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Graduate School of Ajou University
Department of Neuroscience and Technology Course
3. Theses(Master)
MPTP 를 이용한 파킨슨병 동물 모델에서의 케나비노이드 수용체와 바닐로이드 수용체 기능 규명
- Alternative Title
- Studies on the role of CB and TRPV1 receptor in MPTP model of Parkinson's Disease
- Author(s)
- Chung, Young Cheul
- Alternative Author(s)
- Young Cheul, Chung
- Advisor
- 백은주, 진병관
- Department
- 일반대학원 신경과학기술과정
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2010-08
- Language
- eng
- Keyword
- Cannabinoid receptor; Dopaminergic neuron; Parkinson’s disease; Transient receptor potential vanilloid subtype 1; neuroinflammation
- Alternative Abstract
- Parkinson’s disease (PD) is characterized by the degeneration of nigrostriatal dopaminergic (DA) neurons. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exhibit glial activation-derived oxidative stress and inflammation, damaged blood-brain barrier (BBB), infiltrated peripheral immune cells and nigrostriatal DA neuronal damage, and thus serve as an experimental model of PD. Increasing evidence indicates that agonists of cannabinoid (CB) receptor and transient receptor potential vanilloid subtype 1 (TRPV1) have been shown to reduce the production of inflammatory mediators. In addition, recent studies have suggested that these receptors are implicated with the pathogenesis of neurodegenerative disease, such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. The purpose of this study was to investigate the role of CB receptor and TRPV1 on nigrostriatal pathway in MPTP mouse model of PD. Immunohistochemical and biochemical evidence demonstrated that MPTP injection resulted in a significant loss of DA neurons and microglial activation in the nigrostriatal pathway. Western blot analysis and double-label immunohistochemistry show that the translocation of cytosolic proteins (p47phox and Rac1) to the membrane, and p47phox expression of NADPH oxidase in microglia in the SN in vivo, indicating the activation of NADPH oxidase. Reactive oxygen species (ROS) production and oxidative damage, assessed by hydroethidine histochemistry and western blotting, were observed in the SN area in which degeneration of DA neurons occurred. In parallel, RT-PCR analysis and immunohistochemical results showed that glial activation-derived proinflammatory mediators were increased in the MPTP-treated SN. The passage of FITC-labeled albumin (FITC-LA) from blood into SN also showed the MPTP-induced damage of the brain blood barrier (BBB). Additional immunohistotochemical staining revealed peripheral immune cell (T cell, B cell, macrophage and neutorphil) infiltration in the SN and STR. However, treatment with cannabinoids (HU210 and WIN55,212-2) prevents MPTP-induced degeneration of nigrostriatal DA neurons by inhibiting transient expression of proinflammatory cytokines and inducible nitric oxide synthase (iNOS); and attenuating microglial NADPH oxidase activation, reactive oxygen species/reactive nitrogen species production, and consequent oxidative damage. All of these neuroprotective effects were reversed by treatment with CB1 antagonist, AM251 and SR14716a, indicative of CB1 receptor mediation. Moreover, treatment with WIN55,212-2 (agonist of CB1/2) and JWH-133 (selective CB2 agonist) increased survival of DA neurons in the SN, and their fibers in the STR. This neuroprotection is accompanied by preventing of glial activation-derived proinflammatory mediators, BBB disruption and peripheral immune cell infiltration. These in vivo effects were ameliorated by treatment with CB2 antagonists AM630, suggesting direct involvement of CB2 in neuroprotection. Additional study demonstrated that treatment with capsaicin (CAP), TRPV1 agonist, also prevented degeneration of nigrostriatal DA neurons, increased striatal dopamine levels and improved motor function. This neuroprotection afforded by CAP was associated with NADPH oxidase-derived ROS production, reduced expression of pro-inflammatory cytokines by activated microglia. This neuroprotective effects were reversed by treatment with TRPV1 antagonist capsazepine (CZP) and iodo-resinoferatoxin (I-RTX), indicative of TRPV1 receptor mediation. Collectively, these results suggest that cannabinoid and vanilloid system may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with glial activation-derived oxidative stress and proinflammatory mediators, BBB leakage and peripheral immune cell infiltration.
- Fulltext
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- Graduate School of Ajou University > Department of Neuroscience and Technology Course > 3. Theses(Master)
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