Cholinesterase inhibitory and anti-amnesic activity of alkaloids from Corydalis turtschaninovii

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Abstract

In the course of screening plants used in Korean folk medicine as memory enhancers, a 70% ethanol extract of tuber from Corydalis turtschaninovii Besser (Papaveraceae) showed significant acetylcholinesterase (AChE) inhibitory activity. Repeated column chromatography led to the isolation of a new aporphine alkaloid, oxoglaucidaline (9), and a new protoberberine, pseudodehydrocorydaline (13) together with 14 known compounds (18, 1012, and 1416). The chemical structures of isolated compounds were elucidated base on extensive 1D and 2D NMR spectroscopic data. Compounds 116 were investigated in vitro for their anti-cholinesterase activity using the mice cortex AChE enzyme. In further study, the anti-amnesic activities of pseudoberberine (16) in mice on the learning and memory impairments induced by scopolamine (1.0 mg/kg, i.p.) were examined. This alkaloid (5.0 mg/kg, p.o.) administration significantly reversed cognitive impairments in mice by passive avoidance test (P < 0.05). It also reduced escape latencies in training trials and prolonged swimming times in the target quadrant during the probe trial in the water maze task (P < 0.05). These results indicated that Corydalis turtschaninovii due to its alkaloids have anti-cholinesterase activity and pseudoberberine and other alkaloids have anti-amnesic activities that may be useful for cognitive impairment treatment.

Introduction

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease with many cognitive and neuropsychiatric manifestations that result in progressive disability and eventual incapacitation. A decrease of acetylcholine in the brain of patients with AD appears to be a critical element in producing dementia (Becker et al., 1988). Loss of cholinergic cells, particularly in the basal forebrain, is accompanied by loss of the neurotransmitter acetylcholine. One approach is to inactivate acetylcholinesterase (AChE), the enzyme that cleaves synaptic acetylcholine and terminates neuronal signaling. AChE inhibitors increase the availability of acetylcholine in central cholinergic synapses and are the most promising currently available drugs for the treatment of AD (Giacobini, 2000). AChE inhibitors from general chemical classes such as physostigmine, tacrine, donepezil, galanthamine, huperzine A and heptylphysostigmine have been tested for the symptomatic treatment of AD. Although there have been a number of reports on the designing and development of synthetic AChE inhibitors, that were necessary for other studies, which have been reported the AChE inhibitors derived from medicinal plants (Oh et al., 2004, Houghton et al., 2006).

In our screening program to search for AChE inhibitors from plants, a 70% ethanolic extract of Corydalis turtschaninovii Besser forma yanhusuo (Papaveraceae) exhibited significant AChE inhibitory activity (72.5% at 100 μg/mL). Previously reports showed that several species of the genera Corydalis have been used in the treatment of memory dysfunction in folk medicine (Orhan et al., 2004, Houghton et al., 2006). Corydalis turtschaninovii have been used in traditional medicine for the treatment of gastric, duodenal ulcer, cardiac arrhythmia disease (Kamigauchi and Iwasa, 1994), rheumatism, dysmenorrheal (Tang and Eisenbrand, 1992), and memory dysfunction (Orhan et al., 2004, Houghton et al., 2006). This tuber contains several pharmacologically important alkaloids (Sagara et al., 1985, Matsuda et al., 1988, Saito et al., 2004). In this paper, we report the isolation and identification of two new quaternary, together with several alkaloids with regard to active principles in AChE activity, and anti-amnesic effect of pseudoberberine in mice.

Section snippets

Plant material

The tuber of Corydalis turtschaninovii were purchased at Yuseong oriental herbarium market in Daejeon, Korea on September 2006. The plant was botanically identified by Prof. KiHwan Bae, College of Pharmacy, Chungnam National University where the voucher specimens was deposited (CNU-00124).

Extraction and isolation

The tuber of Corydalis turtschaninovii (2.0 kg) were dried and extracted with 70% EtOH. The solution was evaporated and residue (110 g) was diluted with 3% aqueous HCl to give acidic solution and insoluble part.

Identification of active constituents

Repeated column chromatography led to the isolation of 16 compounds (116). All isolated compounds show positive with Dragendoff's reagent. The UV, IR, and other physico-chemical data showed that their chemical structures are belonging to isoquinoline alkaloid. Based on the mass, 1H, and 13C NMR spectra, the isolated alkaloids can be divided to two main skeletons: protoberberine and aporphine skeleton. By comparing spectral data with those reported in the literatures and authentic samples, the

Discussion

As mentioned earlier, AChE inhibitors increased the availability of acetylcholine in central cholinergic synapses and are the most promising currently available drugs for the treatment of AD (Giacobini, 1990, LeDoux, 1993). Scopolamine, which is a muscarinic receptor antagonist and can pass through blood–brain barrier causes amnesia in animals by blocking cholinergic neurotransmission. Cholinergic interneurons in the striatum are an even richer source of AChE and would also be affected strongly

Acknowledgments

This study was partially supported by a grant from the Korean Food and Drug Administration (2007). We are grateful to KBSI for measuring 1D, 2D NMR and MS spectra.

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