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Planta Med 2010; 76(3): 228-234
DOI: 10.1055/s-0029-1186084
Pharmacology
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Cryptotanshinone, an Acetylcholinesterase Inhibitor from Salvia miltiorrhiza, Ameliorates Scopolamine-Induced Amnesia in Morris Water Maze Task

Kelvin Kin-Kwan Wong1 , Michelle Tsz-Wan Ho2 , Huang Quan Lin3 , Kwok-Fai Lau1 , John A. Rudd3 , Ronald Chi-Kit Chung4 , Kwok-Pui Fung3 , Pang-Chui Shaw1 , David Chi-Cheong Wan3
  • 1Department of Biochemistry, The Chinese University of Hong Kong, Shatin, N. T., Hong Kong SAR, P. R. China
  • 2Molecular Biotechnology Programme, The Chinese University of Hong Kong, Shatin, N. T., Hong Kong SAR, P. R. China
  • 3School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N. T., Hong Kong SAR, P. R. China
  • 4Department of Mechanical & Automation Engineering, The Chinese University of Hong Kong, Shatin, N. T., Hong Kong SAR, P. R. China
Further Information

Publication History

received April 20, 2009 revised July 13, 2009

accepted July 24, 2009

Publication Date:
11 September 2009 (online)

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Abstract

Alzheimer's disease (AD) is a common form of dementia which is characterized by the deposition of amyloids in affected neurons and a cholinergic neurotransmission deficit in the brain. The current therapeutic intervention for AD is primarily based on the inhibition of brain acetylcholinesterase (AChE) to restore the brain acetylcholine level. Cryptotanshinone (CT) is a diterpene extracted from the root of Salvia miltiorrhiza, a herb that is commonly prescribed in Chinese medicine to treat cardiovascular disease. In the present study, we demonstrated that CT is an inhibitor of both human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 values of 4.09 and 6.38 µM, respectively. The IC50 ratio of CT for BuChE : AChE was 1.56. CT inhibited human AChE in a reversible manner, and the inhibition showed the characteristics of mixed-type as both the Km and V max were affected by CT. The effect of CT on learning impairment in scopolamine-treated rats was also evaluated by the acquisition protocol of the Morris water maze. The task learning ability of scopolamine-treated rats was significantly reversed by CT (5 mg/kg), and the CT‐fed rats were able to develop a spatial searching strategy comparable to that of the control animals. In addition, chronic CT treatment did not cause hepatotoxicity as measured by blood alanine transferase (ALT) level. Our findings demonstrate the ability of CT to improve task learning in rats with scopolamine-induced cognitive impairment. These results suggest that CT has the potential as a therapeutic drug for treating AD.

Key words

Alzheimer's disease - Salvia miltiorrhiza - Lamiaceae - cryptotanshinone - acetylcholinesterase inhibitor - Morris water maze - searching strategy

References

  • 1 Sisodia S S, Martin L J, Walker L C, Borchelt D R, Price D L. Cellular and molecular biology of Alzheimer's disease and animal models.  Neuroimaging Clin N Am. 1995;  5 59-68
    PubMedGoogle Scholar
  • 2 Beatty W W, Butters N, Janowsky D S. Patterns of memory failure after scopolamine treatment: implications for cholinergic hypotheses of dementia.  Behav Neural Biol. 1986;  45 196-211
    PubMedGoogle Scholar
  • 3 Giacobini E. Cholinergic function and Alzheimer's disease.  Int J Geriatr Psychiatry. 2003;  18 S1-S5
    CrossrefPubMedGoogle Scholar
  • 4 Perry E K, Perry R H, Blessed G, Tomlinson B E. Changes in brain cholinesterases in senile dementia of Alzheimer type.  Neuropathol Appl Neurobiol. 1978;  4 273-277
    CrossrefPubMedGoogle Scholar
  • 5 Perry E K, Tomlinson B E, Blessed G, Bergmann K, Gibson P H, Perry R H. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia.  Br Med J. 1978;  2 1457-1459
    CrossrefPubMedGoogle Scholar
  • 6 Reichman W E. Current pharmacologic options for patients with Alzheimer's disease.  Ann Gen Hosp Psychiatry. 2003;  2 1
    CrossrefPubMedGoogle Scholar
  • 7 Lane R M, Potkin S G, Enz A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia.  Int J Neuropsychopharmacol. 2006;  9 101-124
    PubMedGoogle Scholar
  • 8 Lee D S, Lee S H, Noh J G, Hong S D. Antibacterial activities of cryptotanshinone and dihydrotanshinone I from a medicinal herb, Salvia miltiorrhiza Bunge.  Biosci Biotechnol Biochem. 1999;  63 2236-2239
    CrossrefPubMedGoogle Scholar
  • 9 Jin D Z, Yin L L, Ji X Q, Zhu X Z. Cryptotanshinone inhibits cyclooxygenase-2 enzyme activity but not its expression.  Eur J Pharmacol. 2006;  549 166-172
    CrossrefPubMedGoogle Scholar
  • 10 Suh S J, Jin U H, Choi H J, Chang H W, Son J K, Lee S H, Jeon S J, Son K H, Chang Y C, Lee Y C, Kim C H. Cryptotanshinone from Salvia miltiorrhiza BUNGE has an inhibitory effect on TNF-alpha-induced matrix metalloproteinase-9 production and HASMC migration via down-regulated NF-kappaB and AP-1.  Biochem Pharmacol. 2006;  72 1680-1689
    CrossrefPubMedGoogle Scholar
  • 11 Ren Y, Houghton P J, Hider R C, Howes M J. Novel diterpenoid acetylcholinesterase inhibitors from Salvia miltiorhiza.  Planta Med. 2004;  70 201-204
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Fadda F, Cocco S, Stancampiano R. Hippocampal acetylcholine release correlates with spatial learning performance in freely moving rats.  Neuroreport. 2000;  11 2265-2269
    CrossrefPubMedGoogle Scholar
  • 13 Fadda F, Melis F, Stancampiano R. Increased hippocampal acetylcholine release during a working memory task.  Eur J Pharmacol. 1996;  307 R1-R2
    CrossrefPubMedGoogle Scholar
  • 14 Hu P, Luo G A, Zhao Z Z, Jiang Z H. Quantitative determination of four diterpenoids in Radix Salviae Miltiorrhizae using LC-MS-MS.  Chem Pharm Bull (Tokyo). 2005;  53 705-709
    CrossrefPubMedGoogle Scholar
  • 15 Ellman G L, Courtney K D, Andres Jr V, Feather-Stone R M. A new and rapid colorimetric determination of acetylcholinesterase activity.  Biochem Pharmacol. 1961;  7 88-95
    CrossrefPubMedGoogle Scholar
  • 16 Brody D L, Holtzman D M. Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury.  Exp Neurol. 2006;  197 330-340
    CrossrefPubMedGoogle Scholar
  • 17 Janus C. Search strategies used by APP transgenic mice during navigation in the Morris water maze.  Learn Mem. 2004;  11 337-346
    CrossrefPubMedGoogle Scholar
  • 18 Gandhi C C, Kelly R M, Wiley R G, Walsh T J. Impaired acquisition of a Morris water maze task following selective destruction of cerebellar purkinje cells with OX7-saporin.  Behav Brain Res. 2000;  109 37-47
    CrossrefPubMedGoogle Scholar
  • 19 Xu Z, Zheng H, Law S L, Dong S D, Han Y, Xue H. Effects of a memory enhancing peptide on cognitive abilities of brain-lesioned mice: additivity with huperzine A and relative potency to tacrine.  J PeptSci. 2006;  12 72-78
    PubMedGoogle Scholar
  • 20 Whishaw I Q. Cholinergic receptor blockade in the rat impairs locale but not taxon strategies for place navigation in a swimming pool.  Behav Neurosci. 1985;  99 979-1005
    CrossrefPubMedGoogle Scholar
  • 21 Kim D H, Jeon S J, Jung J W, Lee S, Yoon B H, Shin B Y, Son K H, Cheong J H, Kim Y S, Kang S S, Ko K H, Ryu J H. Tanshinone congeners improve memory impairments induced by scopolamine on passive avoidance tasks in mice.  Eur J Pharmacol. 2007;  574 140-147
    CrossrefPubMedGoogle Scholar
  • 22 Alcala M M, Vivas N M, Hospital S, Camps P, Munoz-Torrero D, Badia A. Characterisation of the anticholinesterase activity of two new tacrine-huperzine A hybrids.  Neuropharmacology. 2003;  44 749-755
    CrossrefPubMedGoogle Scholar
  • 23 Giacobini E. Cholinesterase inhibitors: new roles and therapeutic alternatives.  Pharmacol Res. 2004;  50 433-440
    CrossrefPubMedGoogle Scholar
  • 24 Atack J R, Perry E K, Bonham J R, Candy J M, Perry R H. Molecular forms of acetylcholinesterase and butyrylcholinesterase in the aged human central nervous system.  J Neurochem. 1986;  47 263-277
    PubMedGoogle Scholar
  • 25 Mesulam M, Guillozet A, Shaw P, Quinn B. Widely spread butyrylcholinesterase can hydrolyze acetylcholine in the normal and Alzheimer brain.  Neurobiol Dis. 2002;  9 88-93
    CrossrefPubMedGoogle Scholar
  • 26 Geula C, Mesulam M M. Cholinesterases and the pathology of Alzheimer disease.  Alzheimer Dis Assoc Disord. 1995;  9 (Suppl. 2) 23-28
    CrossrefPubMedGoogle Scholar
  • 27 Xie M Z, Shen Z F. [Absorption, distribution, excretion and metabolism of cryptotanshinone].  Yao Xue Xue Bao. 1983;  18 90-96
    PubMedGoogle Scholar
  • 28 Yu X Y, Lin S G, Chen X, Zhou Z W, Liang J, Duan W, Chowbay B, Wen J Y, Chan E, Cao J, Li C G, Zhou S F. Transport of cryptotanshinone, a major active triterpenoid in Salvia miltiorrhiza Bunge widely used in the treatment of stroke and Alzheimer's disease, across the blood-brain barrier.  Curr Drug Metab. 2007;  8 365-378
    CrossrefPubMedGoogle Scholar
  • 29 Xue M, Cui Y, Wang H Q, Luo Y J, Zhang B, Zhou Z T. Pharmacokinetics of cryptotanshinone and its metabolite in pigs.  Acta Pharm Sin. 1999;  34 81-84
    PubMedGoogle Scholar
  • 30 Winblad B, Jelic V. Long-term treatment of Alzheimer disease: efficacy and safety of acetylcholinesterase inhibitors.  Alzheimer Dis Assoc Disord. 2004;  18 (Suppl. 1) S2-S8
    CrossrefPubMedGoogle Scholar
  • 31 Kumar V, Becker R E. Clinical pharmacology of tetrahydroaminoacridine: a possible therapeutic agent Alzheimer's disease.  Int J Clin Pharmacol Ther Toxicol. 1989;  27 478-485
    PubMedGoogle Scholar
  • 32 Watkins P B, Zimmerman H J, Knapp M J, Gracon S I, Lewis K W. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease.  JAMA. 1994;  271 992-998
    CrossrefPubMedGoogle Scholar
  • 33 Ibebunjo C, Donati F, Fox G S, Eshelby D, Tchervenkov J I. The effects of chronic tacrine therapy on d-tubocurarine blockade in the soleus and tibialis muscles of the rat.  Anesth Analg. 1997;  85 431-436
    CrossrefPubMedGoogle Scholar
  • 34 Lev-Lehman E, Evron T, Broide R S, Meshorer E, Ariel I, Seidman S, Soreq H. Synaptogenesis and myopathy under acetylcholinesterase overexpression.  J Mol Neurosci. 2000;  14 93-105
    CrossrefPubMedGoogle Scholar
  • 35 Braida D, Paladini E, Griffini P, Lamperti M, Maggi A, Sala M. An inverted U-shaped curve for heptylphysostigmine on radial maze performance in rats: comparison with other cholinesterase inhibitors.  Eur J Pharmacol. 1996;  302 13-20
    CrossrefPubMedGoogle Scholar
  • 36 Saucier D, Hargreaves E L, Boon F, Vanderwolf C H, Cain D P. Detailed behavioral analysis of water maze acquisition under systemic NMDA or muscarinic antagonism: nonspatial pretraining eliminates spatial learning deficits.  Behav Neurosci. 1996;  110 103-116
    CrossrefPubMedGoogle Scholar
  • 37 Linstow R E, Harbaran D, Micheau J, Platt B, Riedel G. Dissociation of cholinergic function in spatial and procedural learning in rats.  Neuroscience. 2007;  146 875-889
    CrossrefPubMedGoogle Scholar
  • 38 Mei Z, Zhang F, Tao L, Zheng W, Cao Y, Wang Z, Tang S, Le K, Chen S, Pi R, Liu P. Cryptotanshinone, a compound from Salvia miltiorrhiza modulates amyloid precursor protein metabolism and attenuates beta-amyloid deposition through upregulating alpha-secretase in vivo and in vitro.  Neurosci Lett. 2009;  452 90-95
    CrossrefPubMedGoogle Scholar
  • 39 Turner P R, O'Connor K, Tate W P, Abraham W C. Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory.  Prog Neurobiol. 2003;  70 1-32
    CrossrefPubMedGoogle Scholar

Pang-Chui Shaw

Department of Biochemistry
The Chinese University of Hong Kong

Shatin, N. T.

Hong Kong

People's Republic of China

Phone: + 85 2 26 09 68 03

Fax: + 85 26 03 51 23

Email: pcshaw@cuhk.edu.hk

David C. C. Wan

School of Biomedical Sciences
The Chinese University of Hong Kong

Shatin, N. T.

Hong Kong

People's Republic of China

Phone: + 85 2 26 09 62 52

Fax: + 85 2 26 03 72 46

Email: chicheongwan@cuhk.edu.hk

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