Cognitive-Enhancing Herbal Formulae in Korean Medicine: Identification of Candidates by Text Mining and Literature Review

Abstract

Objective:

The main aims of this study were to identify candidates for cognitive-enhancing herbal formulae from the Korean medicine literature and to obtain preliminary data that experimental and clinical researchers could use to develop new cognitive-enhancing drugs.

Methods:

The authors systematically searched for terms related to cognitive enhancement in Dongui Bogam (or Dongyi Baojian), a seminal Korean medicine book. They also reviewed the existing literature on the effects of candidates for cognitive-enhancing herbal formulae and their main constituents.

Results and Conclusions:

Twenty-three candidates were selected for cognitive-enhancing herbal formulae and their main constituents. For 14 herbal formulae among the 23 candidates, on average 5.6 published research papers per herbal formula describing cognitive-enhancing effects were found. In addition, some published papers were identified for 5 main constituents most frequently used to make up the 23 candidates.

Introduction

In a recent article, the authors listed candidate antiaging medicinal herbs based on the literature review of a classic book of Korean medicine (Dongui Bogam or Dongyi Baojian) as a working template for the development of new antiaging drugs. This list was based on a selection of terms describing the antiaging effects of individual herbs. In addition, previous studies focusing on those antiaging candidates were also reviewed.¹ That article focused only on individual medicinal herbs; the current study includes herbal formulae that enhance cognitive ability as an antiaging effect. Because the category of antiaging effects seemed too comprehensive, this report focuses on herbal formulae that enhance cognition. This article lists candidates for cognitive-enhancing herbal formulae (CCEHFs) based on terms describing the cognitive-enhancing effects of herbal formulae (TCEHFs) mentioned in the Dongui Bogam.

This study also sought to provide basic data for further experimental and clinical studies through a preliminary evaluation of the cognitive-enhancing effects of CCEHFs as reported in previous studies.

The research on herbal formulae has been continued from a recent study on individual herbs because combination therapy along with medicinal herbs is a basic principle of Korean medicine.² Using herbal formulae allows maximizing efficacy while minimizing toxicity.³ An herbal formula is not the simple quantitative addition of individual herbs; rather, it produces an effect greater than the sum of its individual constituents.^4,5

Materials and Methods

The methods of this study are similar to those of the previous study.¹ In brief, two steps were used. In the first step, the Dongui Bogam was screened for TCEHFs and CCEHFs and lists were generated. In the second step, previous studies focusing on the cognitive-enhancing effects of the selected CCEHFs and their main constituents were reviewed. Each step was conducted as detailed below.

Selection of TCEHFs and CCEHFs

A total of 3901 herbal formulae (HF), excluding duplicates, are mentioned in the Dongui Bogam. The selected items were revised as per a revised edition of this book.⁶ The terms describing the effects of herbal formulae (TEHFs) were divided into simple descriptive units to closely interpret the meaning of TEHFs depicting each herbal formula. A total of 11,639 TEHFs were analyzed one by one to determine whether they translated into antiaging and cognitive-enhancing concepts in modern science. As a result, a total of 15 candidates for TCEHFs were selected. Then, 26 experts of classic medical literature who are faculty members of formal institutes of Korean medicine and members of the Society of Korean Medical Classics were recruited. Questionnaires about the lists of candidates and the selection criteria for TCEHFs were created and distributed to the experts from July 24 to August 10, 2014.

Only TCEHFs chosen by more than 50% of the respondents were selected. The threshold was set at 50% so that the range of TCEHFs would be wide. The questionnaire was created by the authors and then finalized by an advisory panel consisting of basic and clinical Korean medicine researchers and biological science researchers (n = 6). The survey result signifies that the experts on Korean medicine literature agree that the 15 TCEHFs chosen by the authors appropriately reflect concepts depicting cognitive-enhancing function as an antiaging effect.

The final list consisted of 15 TCEHFs and 23 CCEHFs that contained at least 1 of 15 TCEHFs (Fig. 1).

FIG. 1.

First research step: selection of the cognitive-enhancing effects of herbal formulae (TCEHFs) and candidates for cognitive-enhancing herbal formulae (CCEHFs) found in the Dongui Bogam. HF, herbal formulae; TEHF, the effects of herbal formulae.

Preliminary evaluation of cognitive-enhancing effects of CCEHFs via analysis of previous studies

The authors searched for previous studies on the 23 CCEHFs and decided whether the studies were related to antiaging and cognitive-enhancing research via discussion with the advisory panel (Fig. 2). Furthermore, studies were sorted into in vitro studies, in vivo studies, clinical studies, and reviews, and the result of each study was reanalyzed for research performance status. Korean databases (Ndsl, Oasis, and Riss) were searched for studies on Korean medicine, along with commonly used scientific databases (such as PubMed, Cochrane, and Scopus). The starting period for these study searches was not defined, but January 31, 2015, was set as the final time point. The following keywords were used: [name of the CCEHF] plus “age, aging.” (Published research papers on cognitive-enhancing effects were selected from among those on antiaging effects on the basis of expert's opinion.)

FIG. 2.

Second research step: preliminary evaluation for cognitive-enhancing effects of CCEHFs via analysis of the results of previous studies.

In addition, it was considered necessary to review the effects of the individual constituents as well as the effects of the herbal formula overall. Therefore, the top five herbs were selected in the order of frequency of use among all individual herbs that made up the 23 CCEHFs; the existing studies were then reviewed with regard to the cognitive-enhancing function of each herb among antiaging effects.

Results and Discussion

List of TCEHFs in the Dongui Bogam

All TEHFs of the 3901 HFs in the Dongui Bogam were divided into simple descriptive units; a total of 11,639 were obtained. TEHFs related to treatment of disease were excluded, and 1384 TEHFs were selected. A total of 744 TEHFs remained except for overlapping terms. Next, 165 TEHFs were identified as exerting specific antiaging effects, excluding 579 terms regarding general health from 744 TEHFs. Fifteen TCEHFs were identified as exerting specific cognitive-enhancing effects among the 165 TEHFs. The expert survey was administered to validate the method described previously. Ten of 11 respondents agreed with the validity of the first step, and 1 respondent disagreed (90.9% vs. 9.1%) (Table 1). The agreement ratio for validation of each TCEHF ranged from 53.8% to 100%. Hence, 15 TCEHFs were finalized via further analysis (Table 2).

Table 1.

Results of Survey Regarding Study Methods

Variable	Data
Valid responses, n (%)	10 (90.9)
Invalid responses, n (%)	1 (9.1)
Total respondents/total subjects, n/n (%)	11/26 (42.3)

Table 2.

15 Cognitive-Enhancing Effects of Herbal Formulae

Effect of herbal formula	Respondents for validity (%)
Cures forgetfulness	76.9
Helps the brain memorize 1000 words in a day	53.8
Improves haziness	69.2
Improves haziness	69.2
Treats mental state as in dementia patients	84.6
Improves mental fatigue	61.5
Cures forgetfulness	69.2
Helps one memorize 1000 words in a day	61.5
Improves mental fatigue	61.5
Enhances lack of mental ability	69.2
Improves haziness	69.2
Improves haziness	69.2
Cures forgetfulness	76.9
Cures forgetfulness	76.9
Cures forgetfulness	76.9

Although some particular expressions of cognitive-enhancing effects of herbal formulae are recorded with different wording in the original text, the expressions are translated into the same words in English because they have similar meaning to each other. Hence, we defined them separately in this table.

List of CCEHFs in the Dongui Bogam

We selected 23 CCEHFs in the Dongui Bogam as CCEHFs depicted with at least more than one term for TCEHFs identified in the preceding process (Table 3).

Table 3.

23 Cognitive-Enhancing Herbal Formulae

Jiajiangubenwan
Jiajianbuxintang
Jiaweiningshenwan
Jiangxindan
Qianghuoyufengtang
Kaixinsan
Guipitang
Guishendan
Sumazhou
Shisiyouyuan
Woxuetang
Longnaochuanxiongwan
Yunlinrunshenwan
Liuweidihuangyuan
Renshengao
Zibuyangrongwan
Zhuangyuanwan
Dingzhiwan
Zhuzidushuwan
Zhuquewan
Chuanxiongshigaosan
Tianwangbuxindan
Congmingtang

Given space considerations, constituents of each herbal formula are provided in Supplementary Table S1. (Supplementary materials are available online at www.liebertpub.com/acm).

Preliminary evaluation of cognitive-enhancing effects of CCEHFs via analysis of previous studies

Previous studies were analyzed regarding 23 CCEHFs. As a result, 181 previous studies on 14 CCEHFs were searched. Seventy-eight papers on 14 CCEHFs were finalized, excluding overlapping studies and those not related to antiaging effects and cognitive-enhancing effects (Fig. 3 and Table 4).

FIG. 3.

Number of previous studies on 14 CCEHFs.

Table 4.

Preliminary Evaluation for Cognitive-Enhancing Effects of 23 Cognitive-Enhancing Herbal Formulae via Analysis of Previous Studies

Herbal formula	Classification of study (n)	Source database	Main outcome
Jiajiangubenwan	VT (2)	1: N,^* O,^* R^* 2: N, O	1: Ameliorates memory impairment as a protection against scopolamine⁷ 2: Inhibits CT99-induced apoptotic cell death in the nervous system⁸
Jiajianbuxintang	VV (1) C (1)	1: N, O, R 2: N	1: Increases neuroprotective effect in the hippocampal CA1⁹ 2: Improves cognitive function in vascular dementia¹⁰
Jiaweiningshenwan	VT (1)	1: N	3: Decreases neuronal damage by inhibiting formation of amyloid-β fragment¹¹

Given space considerations, the 20 other herbal formulae are provided in Supplementary Table S2.

Korean databases.

VT, in vitro study; N, Ndsl; O, Oasis; R, Riss; VV, in vivo study; C, clinical study.

According to Figure 3 and Table 4, several studies evaluated the medicinal herbs (numbers refer to the number of studies): jiajiangubenwan (in vitro study [VT]: 2), jiajianbuxintang (in vivo study [VV]: 1; clinical study [C]: 1), jiaweiningshenwan (VT: 1), qianghuoyufengtang (VT: 1; VV: 1), kaisinsan (VT: 2; VV: 10), guipitang (VT: 4; VV: 13; C: 2; review: 1), liuweidihuangyuan (VT:4, VV:1), zibuyangrongwan (VV: 1), zhuangyuanwan (VT: 1, VV: 1), dingzhiwan (VV: 2), zhuzidushuwan (VV: 2), zhuquewan (VV: 1), tianwangbuxindan (VT: 3, VV: 4, C: 3), and congmingtang (VT: 3, VV: 13).

And according to Table 4, 9 of 23 CCEHFs (jiangxintang, guishendan, renshengao, sumazhou, shisiyouyuan, woxuetang, longnaochuanxiongwan, yunlinrunshenwan, chuanxiongshigaosan) have not been the subject of research studies. Among 14 herbal formulae, an average of 5.6 studies per herbal formula that described their cognitive-enhancing effects was obtained. More than 10 studies were performed on 4 items (kaisinsan, guipitang, tianwangbuxindan, and congmingtang); 1 study each was done on 3 CCEHFs (jiaweiningshenwan, zibuyangnongwan, and zhuquewan).

Some of the studies that sought to prove the cognitive-enhancing effects of CCEHFs have been inconclusive. Meanwhile, the previous studies on cognitive-enhancing effects of CCEHFs were found to show antioxidative and neuroprotective mechanism in the brain.

Preliminary evaluation of cognitive-enhancing effects of main constituents via analysis of previous studies

A total of 232 constituents made up the 23 CCEHFs, but after exclusion of overlapping herbs and combination of duplicate origins, 76 constituents remained.

Herbs used more than 10 times are Poria Sclerotium (21), Radix Ginseng (16), Radix Polygalae (14), Radix Angelicae Gigantis (13), and Radix Rehmanniae (11). Under the premise that the more frequently used constituents for 13 CCEHFs herbs have greater cognitive-enhancing effects, the main existing studies were analyzed with regard to their cognitive-enhancing effects as follows.

Previous studies on Poria Sclerotium and Radix Rehmanniae among the five herbs were not searched at all, and only one relevant study each was found for Radix Polygalae and Radix Angelicae Gigantis. Two studies reported cognitive-enhancing effects of tenuifolin extracted from Radix Polygalae and fermented Radix Angelicae Gigantis.^12,13 In contrast, 27 studies were found for Radix Ginseng, excluding overlapping studies.^{14

–40} Most studies sought to verify the cognitive-enhancing effects of ginsenosides, the pharmacologically active ingredients in ginseng.

Conclusion

Fifteen TCEHFs and 23 CCEHFs were selected from the Dongui Bogam, and a preliminary evaluation of the cognitive-enhancing effects of CCEHFs and their main constituents was done via analysis of previous studies. The results of this study should lay the foundation of experimental and clinical research for development of new herbal formulae related to cognitive enhancement.

Footnotes

Acknowledgments

This research was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A2060970).

Author Disclosure Statement

No competing financial interests exist.

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