KRGE displayed a wide therapeutic time window. These effects were related to reductions in the loss of tyrosine hydroxylase-immunoreactive dopaminergic neurons, apoptosis, microglial activation, and activation of inflammatory factors in the substantia nigra pars compacta and/or striatum after MPTP intoxication. In addition, pretreatment with KRGE activated the nuclear factor erythroid 2-related factor 2 pathways and inhibited phosphorylation of the mitogen-activated protein kinases and nuclear factor-kappa B signaling pathways, as well as blocked the alteration of blood-brain barrier integrity. Conclusion: These results suggest that KRGE may effectively reduce MPTP-induced neurotoxicity with a wide therapeutic time window through multitarget effects including antiapoptosis, antiinflammation, antioxidant, and maintenance of blood-brain barrier integrity. KRGE has potential as a multitarget drug or functional food for safe preventive and therapeutic strategies for PD.

• Journal of Acupuncture Research
• /
• v.27 no.3
• /
• pp.105-116
• /
• 2010

목적 : 이 연구는 MPTP 유발 파킨슨병 동물 모델에서 봉독약침의 신경보호 효과 및 항염증 효과를 확인하기 위해 시행되었다. 방법 : C57BL/6 mice에 신경독소인 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)를 하루에 2시간 간격으로 MPTP-HCl(20mg/kg per dose)을 4번 복강 내 주입하여 중뇌 흑질의 도파민 신경세포를 파괴한 파킨슨병 동물 모델을 유발하였다. 실험군은 MPTP군, MPTP 현종 BVA군, MPTP 곡지 BVA군, MPTP 신수 BVA군의 4군으로 하였다. 마지막 MPTP 투여 2시간 후에 1차로 봉독약침을 시술하고, 그 후 48시간 간격으로 총 5차 연속 시술하였다. 봉독약침액의 농도는 0.2mg/Kg으로 하였고, 경혈은 양측 현종($GB_{39}$), 곡지($LI_{11}$), 신수($BL_{23}$)를 사용했고, 주입량은 각 경혈당 양측으로 각 $20{\mu\ell}$씩 주입하였다. 항염증작용을 알아보기 위해 TH, MAC-1, iNOS HSP70을, 세포사멸에 대한 신경세포의 보호효과를 알아보기 위해 caspase-3을 면역조직화학법을 사용하여 실시하였다. 결과 : 실험 결과 MPTP 유발 파킨슨병 동물 모델에서 현종 곡지 신수혈에 대한 봉독약침은 TH-Immunoreactivity neuron의 감소와 microglial activation을 억제하였다. 봉독약침군 모두 효과를 보였으나 그 중 현종과 신수혈에서 특히 억제작용이 컸다. MAC-1에서는 현종혈이 억제작용이 컸다. HSP70-IR neuron은 곡지에서 유의한 억제작용을 보였으나, iNOS neuron은 모든 군에서 유의한 차이를 보이지 않았다. 또한 세포사멸억제여부 실험에서 봉독약침은 모두 억제작용을 보였으나 특히 곡지자침군에서 caspase-3 발현을 유의하게 억제하였다. 결론 : 이러한 결과는 봉독약침이 MPTP 투여로 인한 중뇌 흑질의 염증에 의한 도파민 신경세포 손상을, 염증을 억제함으로써 항염 효과를 나타냄을 알 수 있으며, 신경세포를 보호하는 활성이 있음을 보여줌과 동시에 세포사멸을 억제하는 활성이 있다고 사료된다.

• Natural Product Sciences
• /
• v.22 no.4
• /
• pp.246-251
• /
• 2016

This study investigated the effects of (-)-sesamin on memory deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of Parkinson's disease (PD). MPTP lesion (30 mg/kg/day, 5 days) in mice showed memory deficits including habit learning memory and spatial memory. However, treatment with (-)-sesamin (25 and 50 mg/kg) for 21 days ameliorated memory deficits in MPTP-lesioned mouse model of PD: (-)-sesamin at both doses improved decreases in the retention latency time of the passive avoidance test and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid, improved the decreased transfer latency time of the elevated plus-maze test, reduced the increased expression of N-methyl-D-aspartate (NMDA) receptor, and increased the reduced phosphorylation of extracellular signal-regulated kinase (ERK1/2) and cyclic AMP-response element binding protein (CREB). These results suggest that (-)-sesamin has protective effects on both habit learning memory and spatial memory deficits via the dopaminergic neurons and NMDA receptor-ERK1/2-CREB system in MPTP-lesioned mouse model of PD, respectively. Therefore, (-)-sesamin may serve as an adjuvant phytonutrient for memory deficits in PD patients.

• The Korean Journal of Physiology and Pharmacology
• /
• v.12 no.2
• /
• pp.65-71
• /
• 2008

The present study examined the inhibitory effect of licorice compounds glycyrrhizin and a metabolite $18{\beta}$-glycyrrhetinic acid on the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse and on the 1-methyl-4-phenylpyridinium ($MPP^+$)-induced cell death in differentiated PC12 cells. MPTP treatment increased the activities of total superoxide dismutase, catalase and glutathione peroxidase and the levels of malondialdehyde and carbonyls in the brain compared to control mouse brain. Co-administration of glycyrrhizin (16.8 mg/kg) attenuated the MPTP effect on the enzyme activities and formation of tissue peroxidation products. In vitro assay, licorice compounds attenuated the $MPP^+$-induced cell death and caspase-3 activation in PC12 cells. Glycyrrhizin up to $100{\mu}M$ significantly attenuated the toxicity of $MPP^+$. Meanwhile, $18{\beta}$-glycyrrhetinic acid showed a maximum inhibitory effect at $10{\mu}M$; beyond this concentration the inhibitory effect declined. Glycyrrhizin and $18{\beta}$-glycyrrhetinic acid attenuated the hydrogen peroxide- or nitrogen species-induced cell death. Results from this study indicate that glycyrrhizin may attenuate brain tissue damage in mice treated with MPTP through inhibitory effect on oxidative tissue damage. Glycyrrhizin and $18{\beta}$-glycyrrhetinic acid may reduce the $MPP^+$ toxicity in PC12 cells by suppressing caspase-3 activation. The effect seems to be ascribed to the antioxidant effect.