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JKM > Volume 39(3); 2018 > Article
Lim, Kim, Kim, Kim, and Jeong: Screening of 56 Herbal formulas covered by the National Health Insurance Service on Dementia-related Factors

Abstract

Objectives

The purpose of this study was to investigate the effects of 56 herbal formulae covered by the National Health Insurance Corporation (NHIC) on dementia-related biomarkers and neuronal cell changes.

Methods

The 56 herbal formulae were extracted with 70% ethanol at 100°C for 2 h. The antioxidant properties was measured by radical scavenging assay using ABTS+ radical. The acetylcholinesterase (AChE) activity was tested by Ellman’s assay and amyloid-β (Aβ) aggregation was determined using fluorescence method. To estimate the inhibitory effects of herbal formulae on neuronal cell death and inflammation using HT22 hippocampal cells and BV-2 microglia, respectively.

Results

Among the 56 herbal formulae, Dangguiyukhwangtang, Banhasasimtang, Samhwangsasimtang, Cheongwiesan, Hwangryunhaedoktang, Banhabaekchulchunmatang, Jaeumganghwatang, Cheongseoikgitang, and Hoechunyanggyuksan has a significant inhibitory effects on acetylcholinesterase (AChE) activity. Doinseunggitang and Samhwangsasimtang exerted the effect on the inhibition of amyloid-β (Aβ) aggregation. Additionally, 10 herbal formulae affected AChE and Aβ aggregation revealed antioxidant activity as well as neuroprotective and anti-neuroinflammation effects in neuronal cell lines.

Conclusions

10 herbal formulae that have been shown to be effective against the major dementia markers have been shown to have antioxidant activity, neuronal cell protection and inhibition of brain inflammation. Further investigation of these herbal formulae will need to be validated in dementia animal models.

Inhibition (%)=[1-{(S-S)/(C-C)}]×100
aggregation inhibition (%)=[1-{(S-S)/(C-C)}]×100

Fig. 1
Inhibitory effects of ethanol extract of herbal formulas on acetylcholinesterase (AChE) activity. (A) Dangguiyukhwangtang (DYT), (B) Banhasasimtang (BST), (C) Samhwangsasimtang (SST), (D) Cheongwiesan (CS), (E) Hwangryunhaedoktang (HHT), (F) Banhabaekchulchunmatang (BBCT), (G) Jaeumganghwatang (JGT), (H) Cheongseoikgitang (CIT), and (I) Hoechunyanggyuksan (HYS).
jkm-39-3-1f1.gif
Fig. 2
Inhibitory effects of ethanol extracts of herbal formulas on amyloid β (Aβ) aggregation. (A) Doinseunggitang (DST) and (B) Samhwangsasimtang (SST).
jkm-39-3-1f2.gif
Fig. 3
ABTS radical scavenging activity of ethanol extracts of dementia effective herbal formulas. (A) Dangguiy-ukhwangtang (DYT), (B) Doinseunggitang (DST), (C) Banhasasimtang (BST), (D) Samhwangsasimtang (SST), (E) Cheongwiesan (CS), (F) Hwangryunhaedoktang (HHT), (G) Banhabaekchulchunmatang (BBCT), (H) Jaeumganghwatang (JGT), (I) Cheongseoikgitang (CIT), and (J) Hoechunyanggyuksan (HYS).
jkm-39-3-1f3.gif
Fig. 4
Neuroprotective effects of ethanol extracts of dementia effective herbal formulas. HT22 cells were exposed to H2O2 in the absence or presence of herbal formula extracts for 6 h. Cell viability was determined using CCK assay kit. The results are expressed as mean ± SEM of three independent experiments. ###P< 0.01 vs vehicle control cells; *, P<0.05 **, P<0.01 ***, P<0.001 vs H2O2-treated cells. (A) Dangguiyukhwangtang (DYT), (B) Doinseunggitang (DST), (C) Banhasasimtang (BST), (D) Samhwangsasimtang (SST), (E) Cheongwiesan (CS), (F) Hwangryunhaedoktang (HHT), (G) Banhabaekchulchunmatang (BBCT), (H) Jaeumganghwatang (JGT), (I) Cheongseoikgitang (CIT), and (J) Hoechunyanggyuksan (HYS).
jkm-39-3-1f4.gif
Fig. 5
Anti-neuroinflammatory effects of ethanol extracts of dementia effective herbal formulas. BV-2 cells were pretreated with herbal formula extracts for 2 h and stimulated with LPS for additional 22 h. Culture supernatants were collected and subjected to NO assay using Greiss reagents. Data represent mean ± SEM from three independent experiments. ###, P<0.001 vs untreated control; *, P<0.05 **, P<0.01 ***, P<0.001 vs LPS-treated group. (A) Dangguiyukhwangtang (DYT), (B) Doinseunggitang (DST), (C) Banhasasimtang (BST), (D) Samhwangsasimtang (SST), (E) Cheongwiesan (CS), (F) Hwangryunhaedoktang (HHT), (G) Banhabaekchulchunmatang (BBCT), (H) Jaeumganghwatang (JGT), (I) Cheongseoikgitang (CIT), and (J) Hoechunyanggyuksan (HYS).
jkm-39-3-1f5.gif
Table 1
Inhibitory Activity of the 56 Herbal Formulas in the National Health Insurance Coverage on AChE Activity and Amyloid-β Aggregation in vitro (at 100 μg/mL)
Herbal formulas Original AChE activity inhibition (%) Amyloid-β aggregation inhibition (%)
1 가미소요산(加味逍遙散) 동의신경정신과학 2.47±0.82 −17.88±6.31
2 당귀육황탕(當歸六黃湯) 한방산부인과학 92.32±0.39 15.38±2.37
3 대시호탕(大柴胡湯) 상한론 3.11±2.26 26.76±17.64
4 대황목단피탕(大黃牧丹皮湯) 동의보감 22.54±2.30 47.47±5.79
5 도인승기탕(桃仁承氣湯) 방약합편 26.42±1.61 74.06±3.44
6 반하사심탕(半夏瀉心湯) 동의보감 83.47±1.00 51.63±1.92
7 백출탕(白朮湯) 동의보감 −18.49±0.78 −17.74±17.80
8 보중익기탕(補中益氣湯) 동원십서 −16.20±1.76 −1.32±1.92
9 보허탕(補虛湯) 의학입문 −16.85±1.65 −5.85±1.10
10 삼황사심탕(三黃瀉心湯) 동의보감 93.30±0.23 76.00±5.57
11 소시호탕(小柴胡湯) 상한론 −8.03±5.33 46.15±2.61
12 시호계지탕(柴胡桂枝湯) 동의보감 −12.85±2.28 36.46±5.62
13 오림산(五淋散) 방약합편 −0.45±1.87 24.56±4.39
14 이중탕(理中湯) 방약합편 −12.23±1.04 23.29±1.60
15 이진탕(二陳湯) 방약합편 −9.22±1.19 −26.37±35.65
16 익위승양탕(益胃升陽湯) 방약합편 −9.85±1.33 −6.76±10.14
17 인진호탕(茵蔯蒿湯) 득효력 30.30±0.32 36.98±2.58
18 조위승기탕(調胃承氣湯) 동의보감 34.33±3.15 64.80±10.10
19 청위산(淸胃散) 방약합편 89.12±0.10 −0.29±16.49
20 팔물탕(八物湯) 방약합편 −2.23±3.80 7.83±15.77
21 황금작약탕(黃金芍藥湯) 방약합편 9.07±1.42 41.89±12.74
22 황련해독탕(黃連解毒湯) 방약합편 96.71±0.31 38.57±5.20
23 갈근탕(葛根湯) 상한론 −4.48±3.32 4.64±0.33
24 갈근해기탕(葛根解肌湯) 방약합편 −13.33±9.08 17.90±0.95
25 구미강활탕(九味羌活湯) 방약합편 −25.32±2.82 16.38±2.43
26 궁소산(芎蘇散) 방약합편 −16.28±2.15 29.62±0.24
27 궁하탕(芎夏湯) 방약합편 −6.82±6.34 21.54±0.54
28 내소산(內消散) 방약합편 −19.34±4.48 4.31±0.06
29 당귀연교음(當歸連翹飮) 동의보감 −18.15±3.04 5.78±4.29
30 대청룡탕(大靑龍湯) 상한론 −24.89±3.82 −3.15±3.40
31 대화중음(大和中飮) 방약합편 −5.67±1.53 7.94±3.70
32 반하백출천마탕(半夏白朮天麻湯) 방약합편 67.71±0.11 −3.94±1.56
33 반하후박탕(半夏厚朴湯) 동의보감 −2.30±1.29 42.42±2.31
34 복령보심탕(茯苓補心湯) 방약합편 −7.89±3.29 21.25±6.75
35 불환금정기산(不換金正氣散) 동의보감 −11.45±2.33 29.31±6.20
36 삼소음(蔘蘇飮) 동의보감 −16.97±2.26 11.76±0.83
37 삼출건비탕(蔘朮健脾湯) 동의보감 −15.97±2.12 0.90±1.80
38 삼호작약탕(蔘胡芍藥湯) 방약합편 −19.57±1.09 25.62±0.48
39 생맥산(生脈散) 천금익방 −27.77±1.66 2.99±3.06
40 소청룡탕(小靑龍湯) 상한론 −13.75±0.41 23.94±2.20
41 승양보위탕(升陽補胃湯) 동의보감 2.22±2.23 22.45±5.68
42 시경반하탕(柴梗半夏湯) 방약합편 −5.00±1.82 47.56±1.95
43 시호소간탕(柴胡疏肝湯) 동양의학대사전 0.23±2.56 28.36±2.78
44 시호청간탕(柴胡淸肝湯) 의종금감 3.07±0.39 44.85±30.86
45 안태음(安胎飮) 동의보감 1.25±1.12 33.49±4.08
46 연교패독산(連翹敗毒散) 동의보감 −7.39±0.81 24.20±6.41
47 오적산(五積散) 방약합편 −1.93±0.26 27.59±4.80
48 인삼패독산(人蔘敗毒散) 동의보감 −3.07±0.43 34.16±1.94
49 자음강화탕(滋陰降火湯) 만병회춘 75.72±0.55 37.48±2.64
50 청상견통탕(淸上蠲痛湯) 제중신편 −2.39±0.71 51.58±3.35
51 청서익기탕(淸署益氣湯) 방약합편 82.60±0.30 25.64±6.89
52 평위산(平胃散) 동의보감 −6.42±0.61 31.08±5.91
53 행소탕(산)(杏蘇湯(散)) 동의보감 −7.73±0.81 25.66±18.14
54 향사평위산(香砂平胃散) 방약합편 1.19±0.65 33.58±7.45
55 형개연교탕(荊芥連翹湯) 방약합편 0.51±0.43 38.42±2.03
56 회춘양격산(回春涼隔散) 방약합편 91.87±0.20 49.94±1.20

Berberine 60.63±0.6

Morin 68.3±6.2
Table 2
Cytotoxicity of Dementia Effective Herbal Formulas Against HT22 cells.
μg/mL 0 12.5 25 50 100

Herbal formula
당귀육황탕 100.00±2.47 100.08±7.36 100.25±11.7 100.40±7.12 100.83±5.36
도인승기탕 100.00±8.63 100.27±2.30 100.68±9.44 100.44±8.58 84.89±6.54
반하사심탕 100.00±3.23 101.82±4.37 100.29±8.48 80.75±8.39 67.01±0.46
삼황사심탕 100.00±7.55 100.92±1.81 100.58±9.79 100.83±9.50 84.83±2.96
청위산 100.00±8.52 102.53±5.83 100.07±3.31 100.40±3.01 100.95±3.43
황련해독탕 100.00±8.89 100.89±3.55 100.48±7.84 106.01±5.02 71.12±0.13
반하백출천마탕 100.00±7.80 100.98±3.18 100.48±7.84 106.01±5.02 71.12±0.13
자음강화탕 100.00±6.31 109.26±7.06 102.77±5.95 94.10±4.37 81.54±1.69
청서익기탕 100.00±2.14 100.74±1.47 100.69±1.25 100.30±4.14 86.70±1.59
회춘양격탕 100.00±3.67 100.51±4.82 100.86±2.18 109.49±4.92 95.66±4.72
Table 3
Cytotoxicity of Dementia Effective Herbal Formulas Against BV-2 cells.
μg/mL 0 12.5 25 50 100

Herbal formula
당귀육황탕 100.00±5.27 102.59±4.92 93.39±4.07 90.08±2.43 83.00±2.50
도인승기탕 100.00±1.38 102.56±2.58 102.78±3.27 95.89±4.55 84.96±5.36
반하사심탕 100.00±3.50 95.99±1.11 98.88±1.79 96.17±1.39 85.98±1.30
삼황사심탕 100.00±8.54 80.96±2.24 73.97±2.81 70.32±2.37 66.39±1.03
청위산 100.00±1.53 97.00±2.48 92.33±2.54 90.15±1.98 83.14±1.33
황련해독탕 100.00±2.95 113.31±5.74 99.46±4.13 91.64±4.15 77.36±2.19
반하백출천마탕 100.00±1.92 99.83±1.66 96.63±1.79 91.97±3.05 91.00±0.90
자음강화탕 100.00±1.19 95.42±1.89 91.31±2.68 90.57±0.88 90.44±1.00
청서익기탕 100.00±1.15 98.55±2.81 94.08±2.15 92.57±1.53 91.27±1.50
회춘양격탕 100.00±2.65 98.31±2.08 95.85±1.40 93.65±0.19 93.44±1.84

참고문헌

1. Son CH, Kim YH, Lim S. A Study on Korean Oriental Medical Doctors’ Use of Uninsured Herbal Extracts and How to Promote the Insurance Coverage of Such Herbal Extracts. J Korean Oriental Med. 2009; 30:4. 64–78.


2. Burns A1, Iliffe S. Dementia. BMJ. 2009; 338:b75
crossref

3. Akhondzadeh S, Abbasi SH. Herbal medicine in the treatment of Alzheimer’s disease. Am J Alzheimers Dis Other Demen. 2006; 21:2. 113–8.
crossref pmid

4. Cho HY, Hong SS, Whang WW, Cho SH. A Retrospective Study on Dementia Outpatients in Oriental Neuropsychiatry Clinic of One Medical Center. J of Oriental Neuropsychiatry. 2010; 21: 4. 137–49.


5. Kim BG, Hyun KC, Kim JW, Whang WW. A Clinical Study on the Effects of Oriental Medical Treatment on Dementia of Alzheimer type. J of Oriental Neuropsychiatry. 1998; 9:1. 25–43.


6. Terasawa K, Shimada Y, Kita T, Yamamoto T, Tosa H, Tanaka N, et al. Choto-san in the treatment of vascular dementia: a double-blind, placebo-controlled study. Phytomedicine. 1997; 4: 1. 15–22.
crossref pmid

7. Matsuda Y, Kishi T, Shibayama H, Iwata N. Yokukansan in the treatment of behavioral and psychological symptoms of dementia: a systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol. 2013; 28:1. 80–6.
crossref pmid

8. Lim HS, Kim Y, Kim OS, Jeong SJ. Screening of 50 Korean Herbal formulas with Inhibitory Effects on Acetylcholinesterase Activity and Amyloid-β Aggregation. Kor J Pharmacogn. 2016; 47:3. 287–294.


9. Ministry of Health and Welfare Notice. No. 2014-562014. Apr. 18.
pmid

10. Lim HS, Ha H, Seo CS, Jin SE, Kim Y, Jeon WY, et al. Comparative study on efficacies and ingredient contents of different solvent extracts of Insampaedok-san. Kor J Herbology. 2012; 27: 6. 115–122.
crossref

11. Ellman GL, Courtney KD, Andres V, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961; 7:88–95.
crossref pmid

12. Habtemariam S. The therapeutic potential of Berberis darwinii stem-bark: quantification of berberine and in vitro evidence for Alzheimer’s disease therapy. Nat Prod Commun. 2011; 6:8. 1089–90.
pmid

13. Hellstrand E, Boland B, Walsh DM, Linse S. Amyloid β-protein aggregation produces highly reproducible kinetic data and occurs by a two-phase process. ACS Chem Neurosci. 2010; 1:13–8.
crossref pmid pmc

14. Lemkul JA, Bevan DR. Morin inhibits the early stages of amyloid β-peptide aggregation by altering tertiary and quaternary interactions to produce “off-pathway” structures. Biochemistry. 2012; 51:30. 5990–6009.
crossref pmid

15. Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-evans C. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radical Biol Med. 1999; 26:1231–7.
crossref pmid

16. Prince M, Ali GC, Guerchet M, Prina AM, Albanese E, Wu YT. Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther. 2016; 8:1. 23
crossref pmid pmc

17. Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008; 148:5. 379–97.
crossref pmid

18. Naik RS, Hartmann J, Kiewert C, Duysen EG, Lockridge O, Klein J. Effects of rivastigmine and donepezil on brain acetylcholine levels in acetylcholinesterase-deficient mice. J Pharm Pharm Sci. 2009; 12:79–85.
crossref pmid

19. Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA. 1993; 90:7915–7922.
crossref pmid pmc

20. Koo JS, Seo BI, Park JH, Roh SS. Analysis of papers on Oriental herbal medicines(prescriptions and herbs) for dementia. Kor J Herbology. 2010; 25:131–137.


21. Kim W, Jeon W, Heo E, Park S, Han C. Literature review and suggestions: dementia clinical studies in Korean Oriental Medicine. Kor J Orient Med. 2011; 17:39–46.


22. Vetrivel KS, Thinakaran G. Amyloidogenic processing of betaamyloid precursor protein in intracellular compartments. Neurology. 2006; 66:S69–73.
crossref pmid

23. Eikelenboom P, van Gool WA. Neuroinflammatory perspectives on the two faces of Alzheimer’s disease. J Neural Transm. 2004; 111:281–94.
crossref pmid

24. Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther. 2003; 304:1–7.
crossref pmid

25. Ministry of Health and Welfare Notice. No. 2015-352015. Feb. 23.
pmid pmc

26. Hsu YL, Kuo PI, Tzeng TF, Sung SC, Yen MH, Lin YT, et al. Huang-lian-jie-du-tang, a traditional Chinese medicine prescription, induces cell-cycle arrest and apoptosis in human liver cancer cells in vitro and in vivo. J Gastroenterol Hepatol. 2008; 23:e290–9.
crossref pmid

27. Lu J, Wang JS, Kong LY. Anti-inflammatory effects of Huang-Lian-Jie-Du decoction, its two fractions and four typical compounds. J Ethnopharmacol. 2011; 134:911–8.
crossref pmid

28. Sasaki K, Sudo T, Kurusu T, Kiuchi T, Yoshizaki F. The mechanism of alteration of monoamine metabolism in brain regions in marble burying behavior-isolated housing mice and effect of oren-gedoku-to on this alteration. Yakugaku Zasshi. 2000; 120:6. 559–67.
crossref pmid

29. Chung SY, Kim JW, Lee JR, Jang HH, Kim HT, Whang WW. The Effects of Whangryonghaedoktang on Morris Water Maze and Tyrosine Hydroxylase Expression in Ventral Tegmental Area and Locus Coeruleus of the Chronic Mild Stress Animal Model of Depression. J of Oriental Neuropsychiatry. 2003; 14:1. 1–16.


30. Guoxin DU, Shangqin LIU, Xiaoxi XIE, Li HE, Xiaoling ZHU, Wenyu RONG, et al. The efficacy of Huang-Lian-Jie-Du-Tang combined with chemotherapy for multiple myeloma. J Clinical Hematology. 2012; 25:5. 306–8.


31. Sao L, Goto K, Shimada Y, Terasawa Y. Clinical comparative study of Huangyang detoxification hot water boiled rhubarb and atorvastatin for hyperlipidemia: including diet control, comparison with Placebo. Japan Toyo Kagaku Journal. 2004; 55:236


32. Tohru S. Significance of Combined Use of Huangyaku Toxin for Insomnia in Manic Condition. Journal of Japan Toyo Medical Journal. 2004; 55:179


33. Kim HY, Shin SH, Lee I. Neuroprotective Effect of Hwangryunhaedok-tang Against Glucose-deprivation Induced Cytotoxicity in PC-12 Cells. Korean J Oriental Physiology & Pathology. 2008; 22:6. 1462–9.


34. Qing F, Xiaoping Z, Jianwei M, Mei S. The therapeutic effect of Huanglian Jiedu Decoction on AD rats and its effect on cytokine content. J of Tradit Chin Med. 2004; 29:6. 575–8.


35. Qiu Y, Chen G, Mei G, Wang W, Wang K, Pan S. Effect of Huanglian Jiedu Decoction on free radical metabolism and IL-6, IL-1β content in brain tissue of mice with APP/PS1 double transgenic Alzheimer’s disease. Stroke and neurological diseases. 2011; 18:2. 72–4.


36. Chen G, Shan P, Qiu Y. Clinical study of Huanglian Jiedu Decoction in the treatment of senile dementia (Heart and Liver). Chinese Journal of Emergency Medicine. 2007; 16:4. 386–7.


37. Ministry of Health and Welfare Notice. No. 2017-2142017. Nov. 27.
pmid

38. Lee JY, Kook YB. Effects of Samhwangsasim-tang on obesity-related metabolic disease in mice. Herbal formula science. 2014; 22:1. 93–104.
crossref

39. Lee HC, Jeong MY, Choi JH, Park SY. Effects of Samhwangsasim-tang Gamibang on Atopic Dermatitis in Mice. Herbal formula science. 2017; 25:3. 337–47.


40. Koo JS, Kwon DK, Seo BI, Park JH, Roh SS, Kim SM, et al. The Antimicrobial Activity of Samhwangsasimtang against pseudomonas aeruginosa 38 isolated from an acne patient. Kor J Herbology. 2010; 25:2. 11–9.


41. Seok SH, Kim JH, Kim GW, Koo BS. A case of insomnia incurable by neuropsychiatric medication alone, but made possible with Sam-Hwang-Sa-Sim-Tang. J of Oriental Neuropsychiatry. 2006; 17:3. 117–29.


42. Shin SU, Lee JS, Kim SS. Effect of modified Samhwangsasim-tang(三黃瀉心湯加味方) on Suspicious Dementia of Multiple Infarction Induced by Hypoxia: A Case Report. J Oriental Rehab Med. 2001; 11:2. 219–26.


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