Non-cholinergic Effects of Huperzine A: Beyond Inhibition of Acetylcholinesterase

Zhang, Hai Yan; Yan, Huaxiao; Tang, Xi

doi:10.1007/s10571-007-9163-z

Cited by 65 publications

(41 citation statements)

References 71 publications

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“…Furthermore, several reports seem to indicate that AChEIs may affect the secretory processes of APP via activation of both PKC, especially PKCα, and mitogen-activated protein kinase (MAPK) [6,7,8]. Moreover, the levels in the membrane compartment of ADAM10, one of the more prominent candidates for α-secretase activity, are also regulated after AChEI treatment [9,10].…”

Section: Introductionmentioning

confidence: 99%

Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer’s Disease in Triple Transgenic Mice (3xTg-AD)

et al. 2012

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Background: Different studies have established that cholinergic neurodegeneration could be a major pathological feature of Alzheimer’s disease (AD). Thus, enhancement of the central cholinergic neurotransmission has been regarded as one of the most promising strategies for the symptomatic treatment of AD, mainly by means of reversible acetylcholinesterase inhibitors (AChEIs). The cognitive-enhancing properties of both huprine X, a new AChEI, and the structurally related huperzine A, as well as their effects on the regulation of several neurochemical processes related to AD have been studied in triple transgenic mice (3xTg-AD). Methods: Seven-month-old homozygous 3xTg-AD male mice, which received chronic intraperitoneal treatment with either saline, huprine X (0.12 µmol·kg^–1) or huperzine A (0.8 µmol·kg^–1) were subjected to a battery of behavioural tests after 3 weeks of treatment and thereafter the brains were dissected to study the neurochemical effects induced by the two AChEIs. Results: Treatments with huprine X and huperzine A improved learning and memory in the Morris water maze and some indicators of emotionality without inducing important adverse effects. Moreover, huprine X and huperzine A activate protein kinase C/mitogen-activated protein kinase pathway signalling, α-secretases (ADAM 10 and TACE) and increase the fraction of phospho-glycogen synthase kinase 3-β. Conclusion: Results obtained herein using a sample of 3xTg-AD animals strongly suggest that the treatment with the two AChEIs not only improves the cognitive performance of the animals but also induces some neurochemical changes that could contribute to the beneficial effects observed.

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Section: Introductionmentioning

confidence: 99%

Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer’s Disease in Triple Transgenic Mice (3xTg-AD)

et al. 2012

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“…Clinically, cholinesterase inhibitors, such as donepezil, galantamine, rivastigmine, and huperzine A (HupA), which are believed to act by blocking acetylcholine degradation and increasing the function of the surviving cholinergic neurons, have been shown to have beneficial effects by improving general cognitive function and reducing behavioral disturbances (Wang et al, 2001;Ceravolo et al, 2004;Erkinjuntti et al, 2004;Sicras and Rejas-Gutierrez, 2004;van der Staay and Bouger, 2005;Alisky, 2006;Mori et al, 2006). Recently, the multiple targets of cholinesterase inhibitors used to treat AD have received increasing attention (Lahiri et al, 2004;Zhang and Tang, 2006;Zhang et al, 2008a;Akaike et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…HupA has several beneficial effects for AD patients (Wang et al, 2006a) and, in China it is one of the most commonly prescribed drugs for many forms of dementia, including AD (Zhang et al, 2008b). Apart from its well-known inhibitory effect on AChE (Zhu and Giacobini, 1995;Cheng et al, 1996;Cheng and Tang, 1998), HupA is considered to have multiple neuroprotective effects including anti-inflammatory and antioxidant properties (Wang and Tang, 2007;Wang et al, 2008;Zhang et al, 2008a), stimulation of the release of soluble a-secretasederived fragments of APP (sAPPa) (Zhang et al, 2004;Peng et al, 2006;Yan et al, 2007), protection against Ab and glutamate-induced neurotoxicity, and regulation of nerve growth factor (Ved et al, 1997;Tang et al, 2005). Interestingly, recent studies have shown that intranasal administration of a nasal gel containing HupA is a suitable system for delivery of HupA to the brain and, hence, provides a potential strategy for chronic AD therapy (Yue et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Huperzine A Activates Wnt/β-Catenin Signaling and Enhances the Nonamyloidogenic Pathway in an Alzheimer Transgenic Mouse Model

Wang

Zheng

Wang

et al. 2011

Neuropsychopharmacol

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Huperzine A (HupA) is a reversible and selective inhibitor of acetylcholinesterase (AChE), and it has multiple targets when used for Alzheimer's disease (AD) therapy. In this study, we searched for new mechanisms by which HupA could activate Wnt signaling and reduce amyloidosis in AD brain. A nasal gel containing HupA was prepared. No obvious toxicity of intranasal administration of HupA was found in mice. HupA was administered intranasally to b-amyloid (Ab) precursor protein and presenilin-1 double-transgenic mice for 4 months. We observed an increase in ADAM10 and a decrease in BACE1 and APP695 protein levels and, subsequently, a reduction in Ab levels and Ab burden were present in HupA-treated mouse brain, suggesting that HupA enhances the nonamyloidogenic APP cleavage pathway. Importantly, our results further showed that HupA inhibited GSK3a/b activity, and enhanced the b-catenin level in the transgenic mouse brain and in SH-SY5Y cells overexpressing Swedish mutation APP, suggesting that the neuroprotective effect of HupA is not related simply to its AChE inhibition and antioxidation, but also involves other mechanisms, including targeting of the Wnt/b-catenin signaling pathway in AD brain.

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“…It easily penetrates the blood-brain barrier (1) and possesses diverse pharmacological functions (2,3). Huperzine A protects cortical neurons from β-amyloid-induced apoptosis in vitro (4), and regulates the expression of nerve growth factor and its receptors (5). Importantly, it selectively inhibits acetylcholinesterase (6).…”

Section: Introductionmentioning

confidence: 99%

Huperzine A inhibits immediate addictive behavior but not behavioral sensitization following repeated morphine administration in rats

Sun

Tian

Cui

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Acetylcholinesterase inhibitors are regarded as promising therapeutic agents to treat addiction. The current study aimed to examine the effects of huperzine A, a cholinesterase inhibitor, on behavioral sensitization induced by repeated morphine administration and relapse induced by contextual conditioning. The present study also assessed whether the state-dependency hypothesis may explain the results. Adult rats were divided into four groups (n=8) and intraperitoneally injected with 0.2, 0.3 or 0.4 mg/kg huperzine A or saline (1 ml/kg, control), for 5 days. The effect of repeated huperzine A administration alone on locomotor activity was assessed. For the experiments that analyzed the development of morphine-induced sensitization, 40 rats were divided into five groups (n=8): Saline+Saline, Saline+Morphine, 0.2, 0.3 and 0.4 mg/kg huperzine A+Morphine. Following a withdrawal period of 7 days, all animals were administered saline or morphine, as appropriate. To test the state-dependency hypothesis, the rats in the Saline+Morphine group were injected with saline and morphine, while the other three groups were administered different doses of huperzine A and morphine. To examine the effect of huperzine A on the expression of morphine-induced sensitization, the rats in huperzine A+Morphine groups were injected with appropriate concentrations of huperzine A, and morphine. The current results indicated that the administration of huperzine A alone did not affect locomotor activity, while higher doses of huperzine A inhibited the addictive behavior induced by morphine at the development phase. Additionally, huperzine A administration during the expression phase of morphine sensitization did not inhibit the relapse induced by administration of saline.Furthermore, 0.4 mg/kg huperzine A inhibited the expression of morphine-induced behavioral sensitization. Therefore, the results of the current study do not support the state-dependency hypothesis.

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Non-cholinergic Effects of Huperzine A: Beyond Inhibition of Acetylcholinesterase

Cited by 65 publications

References 71 publications

Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer’s Disease in Triple Transgenic Mice (3xTg-AD)

Huprine X and Huperzine A Improve Cognition and Regulate Some Neurochemical Processes Related with Alzheimer’s Disease in Triple Transgenic Mice (3xTg-AD)

Huperzine A Activates Wnt/β-Catenin Signaling and Enhances the Nonamyloidogenic Pathway in an Alzheimer Transgenic Mouse Model

Huperzine A inhibits immediate addictive behavior but not behavioral sensitization following repeated morphine administration in rats

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