Re: 중추신경(선조체, 편도체, 후각피질, 시상하부) 뇌신경을 재생하는 한약연구...

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J Tradit Complement Med

. 2014 Apr-Jun;4(2):77–81. doi: 10.4103/2225-4110.130372

Chinese Traditional Medicine and Adult Neurogenesis in the Hippocampus

Endong Zhang 1,2, Jiangang Shen 6, Kwok Fai So 2,3,4,5,✉

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PMCID: PMC4003705  PMID: 24860729

Abstract

Adult neurogenesis is an important therapeutic target in treating neurological disorders. Adult neurogenesis takes place in two regions of the brain: Subventricular zone and dentate gyrus in the hippocampus. The progressive understanding on hippocampal neurogenesis in aging and mood disorders increases the demand to explore powerful and subtle interventions on hippocampal neurogenesis. Traditional Chinese herbal medicine provides an abundant pharmaceutical platform for modulating hippocampal neurogenesis. Recent progress in exploring the effects of Chinese herbal medicine and the related mechanisms opens a new direction for regeneration therapy. The current review gives a thorough summary of the research progress made in traditional Chinese herbal formulas, and the effective compounds in Chinese herbs which are beneficial on hippocampal neurogenesis and the possible mechanisms involved.

초록

성인 신경 발생은 

신경 장애를 치료하는 데 중요한 치료 표적입니다. 

성인의 신경 발생은 

뇌의 두 영역에서 일어납니다: 

해마의 뇌실하 영역과 치상회입니다. 

노화와 기분 장애에서 해마 신경 발생에 대한 이해가 점진적으로 증가함에 따라 

해마 신경 발생에 대한 강력하고 미묘한 개입에 대한 요구가 증가하고 있습니다. 

전통 한약은 

해마 신경 생성을 조절할 수 있는 풍부한 약제학적 플랫폼을 제공합니다. 

최근 한약의 효과와 관련 메커니즘을 탐구하는 데 있어 

진전이 이루어지면서 재생 치료의 새로운 방향이 열리고 있습니다. 

본 리뷰에서는 

전통 한약 처방에 대한 연구 진행 상황과 해마 신경 생성에 

유익한 한약의 효과적인 화합물 및 관련 메커니즘에 대해 자세히 설명합니다.

Keywords: Active components, Hippocampal neurogenesis, Neural progenitor cells, Traditional Chinese herb

INTRODUCTION

Adult neurogenesis is a continuous bioactivity in certain brain regions. This activity is highly reserved during revolution, from oscines to rodents and primates. In mammals, there are two regions in brain continuously generating the new neurons during adulthood, the subventricular zone and the dentate gyrus.[1]

It had been a long-term ambiguity whether adult neurogenesis in the dentate gyrus had substantial functions. In 2008, clear evidence proved that the newly generated neurons in the dentate gyrus projected axons and established synapses with hilar interneurons, mossy cells, and CA3 pyramidal cells, and released glutamate as their main neurotransmitter.[2] The process of maturation and synapse formation of the adult-born dentate granule cells was causally linked to memory and learning in the brain.[3] For instance, many factors known to be beneficial for memory (e.g. running, environment enrichment) also increased the number of new neurons;[4,5,6,7] likewise, factors that impaired memory, such as aging, stress, and several diseases, were associated with lower neurogenesis levels.[8,9] In addition to learning and memory, adult neurogenesis in the dentate gyrus was proved to be involved in psychological disorders such as depression[4] and anxiety.[5] An impairment of adult neurogenesis in the dentate gyrus could be one of the critical factors in the etiology of certain psychiatric disorders.[6]

Given the significance of the adult neurogenesis in the hippocampus, pharmacological interventions on adult neurogenesis are believed to be one of the key strategies to treat psychological disorders and to improve the cognitive functions during aging. In China, over more than 3200 herbs and 300 mineral and animal extracts are used in more than 400 different formulas.[7] Although there exists distinct theories in the history of drug development between the oriental world and the western world,[7] these Chinese herbs and extracts provide an abundant database for the drug screening and development using the modern technologies in modern bioscience research. Great efforts had been made in the last decade to explore the effects of Chinese herbal medicine on promoting adult neurogenesis, and recent progress indicates that these medicines hold promising potential for neural regeneration therapy. This review tries to give a summary and comparison on the recent research articles focusing on the Chinese herbs and adult neurogenesis in the hippocampus.

소개

성체 신경 발생은 특정 뇌 영역에서 지속적으로 일어나는 생체 활동입니다. 이 활동은 포유류에서 설치류와 영장류에 이르기까지 모든 동물이 성장하는 동안 매우 활발하게 이루어집니다. 포유류의 뇌에는 성체기 동안 지속적으로 새로운 뉴런을 생성하는 두 가지 영역, 즉 뇌실하 영역과 치아상교가 있습니다[1].

성체 상아질의 신경 생성이 실질적인 기능을 하는지 여부는 오랫동안 모호했습니다. 2008년, 상아질에서 새로 생성된 신경세포가 축삭을 돌출하고, 힐러 내뉴런, 이끼 세포, CA3 피라미드 세포와 시냅스를 형성하며, 주요 신경 전달 물질인 글루타메이트를 방출한다는 명확한 증거가 밝혀졌습니다.[2] 성인에서 생성된 상아 과립 세포의 성숙 및 시냅스 형성 과정은 뇌의 기억 및 학습과 인과적으로 연결되어 있습니다.[3] 예를 들어 기억에 도움이 되는 것으로 알려진 많은 요인(예 달리기, 환경 강화) 또한 새로운 뉴런의 수를 증가시켰으며[4,5,6,7] 마찬가지로 노화, 스트레스 및 여러 질병과 같은 기억력을 손상시키는 요인들은 신경 생성 수준을 낮추는 것과 관련이 있었습니다. [8,9] 학습과 기억력 외에도 상아질의 성인 신경 발생은 우울증[4] 및 불안과 같은 심리적 장애에 관여하는 것으로 입증되었습니다.[5] 상아질의 성인 신경 발생의 손상은 특정 정신 장애의 원인 중 하나가 될 수 있습니다[6].

해마에서 성인 신경 발생의 중요성을 고려할 때 성인 신경 발생에 대한 약리학 적 개입은 심리적 장애를 치료하고 노화 중인지 기능을 개선하기위한 핵심 전략 중 하나로 여겨집니다. 중국에서는 3200여 종의 약초와 300여 종의 광물 및 동물 추출물이 400여 가지 제형으로 사용되고 있으며,[7] 동양과 서양의 약물 개발 역사에는 서로 다른 이론이 존재하지만[7] 이러한 중국 약초와 추출물은 현대 생명과학 연구의 현대 기술을 이용한 약물 스크리닝 및 개발을 위한 풍부한 데이터베이스를 제공합니다. 지난 10년 동안 성인 신경 발생 촉진에 대한 한약의 효과를 탐구하기 위해 많은 노력을 기울여 왔으며, 최근의 진전은 이러한 약물이 신경 재생 치료에 대한 유망한 잠재력을 가지고 있음을 나타냅니다. 이 리뷰에서는 한약과 해마의 성인 신경 발생에 초점을 맞춘 최근 연구 논문을 요약하고 비교하려고 합니다.

CHINESE HERBS IN FORMULA AND ADULT NEUROGENESIS

In the history of traditional Chinese medicine (TCM), majority of the TCMs are found to be applied as formulas. Several formulas of TCM have been found to be able to promote adult neurogenesis in the dentate gyrus in stressed animals.[8,9,10] LiuWei Dihuang Tang (六味地黃湯 Liū Wèi Dì Huáng Tāng), a Chinese herbal formula used to treat complications of diabetes and glomerulonephritis, was proved to promote hippocampal neurogenesis in adult rats at a dose of 100 mg/kg, which was thought to be associated with improvement in cognitive function in eight radiating arms.[8] More recently, researchers found that oral treatment of Kami-ondam-tang (加味溫膽湯 Jiā Wèi Wēndăn Tāng) at a dose of 50 mg/kg increased the number of the doublecortin-positive cells in the dentate gyrus in naïve rats, and consequently improved the cognitive functions in mice treated for 2 weeks.[10] Another study using kami-shoyo-san (加味逍遙散 Jiā Wèi Xiāo Yáo Săn) reported that in stressed rats, 20 times of standard dose of kami-shoyo-san was able to reverse the impaired neurogenesis in the hippocampus.[9] The above three studies provide evidence that TCM formulas could enhance neurogenesis in the dentate gyrus, both in physical and pathological conditions. However, each formula contained several components based on the theory of TCM. For example, kami-shoyo-san consisted of nine herbal plants [Paeoniae Radix (白芍 Bái Sháo) 4 g, Bupleuri Radix (柴胡 Chái Hú) 4 g, Atractylodis Macrocephalae Rhizoma (白朮 Bái Zhú) 4 g, Liriopis tuber (麥冬 Mài Dōng) 4 g, Angelicae Gigantis Radix (當歸 Dāng Guī) 4 g, Hoelen (茯苓 Fú Ling) 4 g, Menthae Folium (薄荷腦葉 Bò Hé Năo Yè) 2 g, Glycyrrhizae Radix (甘草 Gān Căo) 2 g, and Zingiberis Rhizoma (生薑 Shēng Jiāng) 6 g].[9] The complex composition of TCMs in formula makes it difficult to further explain which component or components in the formula are beneficial for neurogenesis. It is also unknown whether the effective components have synergistic or antagonistic effects.

포뮬러와 성인 신경 발생에 사용되는 한약재

전통 중국 의학(TCM)의 역사에서 대부분의 한약재는 포뮬러로 활용되는 것으로 밝혀졌습니다. 한약의 여러 포뮬러가 스트레스를 받은 동물의 치아교합에서 성체 신경 발생을 촉진할 수 있는 것으로 밝혀졌습니다. [8,9,10]

당뇨병과 사구체신염의 합병증을 치료하는 데 사용되는 한약 처방인 육미지황탕(六味地黃湯 Liū Wèi Dì Huáng Tāng)은 성인 쥐의 해마 신경 생성을 100 mg/kg 용량으로 촉진하는 것으로 입증되었으며, 이는 8개 방사 팔의 인지 기능 개선과 관련이 있는 것으로 여겨졌습니다. [8] 최근에 연구자들은 가미온담탕(加味溫膽湯 지아 웨이 웬단탕)을 50mg/kg 용량으로 경구 치료하면 순진한 쥐의 상아질에서 이중 코르틴 양성 세포의 수가 증가하여 결과적으로 2주간 치료한 쥐의 인지 기능이 개선된다는 것을 발견했습니다. [10] 가미쇼요산(加味逍遙散 Jiā Wèi Xiāo Yáo Săn)을 사용한 또 다른 연구에서는 스트레스를 받은 쥐의 해마에서 표준 용량의 20배의 가미쇼요산이 손상된 신경 생성을 회복시킬 수 있다고 보고했습니다.[9] 위의 세 연구는 TCM 공식이 신체 및 병리학 조건 모두에서 치아교합의 신경 생성을 향상시킬 수 있다는 증거를 제시합니다. 그러나 각 포뮬러에는 한의학 이론에 기반한 여러 가지 성분이 포함되어 있습니다. 예를 들어, 가미쇼요산은 9가지 허브 식물[백복령(白芍 Bái Sháo) 4g, 복령(柴胡 Chái Hú) 4g, 아트락틸로디스 마크로세팔래 뿌리줄기(白朮 Bái Zhú) 4g, 리리오피스 괴경(麥冬 Mài Dōng) 4g, 당귀 당귀(當歸 Dāng Guī) 4g, 회령(茯苓 Fú Ling) 4g, 박하 뇌엽 보헤뇨예(薄荷腦葉 Bò Hé Năo Yè) 2g, 감초(甘草 Gān Căo) 2g, 징기베리스 근경(生薑 Shēng Jiāng) 6g]. [9] 포뮬러에 포함된 한약재의 복잡한 구성으로 인해 포뮬러의 어떤 성분이 신경 생성에 도움이 되는지 자세히 설명하기 어렵습니다. 또한 유효 성분이 시너지 효과를 내는지 길항 효과를 내는지도 알 수 없습니다.

EFFECTIVE COMPONENTS IN CHINESE HERBS AND HIPPOCAMPAL NEUROGENESIS

According to the principle of “Jun-Chen-Zuo-Shi (君-臣-佐-使)” in the traditional Chinese medical theory, every component in a certain Chinese medicine formula is essential and plays its own respective role. In view of the complex composition in Chinese medicine formulas, popular research direction in the modern science to promote the application of Chinese herbs for neurogenesis has been carried out to study the effective components in Chinese herbs which are able to stimulate neurogenesis in the dentate gyrus. Therefore, the effects of extracts of Chinese formulas on neurogenesis are widely investigated. Table 1 summarizes that active components from different Chinese herbs that have been proved to enhance the hippocampal neurogenesis under naïve and pathological conditions.

한약재의 효과적인 성분과 해마 신경 생성

중국 전통 의학 이론의 “군신좌사(君-臣-佐-使)”의 원칙에 따르면, 특정 한약 처방의 모든 성분은 필수적이며 각자의 역할을 수행합니다. 한약 처방의 복잡한 구성을 고려할 때, 한약의 신경 생성을 위한 응용을 촉진하기 위한 현대 과학의 인기 있는 연구 방향은 상아질의 신경 생성을 자극할 수 있는 한약의 유효 성분을 연구하는 것입니다. 따라서 중국 포뮬러 추출물이 신경 발생에 미치는 영향이 광범위하게 조사되고 있습니다. 표 1은 순진하고 병리학적인 조건에서 해마 신경 발생을 향상시키는 것으로 입증 된 다양한 중국 허브의 활성 성분을 요약 한 것입니다.

Table 1.

Effective component in Chinese herbs beneficial to hippocampal neurogenesis

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In addition, a few interesting comparison studies were carried out to screen the useful components in a certain Chinese formula. For instance, Buyang Huanwu Decoction (補陽還五湯 Bŭ Yáng Huăn Wŭ Tāng) is a classic formula that has been used for post-stroke disability for 300 years.[11] It contains Radix Astragali Membranaceus (黄芪根 Huáng Qígēn), Radix Angelicae Sinensis (白芷 Bái Zhĭ), Radix Paeonia Rubra (赤芍 Chì Sháo), Rhizoma Chuanxiong (川穹 Chuān Qióng), Semen Persicae (桃仁 Táo Rén), Flos Carthami (紅花 Hōng Huā), and earthworm (蚯蚓 Qiū Yĭn). The components are mixed in order in the ratio of 120:10:10:10:10:10:4.5 (dry weight). Either with or without earthworm, Buyang Huanwu Decoction displayed a similar stimulating effect on neurogenesis in stroke rats. The result pointed out that earthworm was not a necessary component in Buyang Huanwu Decoction to stimulate neurogenesis after ischemic injury.[12] Besides, the findings from the same group showed that Buyang Huangwu Decoction improved the neurological scores and functional recovery in stroke rats as well.[13]

PRETREATMENT OF CHINESE HERBS AND HIPPOCAMPAL NEUROGENESIS

Considering that Chinese herbs can be used for health maintenance and disease prevention according to the TCM theory, pretreatment of Chinese herbs by modern scientific techniques is widely investigated in neurodegenerative disease models. The stroke model and Alzheimer's disease model can be taken as examples. Pretreatment with Salvia miltiorrhiza Bunge (丹參 Dān Shēn) or ginsenoside Rd both significantly decreased the infarct volume and reduced the sequential inflammatory response after transient focal ischemia in rats.[14,15] Pretreatment with ruscogenin also proved to be neuroprotective in mice subjected to middle cerebral artery occlusion (MCAO).[16] In the in vitro studies, pretreatment of dicaffeoylquinic acids from Herba Erigerontis (燈盞花 Dēng Zhăn Huā),[17] baji jiasu from Radix Morinda Officinalis (巴戟天 Bā Jĭ Tiān),[18] jatrorrhizine from Coptidis Rhizome (黃連 Huáng Lián),[19] Houttuyniae Herba (魚腥草 Yú Xīng Căo),[20] isorhynchophylline from Uncaria rhynchophylla (鉤藤 Gōu Téng),[21] and extracts from Lycium barbarum (wolfberry)[22,23] led to the compounds display their protective effects against Aβ cell toxicity in different types of neuronal cells. More interestingly, a study of the extracts from Feverfew (甘菊 Gān Jú) showed that pretreatment of 30 mg/kg Feverfew extracts displayed a better outcome than post-treatment of Feverfew extracts at the same dose in the rat MCAO model. Pretreatment of Feverfew extracts preserved the neuronal morphology better in CA1 subfield and increased the number of CA1 neurons that survived compared to the post-treatment of Feverfew.[24] This study raised a conception that pretreatment of TCM might lead to a better outcome than the regular treatment did in the MCAO animal model. Nevertheless, pretreatment of Chinese herbal medicine to modulate hippocampal neurogenesis has been hardly investigated.

A pilot study carried out in our lab was on pretreatment of polysaccharides from wolfberry (枸杞子 Gǒu Qí Zĭ) in a rat depression model. It had been previously confirmed in our lab that chronic injection of 30 mg/kg, 40 mg/kg, and 50 mg/kg corticosterone caused a significant loss of hippocampal neurogenesis and subsequently induced a depression-like behavior in those corticosterone-treated rats. Furthermore, 14 days of physical exercise successfully reversed the impairment of hippocampal neurogenesis and the depression-like behavior in both 30 mg/kg and 40 mg/kg corticosterone treated rats, but failed to do so in 50 mg/kg corticosterone-treated rats.[25] However, 7 days of pretreatment plus 14 days of treatment of wolfberry were able to enhance the neuronal differentiation of the hippocampal neurogenesis and reverse the depression-like behavior caused by 50 mg/kg corticosterone injection.[26] Our data together indirectly suggested that a 7-day pretreatment plus a 14-day treatment of wolfberry might have a stronger impact on hippocampal neurogenesis than the running exercise had. The underlying mechanism of the beneficial effects of the 7-day pretreatment of wolfberry on hippocampal neurogenesis was totally unclear. Therefore, future studies need to be carried out to investigate how the pretreatment of Chinese herbs can induce factors beneficial for hippocampal neurogenesis and what kind of beneficial factors for hippocampal neurogenesis can be induced by pretreatment of TCMs.

POSSIBLE MECHANISMS MEDIATING THE EFFECTS OF CHINESE HERBS ON THE HIPPOCAMPAL NEUROGENESISUpregulation of neurotrophic factors by Chinese herbs

Neurotrophic factors, including neural growth factor (NGF), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), etc., play a central role in cellular proliferation, migration, differentiation, and maintenance in the developing brain.[27] Their presence is crucial across the entire life span for maintenance of neuronal functions, structural integrity of neurons, and neurogenesis. Many Chinese herbs exhibited the ability to promote the secretion of neurotrophic factors and thus enhanced neurogenesis in the hippocampus. Kim Hyo Geun and Oh Myung Sook reported that extracts from Mori Fractus (森喜朗山萸 Sēn Xĭ Lăng Shān Yú) increased the level of NGF in the mouse hippocampus in a dose-dependent manner. The increased NGF significantly enhanced the neuronal differentiation and cell proliferation.[28] Yao et al. found that intragastric administration of cornel iridoid glycoside (CIG), an ingredient extracted from a traditional Chinese herb Cornus officinalis (山茱萸 Shān Zhū Yú), obviously enhanced the mRNA expression‎ of VEGF and its receptor Flk-1 and the protein expression‎ of VEGF, 7 and 28 days after ischemia. This enhancement of VEGF level appeared to be responsible for the neurogenesis in the MCAO rats.[29] Fuzi, kam-ondam tang, and curcumin have been reported to be able to increase the mRNA and protein levels of BDNF in the mouse hippocampus, respectively.[10,30,31] Furthermore, the beneficial effects of Fuzi on hippocampal neurogenesis were neutralized by using TrkB receptor blocker, K252a.[31] Therefore, neurotropic factor signaling pathway seemed to be one of the major targets for traditional Chinese herbs to modulate hippocampal neurogenesis.

Modulation of basic helix-loop-helix family proteins

Basic helix-loop-helix (bHLH) is a protein structural motif that characterizes a family of transcription factors.[32] bHLH transcription factors proved to be essential in mammalian neurogenesis.[33] Li et al. found that in vitro, baicalin treatment selectively upregulated the expression‎ of Mash1 and NeuroD1 in neural progenitor cells,[34] the two members in bHLH family that previously proved to be essential for neuronal commitment in neural stem cells,[35] as well as olfactory neurogenesis.[36] The finding provided the evidence that baicalin is able to modulate the transcription factors and, thus, exerts its effects on neurogenesis in mammals.

PI3K/Akt and ERK pathways

Extracellular signal-regulated kinases (ERK) and PI3K/Akt pathways are most frequently associated with regulation of cell growth, survival, and differentiation.[37,38] Salvianolic acid B (Sal B), one of the major ingredients in the water-soluble extracts of S. miltiorrhiza Bunge, dramatically promoted the proliferation of neural progenitor cells in a dose- and time-dependent manner. This process was exclusively mediated by the PI3K/Akt pathway since the stimulation of neural progenitor cells with Sal B was abolished by Ly294002, a PI3K/Akt inhibitor, while U0126 (ERK inhibitor) or DAPT (Notch inhibitor, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester) had little impact on the Sal B–induced proliferation of neural progenitor cells.[39] On the contrary, administration of curcumin to adult mice resulted in a significant increase in the number of newly born neurons in the dentate gyrus of hippocampus. This increase could be blocked by ERK inhibitor, indicating that curcumin promoted hippocampal neurogenesis through the mitogen-activated protein kinase (MEK)/ERK pathway.[40] The above evidence shows that some Chinese herbs enhance hippocampal neurogenesis through the classic kinase pathways such as PI3K/Akt or MEK/ERK pathway.

In summary, traditional Chinese herbs provide an abundant pharmaceutical platform to modulate hippocampal neurogenesis. Exploring the effective components in Chinese herbs beneficial to hippocampal neurogenesis has improved our understanding of how the administration of Chinese herbs affects hippocampal neurogenesis. Considering health maintenance and disease prevention according to TCM theory, pretreatment of Chinese herbs might be promising to induce factors beneficial in modulating hippocampal neurogenesis. Thus, further studies should be carried out focusing on the effects of pretreatment of TCMs on modulation of hippocampal neurogenesis. Although many promising achievements have been made by using TCMs to enhance hippocampal neurogenesis in several animal models, as well as in in vitro cell cultures, few clinical trials have been conducted so far. One limitation impeding the drug clinical trials on neurogenesis is lack of an in-site method to monitor and calculate the neurogenesis in the hippocampus. Therefore, there still exist several challenging tasks to extend the application of TCMs to neurogenesis in clinical cases.

ACKNOWLEDGMENT

This work was supported by the Fundamental Research Funds for the Central Universities (21609101, K. F. So).

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