Promising effects on ameliorating mitochondrial function and enhancing Akt signaling in SH-SY5Y cells by (M)-bicelaphanol A, a novel dimeric podocarpane type trinorditerpene isolated from Celastrus orbiculatus.

Oxidative stress plays an important role in the pathological processes of various neurodegenerative diseases. In this study, we investigated the neuroprotective effects of (M)-bicelaphanol A, which has been the first dimeric podocarpane type trinorditerpene isolated from Celastrus orbiculatus, against hydrogen peroxide (H2O2)-induced injury in human SH-SY5Y neuroblastoma cells. Our study showed that cells pretreated with (M)-bicelaphanol A significantly attenuated H2O2-induced cell viability reduction and cell apoptosis. These neuroprotective effects of (M)-bicelaphanol A were associated with a reduction of reactive oxygen species and an increase in the level of adenosine triphosphate. In addition, (M)-bicelaphanol A pretreatment markedly increased the phosphorylation level of Akt in SH-SY5Y cells. In conclusion, our results for the first time demonstrate that the protection of (M)-bicelaphanol A on SH-SY5Y cells against H2O2-induced oxidative stress may attribute, at least partially, to its attenuation of mitochondrial dysfunction and activation of Akt signaling pathway. Above results shed more light on the molecular mechanisms involved in the neuroprotective effects of (M)-bicelaphanol A, which could be a potential drug candidate for the treatment of oxidative stress-associated neurodegenerative diseases.

Decreased accumulation of subcellular amyloid-ß with improved mitochondrial function mediates the neuroprotective effect of huperzine A.

A number of recent discoveries indicate that huperzine A, an active herbal medicine employed for the treatment of Alzheimer's disease (AD) in China, can afford neuroprotection on in vitro and in vivo models related to mitochondrial dysfunction. However, it is an intricate and highly debated research topic about whether another pharmacological mechanism is involved in the beneficial profiles of huperzine A, independent of its well-recognized potent acetycholinesterase (AChE) inhibitory effect. As an extension, this study for the first time verified the co-occurrence of the beneficial effects of huperzine A on mitochondrial dysfunction and memory deficits in AßPP/PS1 double transgenic mice, at a time point that AChE was not inhibited. Moreover, using isolated brain cortical mitochondria, we confirmed the ameliorating effect of huperzine A on oligomeric Aß1-42-induced ATP reduction and mitochondrial swelling, as well as a decrease in the enzymatic activities of respiratory chain complexes, especially complex II-III and complex IV, which may be attributed to the blockage of oligomeric Aß1-42 from penetrating into mitochondria. These results shed more light on a potential direct target of huperzine A on isolated mitochondria, which may be largely different from its specific inhibition on AChE. This work describes a novel mechanism of neuroprotection by huperzine A and provides important clues for discovering novel therapeutic strategy for AD.

Dibenzocyclooctadiene lignans from Kadsura polysperma and their antineurodegenerative activities.

Eleven new dibenzocyclooctadiene lignans, polysperlignans A-K (1-11), and eight known analogues (12-19) were isolated from the stems of Kadsura polysperma. Their structures and absolute configurations were established using a combination of MS, NMR, CD, and single-crystal X-ray diffraction techniques. Selected compounds were evaluated for activity against ß-amyloid- or hydrogen peroxide-induced neurotoxicity on PC12 cells, and 1, 2, 4, 5, 13, and 16 showed statistically significant neuroprotective effects in these in vitro assays.

Huperzine A alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice.

Huperzine A (HupA) is a potent acetylcholinesterase inhibitor (AChEI) used in the treatment of Alzheimer's disease (AD). Recently, HupA was shown to be active in modulating the nonamyloidogenic metabolism of ß-amyloid precursor protein (APP) in APP-transfected human embryonic kidney cell line (HEK293swe). However, in vivo research concerning the mechanism of HupA in APP transgenic mice has not yet been fully elucidated. The present study indicates that the loss of dendritic spine density and synaptotagmin levels in the brain of APPswe/presenilin-1 (PS1) transgenic mice was significantly ameliorated by chronic HupA treatment and provides evidence that this neuroprotection was associated with reduced amyloid plaque burden and oligomeric ß-amyloid (Aß) levels in the cortex and hippocampus of APPswe/PS1dE9 transgenic mice. Our findings further demonstrate that the amelioration effect of HupA on Aß deposits may be mediated, at least in part, by regulation of the compromised expression of a disintegrin and metalloprotease 10 (ADAM10) and excessive membrane trafficking of ß-site APP cleavage enzyme 1 (BACE1) in these transgenic mice. In addition, extracellular signal-regulated kinases 1/2 (Erk1/2) phosphorylation may also be partially involved in the effect of HupA on APP processing. In conclusion, our work for the first time demonstrates the neuroprotective effect of HupA on synaptic deficits in APPswe/PS1dE9 transgenic mice and further clarifies the potential pharmacological targets for this protective effect, in which modulation of nonamyloidogenic and amyloidogenic APP processing pathways may be both involved. These findings may provide adequate evidence for the clinical and experimental benefits gained from HupA treatment.

Dibenzocyclooctadiene lignans with antineurodegenerative potential from Kadsura ananosma.

Fourteen new dibenzocyclooctadiene lignans, ananolignans A-N (1-14), together with five known compounds, were isolated from the seeds of Kadsura ananosma. The structures and absolute configurations of 1-14 were established using a combination of spectroscopic methods including 1D- and 2D-NMR and CD techniques. The biological activity of the isolated lignans was evaluated, and ananolignan F (6) and ananolignan L (12) showed significant neuroprotective effects in an in vitro assay.

Retrospect and prospect of active principles from Chinese herbs in the treatment of dementia.

With an ageing population, dementia has become one of the world's primary health challenges. However, existing remedies offer limited benefits with certain side effects, which has prompted researchers to seek complementary and alternative therapies. China has long been known for abundant usage of various herbs. Some of these herbal decoctions are effective in stimulating blood circulation, supplementing vital energy and resisting aging, the lack of which are believed to underlie dementia. These herbs are regarded as new and promising sources of potential anti-dementia drugs. With the rapid evolution of life science and technology, numerous active components have been identified that are highly potent and multi-targeted with low toxicity, and therefore meet the requirements for dementia therapy. This review updates the research progress of Chinese herbs in the treatment of dementia, focusing on their effective principles.

Huperzine a improves chronic inflammation and cognitive decline in rats with cerebral hypoperfusion.

Chronic cerebral hypoperfusion has been suggested to contribute to the progression of dementia. Inflammation and white matter lesion (WML) are involved in the pathologic process. This study investigated whether huperzine A, a natural acetylcholinesterase (AChE) inhibitor, has beneficial effects on long-lasting inflammation as well as cognitive impairment in a rat model of cerebral hypoperfusion and how it plays these roles. Chronic cerebral hypoperfusion was induced by occlusion of bilateral common carotid arteries (two-vessel occlusion; 2VO). Huperzine A was initially given 150 min after 2VO and daily for 3, 7, 14, and 28 days. Learning and memory dysfunction as tested by Morris water maze performance was observed in 2VO-operated rats and was significantly improved by huperzine A treatment. WML and activation staining of immune cells were evaluated by Klüver-Barrera (KB) and immunohistochemistry, respectively. Myelin damage and increased immunostains were found in optic tract at all indicated days. Huperzine A treatment significantly ameliorated all these phenomena. Moreover, huperzine A also suppressed overexpression of the inflammatory factor tumor necrosis factor-alpha (TNF-alpha) and overphosphorylation of JNK and p38 mitogen-activated protein kinases (MAPKs) in a cell model of chronic hypoxia. Preincubation with mecamylamine (MEC), a nicotinic acetylcholine receptor (nAChR) antagonist, for 30 min before hypoxia notably reversed the effects of huperzine A on TNF-alpha production and MAPKs phosphorylation. In conclusion, delayed and chronic administration of huperzine A could protect against 2VO-induced cognitive impairment, which might be related to its beneficial effects on WML, and the nAChR-dependent cholinergic anti-inflammation pathway plays an important role.

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment.

Vascular dementia (VaD) is a progressive neurodegenerative disease with a high prevalence. Several studies have recently reported that VaD patients present cholinergic deficits in the brain and cerebrospinal fluid (CSF) that may be closely related to the pathophysiology of cognitive impairment. Moreover, cholinergic therapies have shown promising effects on cognitive improvement in VaD patients. The precise mechanisms of these cholinergic agents are currently not fully understood; however, accumulating evidence indicates that these drugs may act through the cholinergic anti-inflammatory pathway, in which the efferent vagus nerve signals suppress pro-inflammatory cytokine release and inhibit inflammation, although regulation of oxidative stress and energy metabolism, alleviation of apoptosis may also be involved. In this paper, we provide a brief overview of the cholinergic treatment strategy for VaD and its relevant mechanisms of anti-inflammation.Acta Pharmacologica Sinica (2009) 30: 879-888; doi: 10.1038/aps.2009.82.

Monoterpene glucosides from Paeonia lactiflora.

Four new "cage-like" monoterpene glucosides (1-4) were isolated from Paeonia lactiflora. The structures of these compounds were established by spectroscopic methods, mainly 1D and 2D NMR, and mass spectrometric analysis. Compound 4 exhibited moderate cell-protective activity against hydrogen peroxide-induced PC12 cell damage.

Phenolic compounds with cell protective activity from the fruits of Livistona chinensis.

Two new depsidones, livistones A (1) and B (2), and a new benzofurane, livistone C (3), together with the 11 known compounds including three stilbenes (4-6), four steroids, three flavan-3-ols, and an alkaloid were isolated from the fruits of Livistona chinensis. The structures of the new compounds were determined by spectroscopic methods. Compounds 1, 4-6 exhibited remarkable cell protective activities against H(2)O(2)-induced SH-SY5Y cell damage.

Huperzine A protects isolated rat brain mitochondria against beta-amyloid peptide.

Our previous work in cells and animals showed that mitochondria are involved in the neuroprotective effect of huperzine A (HupA). In this study, the effects of HupA on isolated rat brain mitochondria were investigated. In addition to inhibiting the Abeta(25-35) (40 microM)-induced decrease in mitochondrial respiration, adenosine 5'-triphosphate (ATP) synthesis, enzyme activity, and transmembrane potential, HupA (0.01 or 0.1 microM) effectively prevented Abeta-induced mitochondrial swelling, reactive oxygen species increase, and cytochrome c release. More interestingly, administration of HupA to isolated mitochondria promoted the rate of ATP production and blocked mitochondrial swelling caused by normal osmosis. These results indicate that HupA protects mitochondria against Abeta at least in part by preserving membrane integrity and improving energy metabolism. These direct effects on mitochondria further extend the noncholinergic functions of HupA.

Potential therapeutic targets of huperzine A for Alzheimer's disease and vascular dementia.

Huperzine A (HupA), a novel Lycopodium alkaloid isolated from Chinese folk medicine Huperzia serrata (Qian Ceng Ta), is a potent, selective and well-tolerated inhibitor of acetylcholinesterase (AChE). It has been proven to significantly improve the learning and memory impairment in Alzheimer's disease (AD) and vascular dementia (VaD) patients in China. Interestingly, our recent data indicate that HupA also possesses other protective functions. This paper will give an overview on the protective effects of HupA, which includes regulating beta-amyloid precursor protein (APP) metabolism, protecting against Abeta-mediated oxidative stress, apoptosis and mitochondrial dysfunction, as well as anti-inflammation. The multiple neuroprotective effects of HupA might yield additional beneficial effects in AD and VaD therapy.

Huperzine A exhibits anti-inflammatory and neuroprotective effects in a rat model of transient focal cerebral ischemia.

Huperzine A, a reversible and selective acetylcholinesterase (AChE) inhibitor, has been reported to display neuroprotective properties. The present study investigated the protective effects of huperzine A in a rat model of transient focal cerebral ischemia created by middle cerebral artery occlusion (MCAO). Huperzine A (0.1 mg/kg), administrated intraperitoneally at the onset of occlusion and 6 h later, markedly restored regional cerebral blood flow, reduced infarct size, and decreased neurological deficit score at 24 h after reperfusion. Along with inhibiting AChE activity, huperzine A inhibited nuclear translocation of transcription factor nuclear factor-kappa B, decreased overexpression of proinflammatory factors in both ipsilateral cortex and striatum, and suppressed activation of glial cells in the ischemic penumbra. Neurological deficit and glial cells activation were also reduced by daily administration of huperzine A for 14 days. Mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, totally abolished the inhibitory effects of huperzine A on ischemia-induced glial cells activation. Meanwhile, mecamylamine partially reversed the infarct size-reducing effects of huperzine A. In conclusion, our results demonstrate that huperzine A exhibits neuroprotective effects against transient focal cerebral ischemia-induced brain injury and suggest that the protection mechanism may involve a cholinergic anti-inflammatory pathway, in which nAChR plays an essential role.

Walsucochins A and B with an unprecedented skeleton isolated from Walsura cochinchinensis.

Walsucochins A (1) and B (2) with an unprecedented skeleton were isolated from Walsura cochinchinensis. Their structures including absolute configuration were elucidated by spectral methods. A biosynthetic pathway of 1 and 2 was postulated. Both 1 and 2 exhibited significant cell protecting activities against H2O2-induced PC12 cell damage.

Non-cholinergic effects of huperzine A: beyond inhibition of acetylcholinesterase.

The use of acetylcholinesterase inhibitors to decrease the breakdown of the neurotransmitter acetylcholine has been the main symptomatic therapy for mild to moderate Alzheimer's patients, though the etiology of Alzheimer's disease remains unclear and seems to involve multiple factors. Further evidence has indicated that some of these acetylcholinesterase inhibitors also have non-cholinergic functions on the pathogenesis of Alzheimer's disease including the formation and deposition of beta-amyloid. Huperzine A, a potent and reversible inhibitor of acetylcholinesterase that was initially isolated from a Chinese herb, has been found to improve cognitive deficits in a broad range of animal models and has been used for Alzheimer's disease treatment in China. The novel neuroprotective effects of huperzine A might yield beneficial effects in Alzheimer's disease therapy and provide a potential template for the design of new selective and powerful anti-Alzheimer's drugs. The present paper gives an overview on the neuroprotective effects of huperzine A beyond its acetylcholinesterase inhibition. These effects include regulating beta-amyloid precursor protein metabolism, protecting against beta-amyloid-mediated oxidative stress and apoptosis. The structure-function relationship of huperzine A is also discussed.

Pharmacodynamic study of FS-0311: a novel highly potent, selective acetylcholinesterase inhibitor.

(1) This study was to evaluate the anti-cholinesterase (ChE), cognition enhancing and neuroprotective effects of FS-0311, a bis-huperzine B derivative. (2) ChE activity was evaluated using a spectrophotometric method. Cognitive deficits in mice were induced by scopolamine or transient brain ischemia and reperfusion. Water maze was used to detect the cognitive performance. PC12 cell injury was induced by beta-amyloid 25-35 (Abeta(25-35)), oxygen-glucose deprivation (OGD), or staurosporine treatment. (3) FS-0311 was a potent, highly specific inhibitor of acetylcholinesterase (AChE). FS-0311 bound to AChE in a reversible manner, causing linear mixed-type inhibition. FS-0311 had a high oral bioavailability and a long duration of AChE inhibitory action in vivo. FS-0311 was found to antagonize cognitive deficits induced by scopolamine or transient brain ischemia and reperfusion in a water maze task. FS-0311 possessed the ability to protect PC12 cells against Abeta(25-35) peptide toxicity, OGD insult and staurosporine-induced apoptosis. The neuroprotective effects of FS-0311 appeared to reflect an attenuation of oxidative stress. (4) With the profile of anti-ChE and neuroprotective activities, FS-0311 might be a promising candidate in neurodegenerative diseases, such as Alzheimer's disease and Vascular dementia.

Treating senile dementia with traditional Chinese medicine.

Senile dementia is a syndrome in the elderly involving deficits in memory and cognition. There has been a long history of research and medical practice in dementia in China, during which the ancient Chinese people have formed a whole theory and accumulated abundant experience in the treatment of dementia. During recent decades, with new theories and technologies being digested and integrated, progress has been made in the medical and pharmacy research on senile dementia in China. In this review, we will focus on the traditional opinion, clinical practice, and recent progress in pharmacological research in China towards the treatment of dementia. We also discuss the potential trends of global convergence.

Study on dual-site inhibitors of acetylcholinesterase: Highly potent derivatives of bis- and bifunctional huperzine B.

Natural (-)-huperzine B (HupB), isolated from Chinese medicinal herb, displayed moderate inhibitory activity of acetylcholinesterase (AChE). Based on the active dual-site of AChE, a series of novel derivatives of bis- and bifunctional HupB were designed and synthesized. The AChE inhibition potency of most derivatives of HupB was enhanced about 2-3 orders of magnitude as compared with the parental HupB. Among bis-HupB derivatives, 12h exhibited the most potent in the AChE inhibition and has been evaluated for its pharmacological actions in vivo on ChE inhibition, cognitive enhancement, and neuroprotection. The docking study on the bis-HupB derivatives 12 series with TcAChE has demonstrated that the ligands bound to the dual-site of the enzyme in different level.

Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease.

In recent years, the most common pharmacological treatment for Alzheimer's disease (AD) has been acetylcholinesterase (AChE) inhibition. However, this single-target approach has limited effectiveness and there is evidence that a multitarget approach might be more effective. Huperzine A (HupA), a novel alkaloid isolated from a Chinese herb, has neuroprotective effects that go beyond the inhibition of AChE. Recent data have demonstrated that HupA can ameliorate the learning and memory deficiency in animal models and AD patients. Its potentially beneficial actions include modification of beta-amyloid peptide processing, reduction of oxidative stress, neuronal protection against apoptosis, and regulation of the expression and secretion of nerve growth factor (NGF) and NGF signaling.