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.     

Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine

Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase(AChE). Compared with tacrine, donepezil, and rivastigmine, HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action. HupA has been found to improve cognitive deficits in a broad range of animal models. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53, and caspase-3, protect mitochondria, upregulate nerve growth factor and its receptors, and interfere with amyloid precursor protein metabolism. Antagonizing effects of HupA on N-methyl-D-aspartate receptors and potassium currents may also contribute to its neuroprotection as well. Pharmacokinetic studies in rodents, canines, and healthy human volunteers indicated that HupA was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate with the property of slow and prolonged release after oral administration. Animal and clinical safety tests showed that HupA had no unexpected toxicity, particularly the dose-limiting hepatotoxicity induced by tacrine. The phase IV clinical trials in China have demonstrated that HupA significantly improved memory deficits in elderly people with benign senescent forgetfulness, and patients with Alzheimer disease and vascular dementia, with minimal peripheral cholinergic side effects and no unexpected toxicity. HupA can also be used as a protective agent against organophosphate intoxication.     

Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease

HupA is a potent, reversible and selective inhibitor of AChE with a rapid absorption and penetration into the brain in animal tests. It exhibits memory-enhancing activities in animal and clinical trials. Compared to tacrine and donepezil, HupA possesses a longer duration of action and higher therapeutic index, and the peripheral cholinergic side effects are minimal at therapeutic doses. This review article deals with a comprehensive survey of the progress in chemical and pharmacological studies of HupA including the isolation and structure elucidation, pharmacological actions, total synthesis, SAR studies and the future development of HupA. Recently, it has been reported that HupA could reduce neuronal cell death caused by glutamate. The dual bio-activities of HupA would further enhance its value and potentiality as the therapeutic agent for Alzheimer s disease.     

Bivalent ligands derived from Huperzine A as acetylcholinesterase inhibitors

The naturally occurring alkaloid Huperzine A (HupA) is an acetylcholinesterase (AChE) inhibitor that has been used for centuries as a Chinese folk medicine in the context of its source plant Huperzia Serrata. The potency and relative safety of HupA rendered it a promising drug for the ameliorative treatment of Alzheimer's disease (AD) vis-à-vis the "cholinergic hypothesis" that attributes the cognitive decrements associated with AD to acetylcholine deficiency in the brain. However, recent evidence supports a neuroprotective role for HupA, suggesting that it could act as more than a mere palliative. Biochemical and crystallographic studies of AChE revealed two potential binding sites in the active-site gorge of AChE, one of which, the "peripheral anionic site" at the mouth of the gorge, was implicated in promoting aggregation of the beta amyloid (Abeta) peptide responsible for the neurodegenerative process in AD. This feature of AChE facilitated the development of dual-site binding HupA-based bivalent ligands, in hopes of concomitantly increasing AChE inhibition potency by utilizing the "chelate effect", and protecting neurons from Abeta toxicity. Crystal structures of AChE allowed detailed modeling and docking studies that were instrumental in enhancing the understanding of underlying principles of bivalent inhibitor-enzyme dynamics. This monograph reviews two categories of HupA-based bivalent ligands, in which HupA and HupA fragments serve as building blocks, with a focus on the recently solved crystallographic structures of Torpedo californica AChE in complex with such bifunctional agents. The advantages and drawbacks of such structured-based drug design, as well as species differences, are highlighted and discussed.     

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

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 β-amyloid (Aβ) 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 Aβ levels and Aβ 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 GSK3α/β activity, and enhanced the β-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/β-catenin signaling pathway in AD brain.     

Vaccine development for Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of age-related cognitive decline. Both active and passive immunization paradigms have illustrated the potential to prevent and reverse established AD pathology in transgenic and non-transgenic animal models of AD. Follow-up studies have shown that changes in amyloid burden observed with immunization could rescue cognitive deficits in both young and aged mice. Despite the success of immunotherapy in animal models, clinical trials were halted early. It has become clear that more preclinical work was needed before initiating trials, as most of the adverse events observed in patients could have been predicted using animal models. Despite these setbacks, clinical trials have demonstrated the utility of amyloid-beta (Abeta) vaccination in reducing amyloid pathology and potentially reducing cognitive decline. Several novel approaches to immunotherapy, including modified immunogens, adjuvants and modes of administration have been designed, which hold promise for human testing. Clinical trials using a safer vaccine, which is potent enough to elicit a robust antibody response in the absence of encephalitis may prove effective in mitigating progressive neurodegeneration seen in AD. If so, Abeta vaccination could supplant current symptomatic treatment and represent one of the first therapeutic options for AD based on the amyloid cascade hypothesis.     

Progress in clinical, pharmacological, chemical and structural biological studies of huperzine A: a drug of traditional chinese medicine origin for the treatment of Alzheimer's disease

HupA is a potent, reversible AChEI, which crosses the blood-brain barrier smoothly, and shows high specificity for AChE with a prolonged biological half-life. It has been approved as the drug for the treatment of AD in China, and marketed in USA as a dietary supplement. HupA has been the subject of investigations by an ever-increasing number of researchers since 1980's. In the last four years, HupA has been further studied in many aspects such as the chemical synthesis, structural modification, structure-activity relationship, various biological effects, and mechanisms of action. A number of papers dealing with the computational modeling and X-ray crystallographic studies of HupA-AChE complex have also been published. This review represents a comprehensive documentation of the progress in the studies on HupA during the period of 1999-2002.     

Animal models of stroke: do they have value for discovering neuroprotective agents?

There has been a series of high-profile failures of drugs in clinical trials of acute ischaemic stroke that were designed to meet criteria necessary for drug regulatory approval. This has, again, called into question the value of animal models for identifying effective neuroprotective agents. Here, we review evidence that physiological changes (reperfusion, hyperglycaemia, hypothermia and blood pressure) produce comparable changes in outcome in both animal models and human stroke patients, which indicates that the models should identify clinically effective neuroprotective agents. We suggest that most clinical failures have occurred because compounds were administered differently in animal and clinical studies. We review earlier guidelines on the information that is necessary from preclinical studies before a compound enters clinical trials, and propose modifications to these guidelines.     

Pharmacological treatment of comorbid PTSD and substance use disorder: Recent progress

Previous research has identified a strong association between posttraumatic stress disorder (PTSD) and substance use disorder (SUD), necessitating the development of treatments that address both conditions. Some pharmacotherapies are effective for the treatment of PTSD and SUD alone, however; no medications have been proven to be effective for the combination of these conditions. We review the recent advances in pharmacological treatment of comorbid PTSD and SUD. A randomized clinical trial of sertraline, a serotonin reuptake inhibitor (SSRI), did not show overall efficacy for comorbid PTSD and alcohol dependence (AD), although it may have efficacy among light drinkers. Another clinical trial demonstrated the efficacy of both disulfiram and naltrexone for the treatment of AD in individuals with PTSD. A more recent clinical trial suggested that norepinephrine uptake inhibitors may also have efficacy for the treatment of comorbid PTSD and AD. In animal and preliminary human studies, brain norepinephrine and glutamate/GABA have emerged as potential treatment targets for comorbid PTSD and SUD. Noradrenergic medications that are promising for comorbid PTSD and SUD include prazosin, guanfacine, and atomoxetine. Promising glutamate/GABA medications include topiramate, memantine, acamprosate, N-acetylcysteine (NAC), and ketamine. The safety and efficacy of these medications for the treatment of PTSD and SUD need to be tested in controlled clinical trials.     

Brimonidine

Brimonidine tartrate is a highly selective alpha2-adrenergic receptor agonist indicated for the chronic treatment of glaucoma and ocular hypertension. Glaucoma, a serious worldwide public health problem causing blindness in 5.2 million people, is treated by drugs that lower the intraocular pressure (IOP), a primary risk factor in glaucomatous optic neuropathy. Currently, beta-blockers are the most common therapy. In two 12-month clinical comparison trials with timolol 0.5% (n = 926), twice-daily brimonidine produced IOP lowering comparable to twice-daily timolol. In a 3-month trial with betaxolol 0.25% suspension (n = 206), twice-daily brimonidine was more effective in lowering IOP than twice-daily betaxolol. Brimonidine was well-tolerated ocularly and systemically in these trials. It caused no clinically significant mean changes in heart rate or blood pressure. Brimonidine produced no significant effect on FEV1 in clinical trials, and it is not contraindicated in patients with cardiopulmonary disease. Brimonidine 0.2% dosed twice daily has clinical utility as a first-line drug therapy. It is an effective and safe alternative to beta-blockers, particularly in patients at risk for pulmonary or cardiovascular disease. It decreases aqueous humour production and increases uveoscleral outflow, and has an additive ocular hypotensive effect used concomitantly with other agents. Brimonidine has demonstrated neuroprotective properties in laboratory animal studies. Additional studies are warranted to determine whether brimonidine has clinical benefit in protecting the optic nerve head from glaucomatous damage. Brimonidine is an important contribution to glaucoma management.     

Does lithium prevent Alzheimer's disease?

Lithium salts have a well-established role in the treatment of major affective disorders. More recently, experimental and clinical studies have provided evidence that lithium may also exert neuroprotective effects. In animal and cell culture models, lithium has been shown to increase neuronal viability through a combination of mechanisms that includes the inhibition of apoptosis, regulation of autophagy, increased mitochondrial function, and synthesis of neurotrophic factors. In humans, lithium treatment has been associated with humoral and structural evidence of neuroprotection, such as increased expression of anti-apoptotic genes, inhibition of cellular oxidative stress, synthesis of brain-derived neurotrophic factor (BDNF), cortical thickening, increased grey matter density, and hippocampal enlargement. Recent studies addressing the inhibition of glycogen synthase kinase-3 beta (GSK3B) by lithium have further suggested the modification of biological cascades that pertain to the pathophysiology of Alzheimer's disease (AD). A recent placebo-controlled clinical trial in patients with amnestic mild cognitive impairment (MCI) showed that long-term lithium treatment may actually slow the progression of cognitive and functional deficits, and also attenuate Tau hyperphosphorylation in the MCI-AD continuum. Therefore, lithium treatment may yield disease-modifying effects in AD, both by the specific modification of its pathophysiology via inhibition of overactive GSK3B, and by the unspecific provision of neurotrophic and neuroprotective support. Although the clinical evidence available so far is promising, further experimentation and replication of the evidence in large scale clinical trials is still required to assess the benefit of lithium in the treatment or prevention of cognitive decline in the elderly.     

The pharmacology of chlormethiazole: a potential neuroprotective agent?

Chlormethiazole is a thiazole derivative with a long history of use as a sedative agent. The mode of action of the drug has been partly worked out and has been established with recognition that its mechanism of action involves potentiation of GABA activity, the major intrinsic inhibitory neurotransmitter. Animal models of stroke ranging from rodents to primates have suggested an optimistic role for chlormethiazole in preventing both anatomical and functional deleterious effects of stroke. Phase III clinical trials, therefore, proceeded but unfortunately with very little success. Recently, the animal models have been revisited in an attempt to identify causes for this discrepancy between the results from preclinical and clinical studies. This review studies the pharmacological roots of chlormethiazole from its origin through to its licensed and novel applications. Emphasis is placed on discussing the animal experiments which led to its grooming as a neuroprotective agent and also on the human trials. The review seeks to explain the discrepancies between animal and human studies, which include short survival times of experimental subjects, speed of drug administration and fundamental differences between species. The primate model of stroke perhaps offers the nearest alternative to phase III trials and has recently been used to compare a number of newer neuroprotective agents with greater efficacy than chlormethiazole. In addition, novel approaches involving human neurochemical analyses in vivo are described which may help bridge the gap between animal models and future phase III trials.     

Defining the mechanism of action of 4-phenylbutyrate to develop a small-molecule-based therapy for Alzheimer's disease

4-phenylbutyrate (PBA) is a small molecule that restores cognitive deficits in animal models of Alzheimer's disease (AD). Although the molecular basis of the cognitive benefits of PBA remains unknown, a multi-modal/multi-target mechanism has been proposed. Putative targets of this drug are different from those of drugs that are now used in clinical trials. As PBA is already administered to patients with congenital defects affecting enzymes in the urea cycle, it can be rapidly tested in AD clinical trials. However, the main drawback to its therapeutic use is the high dosage required (up to 15 g/day). Thus, deciphering the precise mechanism(s) of action of this drug may enable novel drugs with similar therapeutic effects to PBA to be developed that can be used at more manageable doses.     

Novel neuroprotective effects of the aqueous extracts from Verbena officinalis Linn

Verbena officinialis Linn. (Verbenaceae) is a perennial plant which has been used as herbal medicine or health supplement in both Western and Eastern countries for centuries. It has been used to treat acute dysentery, enteritis, amenorrhea and depression. In view of its wide array of biological effects, we hypothesized that V. officinalis can exert cytoprotective effects on cells of the central nervous system. Pre-treatment of aqueous extracts of V. officinalis significantly attenuated the toxicity of beta-amyloid (Abeta) peptide and reducing agent dithiothreitol in primary cultures of cortical neurons. As extracellular accumulation of Abeta peptide is an important cytotoxic factor involved in Alzheimer's disease (AD), we have further explored its neuroprotective effect against Abeta. Treatment of V. officinalis attenuated Abeta-triggered DEVD- and VDVAD-cleavage activities in a dose-dependent manner. Further studies elucidated that phosphorylation of both interferon-inducing protein kinase (PKR) and c-Jun N-terminal kinase (JNK) was attenuated in Abeta-treated neurons. Taken together, we have proved our hypothesis by showing the novel neuroprotective effects of V. officinalis. As V. officinalis has long been used for many years to be a folk medicine, our study may provide a lead for its potential to be a neuroprotective agent against neuronal loss in AD.     

Evaluation of memantine for neuroprotection in dementia

Memantine, a non-competitive NMDA antagonist, has been approved for use in the treatment of dementia in Germany for over ten years. The rationale for use is excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent against this pathomechanism, which is also implicated in vascular dementia. HIV-1 proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection and the neurotoxicity caused by HIV-1 proteins can be blocked completely by memantine. Memantine has been investigated extensively in animal studies and following this, its efficacy and safety has been established and confirmed by clinical experience in humans. It exhibits none of the undesirable effects associated with competitive NMDA antagonists such as dizocilpine. The efficacy of memantine in a variety of dementias has been shown in clinical trials. Memantine is considered to be a promising neuroprotective drug for the treatment of dementias, particularly Alzheimer’s disease for which there is no neuroprotective therapy available currently. It can be combined with acetylcholinesterase inhibitors which are the mainstay of current symptomatic treatment of Alzheimer’s disease. Memantine has a therapeutic potential in numerous CNS disorders besides dementias which include stroke, CNS trauma, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, drug dependence and chronic pain. If memantine is approved by the FDA for some of these indications by the year 2005, it can become a blockbuster drug by crossing the US$1 billion mark in annual sales.     

Davunetide: a review of safety and efficacy data with a focus on neurodegenerative diseases

Davunetide is the first neuroprotective peptide in its class, and has preclinical evidence for neuroprotective, neurotrophic and cognitive protective properties. Davunetide has also been shown to prevent apoptosis or programmed-cell death in a range of in vitro and in vivo models by promoting microtubule stabilization. Potential clinical uses of davunetide include neurodegenerative disorders such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD) or cognitive impairment in other diseases such as schizophrenia where microtubule structure and function is known to be impaired. The nonclinical and clinical safety of davunetide is reviewed here in detail. Pre-clinical toxicology studies in rats and dogs using the maximum feasible dose of davunetide provide strong evidence that davunetide is well-tolerated. Similarly, data from 10 separate clinical trials of davunetide, investigating safety and efficacy provide evidence that davunetide is generally safe and well-tolerated, and has shown some signs of clinical efficacy.     

Evaluation of memantine for neuroprotection in dementia

Memantine, a non-competitive NMDA antagonist, has been approved for use in the treatment of dementia in Germany for over ten years. The rationale for use is excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent against this pathomechanism, which is also implicated in vascular dementia. HIV-1 proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection and the neurotoxicity caused by HIV-1 proteins can be blocked completely by memantine. Memantine has been investigated extensively in animal studies and following this, its efficacy and safety has been established and confirmed by clinical experience in humans. It exhibits none of the undesirable effects associated with competitive NMDA antagonists such as dizocilpine. The efficacy of memantine in a variety of dementias has been shown in clinical trials. Memantine is considered to be a promising neuroprotective drug for the treatment of dementias, particularly Alzheimer's disease for which there is no neuroprotective therapy available currently. It can be combined with acetylcholinesterase inhibitors which are the mainstay of current symptomatic treatment of Alzheimer's disease. Memantine has a therapeutic potential in numerous CNS disorders besides dementias which include stroke, CNS trauma, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, drug dependence and chronic pain. If memantine is approved by the FDA for some of these indications by the year 2005, it can become a blockbuster drug by crossing the US$1 billion mark in annual sales.     

Current evidence for neuroprotective effects of nicotine and caffeine against Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting 1 to 3% of individuals over the age of 65 years. While effective therapy exists for treating the bradykinesia, rigidity and tremor associated with the disease, the cause is unknown. There is no treatment available to prevent or slow the progressive neuronal loss in the substantia nigra and associated decreased levels of dopamine in the striatum that underlie the cardinal features of the disease. Both retrospective and prospective epidemiological studies have consistently demonstrated an inverse association between cigarette smoking and PD, leading to theories that smoking in general and nicotine in particular might be neuroprotective. Nicotine has been shown in animals to stimulate the release of dopamine in the striatum, and to preserve nigral neurons and striatal dopamine levels in laboratory animals with lesioned nigrostriatal pathways. Coffee and caffeine consumption have also been shown in epidemiological studies to be inversely related to PD risk. Caffeine is an adenosine A(2A) receptor antagonist that enhances locomotor activity in animal models of parkinsonism. Theophylline, a related compound that has A(2A) receptor blocking properties, has been shown in one small trial to improve motor function in patients with PD. Recently, potent and highly selective A(2A) receptor antagonists have been developed that have demonstrated improvement in motor function in animal models of parkinsonism. Exciting findings are emerging that demonstrate attenuation of dopaminergic neurotoxicity with caffeine and other adenosine receptor antagonists in mice given the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), suggesting that these compounds may be neuroprotective. Evidence for the neuroprotective potential of nicotine and caffeine is compelling, but further work is needed before testing these and related compounds in clinical trials for both individuals at high risk of developing PD and those with early, untreated disease.     

An update on huperzine A as a treatment for Alzheimer's disease

Huperzine A is a natural cholinesterase inhibitor derived from the Chinese herb Huperzia serrata. There is evidence that huperzine A may compare favorably in symptomatic efficacy to cholinesterase inhibitors in use. In addition, huperzine A has antioxidant and neuroprotective properties that suggest that it may be useful as a disease-modifying treatment for Alzheimer's disease (AD). The drug is available as a nutriceutical in the US. However, there have been no published controlled clinical trials outside China assessing its toxicity and efficacy. This paper reviews the development of huperzine A as a treatment for AD, including the Phase II trial now under way in the US.