Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Protective Effects of Quercetin-3-O-glucuronide against 1-methyl-4-phenylpyridinium-induced Neurotoxicity

1-methyl-4-phenylpyridinium으로 유도된 신경 손상에 대한 quercetin-3-O-glucuronide의 보호 효과

  • Pariyar, Ramesh (Institute of Pharmaceutical Research and Development,College of Pharmacy, Wonkwang University) ;
  • Bastola, Tonking (Institute of Pharmaceutical Research and Development,College of Pharmacy, Wonkwang University) ;
  • Seo, Jungwon (Institute of Pharmaceutical Research and Development,College of Pharmacy, Wonkwang University)
  • Received : 2019.02.09
  • Accepted : 2019.02.21
  • Published : 2019.02.28
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Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disease that mainly affects motor system with clinical features such as bradykinesia, rigidity, tremor and abnormal posture. PD is characterized by the death of dopaminergic neurons in the substantia nigra pars compacta, which is associated with accumulation of oxidative stress and dysregulation of intracellular signaling pathway. Quercetin-3-O-glucuronide (Q3GA), a major metabolite of quercetin, has been reported to have neuroprotective effects. In this study, we examined the neuroprotective effect of Q3GA against 1-methyl-4-phenyl pyridinium ($MPP^+$)-induced neurotoxicity of PD and the underlying molecular mechanisms in SH-SY5Y cells. MTT and LDH assay showed that Q3GA significantly decreased $MPP^+$-induced cell death, which is accompanied by a reduction in poly (ADP-ribose) polymerase (PARP) cleavage. Furthermore, it attenuated $MPP^+$-induced intracellular reactive oxygen species (ROS) with the reduction of Bax/ Bcl-2 ratio. Moreover, Q3GA significantly increased the phosphorylation of Akt and cAMP response element binding protein (CREB), but it has no effects on the phosphorylation of extracellular signal-regulated kinase (ERK). Taken together, these results demonstrate that Q3GA significantly attenuates $MPP^+$-induced neurotoxicity through ROS reduction and Akt/CREB signaling pathway in SH-SY5Y cells. Our findings suggest that Q3GA might be one of the potential candidates for the prevention and/or treatment of PD.

파킨슨병은 운동완서, 근육경직, 진전 및 비정상적인 자세 등을 임상적 특징으로 하는 주로 운동 신경계에 영향을 주는 진행성 신경 퇴행성 질환이다. 파킨슨병은 산화 스트레스와 세포 내 신호 전달 경로의 조절 장애에 의한 뇌 흑색치밀부에서의 도파민성 신경세포의 사멸을 특징으로 한다. Quercetin의 주요 대사산물인 Quercetin-3-O-glucuronide (Q3GA)는 신경 보호 효과가 있는 것으로 보고 되어 왔다. 본 연구에서는 SH-SY5Y 세포에서 1-methyl-4-phenyl pyridinium ($MPP^+$)에 의해 유도된 신경 독성에 대한 Q3GA의 신경 보호 효과와 그 분자 조절 기전을 조사하였다. Q3GA는 $MPP^+$에 의해 유도된 세포 사멸을 유의적으로 감소시켰으며 PARP 절단을 감소시켰다. 또한, Bax/Bcl-2 비율의 감소와 함께 $MPP^+$에 의해 증가된 세포 내 ROS를 감소시켰다. Q3GA는 $MPP^+$에 의해 감소된 Akt와 CREB의 인산화를 유의적으로 회복시켰지만, ERK에는 영향을 미치지 않았다. 이 결과는 Q3GA가 ROS 생산 억제와 Akt/CREB 신호 전달 경로를 통해 $MPP^+$ 에 의해 유도된 신경 독성을 억제시킬 수 있음을 시사한다. 본 연구는 Q3GA가 파킨슨병에 대한 예방제 또는 치료제로 개발될 수 있는 가능성을 제시한다.

Keywords

SMGHBM_2019_v29n2_191_f0001.png 이미지

Fig. 1. Q3GA protectes SH-SY5Y cells against MPP+-induced cytotoxicity.

SMGHBM_2019_v29n2_191_f0002.png 이미지

Fig. 2. Q3GA suppresses MPP+-induced intracellular accumulation of ROS in SH-SY5Y cells.

SMGHBM_2019_v29n2_191_f0003.png 이미지

Fig. 3. Q3GA markedly attenuates MPP+ -induced PARP proteolysis and Bax/Bcl2 ratio.

SMGHBM_2019_v29n2_191_f0004.png 이미지

Fig. 4. MPP+ decreases Akt and CREB phosphorylation, whereas Q3GA reverses those effects.

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