Z-ligustilide isolated from Radix Angelicae sinensis ameliorates the memory impairment induced by scopolamine in mice
Graphical abstract
Z-ligustilide isolated from Radix Angelicae sinensis ameliorates protects against scopolamine-memory deficits in mice.
Introduction
Alzheimer's disease (AD), the most common form of dementia, is clinically characterized by progressive memory loss and cognitive dysfunction. Typical neuropathological changes in AD, including the formation of dystrophic neurites around a central core of amyloid plaques, the formation of neurofibrillary tangles made up of a highly phosphorylated form of the microtubule-associated protein tau in the perikaryia of certain neurons, and loss of vulnerable neurons, have been reported [1]. Up to date, the molecular mechanisms that underlie the pathogenesis of AD remain largely unclear. However, animal and human studies suggest that one major factor in the early stages of AD and age-related senile central nervous system dysfunction is associated with the widespread loss of acetylcholine (ACh)-containing neurons, shown by the reduced choline acetyltransferase (ChAT) activity, choline uptake, ACh synthesis and loss of perikaya of ACh-containing from the nucleus basalis of Meynert [2]. Pharmacological and neurochemical evidence has further correlated the severity of memory impairment with the degree of cholinergic hypofunction, which has led to ACh-mimetics drugs now available to treat AD [3], [4]. Inhibiting acetylcholinesterase (AChE), the enzyme responsible for ACh catabolism, is the most common approach [1], [4]. The first AChE inhibitors (e.g. tacrine) were associated with significant side-effects and short plasma-half-lives, second-generation compounds (e.g. donepezil, rivastigmine and galanthamine) have better profiles [4]. However, efficacy of these approved AChE inhibitors is modest and is not evident in a substantial minority of patients [5].
The accumulated data suggest that several different pathophysiological pathways may also be involved in the early stages of AD, including dysfunctional Aβ protein metabolism, abnormalities in glutamatergic, adrenergic, serotonergic, and dopaminergic neurotransmission, and the potential involvement of inflammatory, oxidative, and hormonal pathways [5]. Consequently, these pathways are the potential targets for AD treatment and prevention strategies [6], [7]. For example, clinical studies suggest that prophylactic treatment with anti-inflammatory agents decrease the risk of developing AD, and memantine, a uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, has been indicated for the treatment of moderate to several AD [8], [9]. Therefore, the neuroprotective agents together with improving the cholinergic hypofunction probably provide a promising treatment strategy for AD.
Z-ligustilide (LIG; Fig. 1) is the main active ingredient of many Umbelliferae medicinal plants, such as Radix Angelicae sinensis and Ligusticum chuanxiong[10], [11]. Our previous studies found that LIG significantly prevented chronically hypoperfused- and Aβ25–35-induced cognitive deficits and brain damage by partially improving central cholinergic activity, inhibiting the neuroinflammatory response, inhibiting Aβ neurotoxicity, and enhancing anti-oxidant effects [12], [13], [14], [15]. Our findings imply that LIG may synergistically enhance cognition and neuroprotection via both cholinergic and non-cholinergic mechanisms. Based on the cholinergic hypothesis, the muscarinic receptor antagonist scopolamine has been a useful pharmacological tool for producing a model of AD-like memory deficits and cholinergic hypofunction [16]. Therefore, the present study explored the effect of LIG on scopolamine-induced memory impairment and central cholinergic hypofunction in mice. The Morris water maze and Y-maze were used to measure the effects of prolonged oral LIG administration on the impairment in spatial long-term memory and short-term memory, respectively. AChE and ChAT activities in the cerebral cortex were also examined spectrophotometrically.
Section snippets
Preparation of Z-ligustilide
Radix A. sinensis was purchased from its cultivation base at the Good Agricultural Practice in Min Xian County, Gansu Province, China. Its identity was confirmed by comparison with descriptions of its characteristics and the appropriate monograph in the 2010 Chinese Pharmacopeia. Z-ligustilide was prepared by a well-established procedure in our laboratory. Briefly, A. sinensis essential oil was extracted using supercritical-CO2 fluid. Z-ligustilide was isolated from the oil by silica–gel column
Results and discussion
Learning and memory deficits are the early clinical manifestations of AD. The present study explored the effect of long-term LIG administration on scopolamine-induced memory impairment in mice. The Morris water maze was used to estimate spatial long-term memory [12], [13]. In the hidden platform trial on 4 consecutive days, the two-way ANOVA revealed that both the group factor and number of days had significant effects on spatial long-term memory (F5,54 = 10.851 and F3,162 = 44.894, respectively, p <
Acknowledgments
The present work was supported by the Science Foundation from the Science & Technology Department of Sichuan Province, China (no. 2009SZ0142).
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