Reviews 203 Review on Experimental Research of Herbal Medicines with Anti-Amnesic Activity Authors Ming Tsuen Hsieh 1, Wen Huang Peng1, Chi Rei Wu1, Kit Ying Ng2, Chuen Lung Cheng2, Hong Xi Xu2 Affiliations 1 Graduate Institute of Chinese Pharmaceutical Sciences, College of Pharmacy, China Medical University, Taichung, Taiwan 2 Hong Kong Jockey Club Institute of Chinese Medicine, Hong Kong, Peopleʼs Republic of China Key words Abstract AChE: acetylcholinesterase l" amnesia ! AD: Alzheimerʼs disease l" herbal medicines Amnesia is characterized by the inability to form AGR: Acori graminei Soland., Araceae rhi- l" cholinergic system memories or total or partial loss of memory sec- zome l" GABAergic system ondary to cerebral malfunction following degen- AMPA: alpha-amino-3-hydroxy-5-methyl- l" glutaminergic system l" memory enhancement erative diseases, cerebral infections, traumatic in- 4-isoxazolepropionic acid juries and emotional events which could be dif- BBB: blood-brain barrier ferentiated from dementia. However, no effective BDPH: n-butylidenephthalide treatment for amnesia is currently available. cDNA: complimentary deoxyribonucleic Much research effort has been focused on devel- acid oping new drugs from herbal medicines which ChAT choline-acetyltransferase have multifunctional properties. Novel plant ex- CNS: central nervous system tracts and their major or bioactive components E‑p-MCA: E‑p-methoxycinnamic acid including alkaloids, flavonoids, glycosides and FDA: Food and Drug Administration saponins with promising antioxidant effects, vari- GABA: gamma-aminobutyric acid ous effects on cholinergic, GABAergic, glutami- GBE: Ginkgo biloba L., Ginkgoaceae extract nergic, serotonergic, catecholaminergic and hista- GSH: glutathione minergic systems, enhancement of cerebral blood HBA: p-hydroxybenzyl alcohol flow and elevation of ribonucleic acid (RNA) as LDW: Liuwei Dihuang Wang well as protein levels have been studied. In this LTP: long-term potentiation review, we discuss the research findings on novel MAO: monoamine oxidase received August 21, 2009 plant extracts and their bioactives with anti-am- MCA‑Hg: 8-O‑E‑p-methoxycinnamoylharpa- revised October 7, 2009 nesic effects on different neurotransmitter sys- gide accepted Nov. 20, 2009 tems. Developing new drugs from herbal medi- MDA: malondialdehyde Bibliography cines for the treatment of amnesia is a hopeful at- NMDA: N-methyl-D-aspartic acid DOI http://dx.doi.org/ tempt to meet the unmet medical needs. PD/PT ratio: protopanaxadiol/protopanaxatriol 10.1055/s-0029-1240707 ratio This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Published online December 23, 2009 RGTS: red ginseng total saponins Planta Med 2010; 76: 203–217 Abbreviations RNA: ribonucleic acid © Georg Thieme Verlag KG ! RT‑PCR: reverse transcriptase polymerase Stuttgart · New York · 5,7-DHT: 5,7-dihydrotroptamine chain reaction ISSN 0032‑0943 5-HT: serotonin SOD: superoxide dismutase Correspondence 6-OHDA: 6-hydroxydopamine TBARS: thiobarbituric acid reactive species Dr. Hong Xi Xu ACh: acetylcholine Hong Kong Jockey Club Institute of Chinese Medicine Unit 703, 7/F Bio-Informatics Centre Introduction cerebral infections such as herpes or encephalitis, Hong Kong Science Park ! Shatin traumatic injuries such as stroke, alcohol or drug Hong Kong Amnesia is characterized by the inability to form abuse and emotional events such as psychological Peopleʼs Republic of China memories or total or partial loss of memory sec- trauma. The limbic system, comprised of the hip- Phone: + 85234062873 Fax: + 852 35517333 ondary to cerebral malfunction following degen- pocampus, amygdala and parts of the cortex, is [email protected] erative diseases such as Alzheimerʼs disease (AD), responsible for retrieving memory. Memory for- Hsieh MT et al. Review on Experimental … Planta Med 2010; 76: 203–217 204 Reviews mation can be broadly categorized into three distinctive stages, hance the activity of active components from other herbs in ac- namely learning acquisition, memory consolidation and retriev- cordance with traditional practices including traditional Chinese al. Despite the extensive causes of amnesia, the major affected and Ayurvedic medicines. brain regions are usually the subcortical region called the dience- Herbal medicines may confer anti-amnesic protection by scav- phalon and the cortical region called the medial temporal lobe enging free radicals, enhancing cerebral blood flow, restoring ri- [1]. The definition of amnesia can vary considerably according to bonucleic acid (RNA) and protein levels. Besides, neurotransmit- different agreements on the term. This review focuses on recent ter systems were shown to play pivotal roles in cognitive pro- literature on anterograde amnesia, which is the impaired ability cesses where interactions between systems give rise to memory to learn new information following the onset of amnesia, and ret- formation, consolidation and retrieval. Meanwhile, deficits in rograde amnesia, which is the impaired ability to recall past cholinergic, GABAergic, glutaminergic, serotonergic, catechola- events and previously familiar information. Although amnesia is minergic and histaminergic neurotransmissions can account at easily confused with dementia, they are distinguishable from least partly for the pathophysiology of amnesia. Long-term po- each other. Unlike dementia, the amnesic memory loss does not tentiation is an important process in learning and memory, the affect a personʼs intelligence, general knowledge, awareness, at- action of which can be affected by changes in cholinergic, dopa- tention span, judgment, personality or identity. Amnesia can minergic, noradrenergic and serotonergic systems [8–12]. Nu- happen to people at any age which can be a heavy burden to fam- merous research findings have revealed the involvement of ily members and the society, and requires extensive medical care different neurotransmitters in memory processes. Glutamate, and support schemes. GABA, dopamine and acetylcholine were shown to have stronger No conventional or alternative therapy is currently available to impacts on cognitive processes than serotonin and norepineph- cure amnesia. Current therapeutic strategies for amnesia are rine [13]. As reported in a number of experimental paradigms, mainly focused on enhancing or restoring cerebral circulation, re- administration of NMDA antagonists like MK-801and APV, AMPA storing the level of neurotransmitters including acetylcholine antagonists like NBQX and CNQX, GABAA agonists like diazepam (ACh), scavenging free radicals and restoring cell membrane flu- and muscimol, GABAB antagonist (CGP 464 381) and agonist (ba- idity. In the management of amnesia as well as AD, sustained clofen), muscarinic antagonists like scopolamine and atropine, treatment with cholinesterase inhibitors including donepezil, ri- nicotinic antagonist like mecamylamine, serotonin 5-HT1A ago- vastigmine, galantamine and tacrine have been used. However, nist like alaproclate and buspirone, norepinephrine α‑1 antago- these drugs have questionable efficacy and may induce severe nist like prazosin, α‑2 agonist like dexmedetomidine and a β an- side effects including nausea, vomiting, diarrhea and muscle tagonist like propranolol, and dopamine D-2 antagonists like hal- cramps. operidol and sulpiride led to memory impairment, while the uses Since ancient times, herbal medicines have been documented of AMPA agonist like piperidine and norepinephrine α‑1 agonist and used for nootropics (cognition-enhancing agents which aim like St-587 resulted in memory enhancement [13]. at improving concentration, memory retention and problem- The literature was retrieved by searches of the most popular da- solving ability). In China, for example, the use of Panax ginseng tabase Pubmed, using different combinations of keywords in- C.A. Meyer (Araliaceae) to promote health and improve learning cluding “herbs”, “herbal medicines”, “amnesia”, “memory en- and memory is well documented [2–4]. Nowadays, Ginkgo biloba hancement”, “anti-oxidant”, “cholinergic”, “GABAergic”, “gluta- L. (Ginkgoaceae) extract (GBE) has been widely used as a health minergic”, “serotonergic”, “catecholaminergic” and “histaminer- supplement to promote memory and standardized GBE has been gic”. The search covered the period from 1983 to March 2009. Re- approved in the German Commission E Monograph for the symp- views and research articles related to retrograde and anterograde tomatic treatment of the memory impairment, concentration amnesia were included. Additional papers of interest were re- difficulties and depression that result from organic brain disease trieved from the reference lists of the above articles. We man- [5]. In the past few years, the uses of herbal medicines for the ually retrieved some recognized articles which are not available treatment of cognitive impairments such as amnesia, AD or de- electronically. To construct a meaningful discussion on anti-am- mentia have been widely studied; some drugs developed from nesic effect of herbal medicine, studies totally without any at- herbs have shown prominent clinical improvements. A good ex- tempt at mechanistic elucidation were excluded. ample is galantamine (also known as galanthamine), which is an This paper summarizes the research findings and provides an alkaloid extracted from the bulbs of Galanthus nivalis L. (Amaryl- overview of herbal medicines as treatments for both retrograde lidaceae) with a promising effect