1,2,3,4,6-Penta-O-gallolyl-β-D-glucose가 인간 유래 신경모세포주인 SK-N-SH세포의 인지기능 표지자에 미치는 영향

국문 초록 (Abstract)

인구의 고령화에 따른 노인 인구 증가로 지난 10년간 치매환자수와 경도인지장애 환자수가 급증하였다. 치매는 예방이 중요한 만큼 인지기능 향상에 도움을 줄 수 있는 기능성 소재 탐색에 대한 연구가 필요하다. 한편, PGG는 다양한 약용식물에 함유되어있는 gallotannins로 소교세포에서 항염증효과, amyloid beta 단백질 침착 억제효과, beta-secretase 억제효과가 알려져 있으나 인지 기능과 관련된 지표들에 대한 연구는 부족한 실정이다. 이에 본 연구에서는 PGG가 신경모세포주인 SK-N-SH세포에서 인지기능과 관련된 인자에 미치는 영향을 검토하고 관련 기전에 대해 평가하였다. 퇴행성질환 등에서 그 분비가 증가되는 AChE 효소활성이 PGG 처리에 의해 시험관실험과 세포실험에서 모두 억제되었다. 또한, PGG는 neurotrophin 중의 하나인 BDNF mRNA 및 단백질 발현을 증가하였다. 이러한 PGG의 BDNF 발현 증가에 대한 분자적 기전을 확인하기 위해 CAMKII-CREB 신호경로를 측정한 결과, PGG는 CAMKII를 인산화하였고, BDNF의 전사 인자인 CREB를 활성화하였다. 이상의 결과로부터, hydrolyzed tannins의 하나인 PGG가 신경세포에서 CAMKII-CREB 경로를 활성화함으로써 BDNF의 발현을 증가시킬 뿐만 아니라 AChE 활성을 억제하는 것으로 나타났다. 추가적으로 이러한 PGG의 효과가 인지기능이 저하된 동물모델 등에서도 효과가 있는지를 검토할 필요가 있다. 이러한 자료가 축적이 된다면 향후 PGG가 인지기능 개선을 위한 기능성 소재로서의 사용될 가능성이 있을 것으로 생각된다.

다국어 초록 (Multilingual Abstract)

Cognitive impairment and Alzheimer’s disease are serious social problems associated with the rising elderly population in Korea. 1,2,3,4,6-Penta-O-galloyl-β-D-glucopyranose (PGG) is a gallotannin isolated from medicinal plants such as Rhus chinensis. This study was performed to evaluate the effect of PGG on biomarkers related to cognitive function in human neuroblastoma SK-N-SH cells. Inhibition of acetylcholinesterase (AChE) activity is considered to be one of the main therapeutic strategies. PGG inhibited AChE activity in the test tube as well as in SK-N-SH cells. In addition, PGG induced protein and mRNA expression of brain-derived neurotrophic factor (BDNF), which is a mammalian neurotrophin that plays major roles in the development, maintenance, repair, and survival of neuronal populations. As one of the underlying molecular mechanisms that induce BDNF expression, PGG induced the activation of Ca<SUP>2+</SUP>/calmodulin (CaM)-dependent protein kinase II (CaMKII)-cAMP response element binding protein (CREB) pathway. In conclusion, PGG may be an useful material for improving cognitive function.

목차 (Table of Contents)

• Abstract
• 서론
• 재료 및 방법
• 결과 및 고찰
• 요약
• References

참고문헌 (Reference)

1 황상구, "건강보험 청구자료를 이용한 알츠하이머 치매 치료제와 콜린알포세레이트의 처방 양상 분석" 한국임상약학회 29 (29): 1-8, 2019

2 Hee-Ju Lee, "β-Secretase (BACE1) Inhibitors from Sanguisorbae Radix" 대한약학회 28 (28): 799-803, 2005

3 Jabril E, "The role of acetylcholinesterase inhibitors such as neostigmine and rivastigmine on chronic pain and cognitive function in aging : A review of recent clinical applications" 5 : 175-183, 2019

4 Mendonca P, "The attenuating effects of 1, 2, 3, 4, 6-penta-O-galloyl-beta-D-glucose on inflammatory cytokines release from activated BV-2 microglial cells" 15 : 9-15, 2017

5 Wang Y, "The Role of Dopamine D1 and D3 Receptors in N-Methyl-D-Aspartate(NMDA)/GlycineB Site-Regulated Complex Cognitive Behaviors following Repeated Morphine Administration" 20 : 562-574, 2017

6 Gold PW, "The PPARg system in major depression : pathophysiologic and therapeutic implications" 22 : 9248-, 2021

7 Ren Y, "Synthesis and structure-activity relationship study of antidiabetic penta-O-galloyl-D-glucopyranose and its analogues" 49 : 2829-2837, 2006

8 Statistics Korea, "Statistics on the Aged"

9 이혜인, "SK-N-SH 세포에서 도라지, 더덕, 옥수수수염, 가시오가피의 Nitric Oxide에 의한 세포 독성 억제 효과" 한국식품영양과학회 48 (48): 823-832, 2019

10 Kandiah N, "Rivastigmine : the advantages of dual inhibition of acetylcholinesterase and butyrylcholinesterase and its role in subcortical vascular dementia and parkinson’s disease dementia" 12 : 697-707, 2017

11 Bekinschtein P, "Persistence of long-term memory storage requires a late protein synthesis and BDNF-dependent phase in the hippocampus" 53 : 261-277, 2007

12 Barbacid M, "Neurotrophic factors and their receptors" 7 : 148-155, 1995

13 Luca CDA, "Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer" 21 : 7777-, 2020

14 Abhijit D, "Natural products against Alzheimer's disease : Pharmaco-therapeutics and biotechnological interventions" 35 : 178-216, 2017

15 Patel SS, "Medicinal plants with acetylcholinesterase inhibitory activity" 29 : 491-529, 2018

16 Lisman J, "Mechanisms of CaMKII action in long-term potentiation" 13 : 169-182, 2012

17 Dong Y, "Involvement of autophagy induction in penta-1, 2, 3, 4, 6-O-galloyl-beta-D-glucose-induced senescence-like growth arrest in human cancer cells" 10 : 296-310, 2014

18 Tu Z, "Inhibition of Rabies virus by 1, 2, 3, 4, 6-penta-O-galloyl-beta-d-glucose involves mTORdependent autophagy" 10 : 201-, 2018

19 "Health insurance review & assessment service"

20 Corpuz HM, "Fermented rice peptides attenuate scopolamine-induced memory impairment in mice by regulating neurotrophic signaling pathways in the hippocampus" 1720 : 146322-, 2019

21 Deogracias R, "Expression of the neurotrophin receptor trkB is regulated by the cAMP/CREB pathway in neurons" 26 : 470-480, 2004

22 Baek H, "Experimental study on the effects of Bohyulanshin-tang on brain-derived neurotophic factor expression in SK-N-SH cell line" 2 : 139-145, 2005

23 Briggs R, "Drug treatments in Alzheimer’s disease" 16 : 247-253, 2016

24 Araki S, "Coordination between Calcium/Calmodulin-Dependent Protein Kinase II and Neuronal Nitric Oxide Synthase in Neurons" 21 : 7997-, 2020

25 Chen S, "Combined serum levels of multiple proteins in tPA-BDNF pathway may aid the diagnosis of five mental disorders" 7 : 6871-, 2017

26 Guo XX, "Brainderived neurotrophic factor mediated perfluorooctane sulfonate induced-neurotoxicity via epigenetics regulation in SK-N-SH cells" 18 : 893-, 2017

27 Bruno LG, "Brain-Derived Neurotrophic Factor in Brain Disorders : Focus on Neuroinflammation" 56 : 3295-3312, 2019

28 Kim YH, "Antidepressant-Like and Neuroprotective Effects of Ethanol Extract from the Root Bark of Hibiscus syriacus L" 2018 : 7383869-, 2018

29 Numakawa T, "Action of brain-derived neurotrophin factor in the neurogenesis and neuronal function, and its involvement in the pathophysiology of brain diseases" 19 : 3650-, 2018

30 Fujiwara H, "A traditional medicinal herb Paeonia suffruticosa and its active constituent 1, 2, 3, 4, 6-penta-O-galloyl-beta-Dglucopyranose have potent anti-aggregation effects on Alzheimer's amyloid beta proteins in vitro and in vivo" 109 : 1648-1657, 2009

31 Knight R, "A systematic review and meta-analysis of the effectiveness of acetylcholinesterase inhibitors and memantine in treating the cognitive symptoms of dementia" 45 : 131-151, 2018