Neuroprotective properties of valproate: potential benefit for AD and tauopathies

Neuropsychiatric disturbances are extremely common in Alzheimer's disease (AD), and represent integral features of the illness, as well as appropriate targets for therapy. We are interested in designing trials aimed at preventing or delaying the emergence of psychopathology in AD. For symptomatic treatment of agitation, mood stabilizers, particularly sodium valproate, have proved to be beneficial in some patients. Since these effects take several weeks to emerge, we considered that they might be dependent on potentially neuroprotective actions of valproate, such as inhibition of apoptosis and slowing of neurofibrillary tangle formation. In this article we present the rationale for testing the neuroprotective potential of valproate experimentally in mouse models of tauopathy and in a clinical trial of patients with AD who lack psychopathology at baseline. Together, these studies will provide important tests of the hypothesis that valproate, either through inhibition of tau phosphorylation or some other mechanism, is a useful therapeutic agent to modify disease progression in AD.     

Six psychotropics for pre-symptomatic & early Alzheimer's(MCI),Parkinson's,and Huntington's disease modification

The quest for neuroprotective drugs to slow the progression of neurodegenerative diseases(NDDs),including Alzheimer's disease(AD),Parkinson's disease(PD),and Huntington's disease(HD),has been largely unrewarding.Preclinical evidence suggests that repurposing quetiapine,lithium,valproate,fluoxetine,donepezil,and memantine for early and pre-symptomatic disease-modification in NDDs may be promising and can spare regulatory barriers.The literature of these psychotropics in early stage and pre-symptomatic AD,PD,and HD is reviewed and propitious findings follow.Mild cognitive impairment(MCI) phase of AD:salutary human randomized controlled trial findings for low-dose lithium and,in selected patients,donepezil await replication.Pre-symptomatic AD:human epidemiological data indicate that lithium reduces AD risk.Animal model studies(AMS) reveal encouraging results for quetiapine,lithium,donepezil,and memantine.Early PD:valproate AMS findings show promise.Pre-symptomatic PD:lithium and valproate AMS findings are encouraging.Early HD:uncontrolled clinical data indicate non-progression with lithium,fluoxetine,donepezil,and memantine.Pre-symptomatic HD:lithium and valproate are auspicious in AMS.Many other promising findings awaiting replication(valproate in MCI;lithium,valproate,fluoxetine in pre-symptomatic AD;lithium in early PD;lithium,valproate,fluoxetine in pre-symptomatic PD;donepezil in early HD;lithium,fluoxetine,memantine in pre-symptomatic HD) are reviewed.Dose- and stage-dependent effects are considered.Suggestions for signal-enhancement in human trials are provided for each NDD stage.     

Six psychotropics for pre-symptomatic & early Alzheimer’s (MCI), Parkinson’s,and Huntington’s disease modiifcation

The quest for neuroprotective drugs to slow the progression of neurodegenerative diseases (NDDs), includ-ing Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), has been largely unrewarding. Preclinical evidence suggests that repurposing quetiapine, lithium, valproate, fluoxetine, donepezil, and memantine for early and pre-symptomatic disease-modiifcation in NDDs may be promising and can spare regulatory barriers. The literature of these psychotropics in early stage and pre-symptomatic AD, PD, and HD is reviewed and propitious ifndings follow. Mild cognitive impairment (MCI) phase of AD: salutary human randomized controlled trial ifndings for low-dose lithium and, in selected patients, donepezil await replication. Pre-symptomatic AD: human epidemiological data indicate that lithium reduc-es AD risk. Animal model studies (AMS) reveal encouraging results for quetiapine, lithium, donepezil, and memantine. Early PD: valproate AMS ifndings show promise. Pre-symptomatic PD: lithium and valproate AMS ifndings are encouraging. Early HD: uncontrolled clinical data indicate non-progression with lithium, lfuoxetine, donepezil, and memantine. Pre-symptomatic HD: lithium and valproate are auspicious in AMS. Many other promising ifndings awaiting replication (valproate in MCI; lithium, valproate, lfuoxetine in pre-symptomatic AD; lithium in early PD; lithium, valproate, lfuoxetine in pre-symptomatic PD; donepezil in early HD; lithium, lfuoxetine, memantine in pre-symptomatic HD) are reviewed. Dose- and stage-de-pendent effects are considered. Suggestions for signal-enhancement in human trials are provided for each NDD stage.     

From anti-Parkinson's drug rasagiline to novel multitarget iron chelators with acetylcholinesterase and monoamine oxidase inhibitory and neuroprotective properties for Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial syndrome involving a complex array of different, while related, factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel hybrid molecules with multimodal activity, including: i) M30, the brain permeable selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity; ii) HLA20, a brain permeable metal chelator with neuroprotective activity; iii) HLA20A, an acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity; iv) M30D, an AChE and MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity; and v) analogs of the neuroprotective aminoacid peptide, NAPVSIPQ. HLA20A and M30D act as pro-chelators and can be activated to liberate their respective active chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on antioxidant-chelating potency and AchE and MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including modulation of amyloid-β and amyloid-β protein precursor expression/processing; induction of cell cycle arrest; inhibition of neuronal death markers; and upregulation of neurotrophic factors, as well as activation of protein kinase signaling pathways.     

Psychopharmacological neuroprotection in neurodegenerative diseases, part III: criteria-based assessment: a report of the ANPA committee on research

Neuroprotective therapies for neurodegenerative diseases (NDDs) have proven elusive. The established psychotropic agents commonly used to treat the neuropsychiatric manifestations of NDDs are potential neuroprotective therapies, and neuropsychiatrists and others may benefit from a knowledge of the neuroprotective properties of these medications. This report identifies FDA-approved, first-line psychotropic drugs affecting intracellular mechanisms and meriting disease-modifying clinical trials in NDDs. The authors evaluated evidence for neuroprotection according to 1) preclinical; and 2) clinical criteria. Despite low-to-moderate preclinical evidence scores and scant clinical evidence, the most promising investigative priorities are 1) lithium and paroxetine in Alzheimer's disease (AD); 2) lithium in tauopathies (frontotemporal lobar degeneration [FTLD], FTDP-17); 3) lithium-plus-valproate in AD and amyotrophic lateral sclerosis; 4) pramipexole and valproate in Parkinson's disease; 5) amantadine and buspirone in multiple system atrophy; and 6) antidepressants in Huntington's disease. Preliminary clinical results signal caution regarding olanzapine use in AD and poor tolerability of lithium in progressive supranuclear palsy and corticobasal degeneration. These preliminary findings can lead to further clinical drug trials on the use of these well-known medications, not only for their psychotropic effects, but also for neuroprotection in NDDs.     

Cotinine: A Potential New Therapeutic Agent against Alzheimer's disease

Tobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. However, the undesired side‐effects of nicotine and the absence of clear evidence of positive effects of this drug on the cognitive abilities of AD patients have decreased the enthusiasm for its therapeutic use. In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side‐effects of its precursor. Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid‐beta (Aβ)) burden in AD mice. In AD, cotinine's positive effect on memory is associated with the inhibition of Aβ aggregation, the stimulation of pro‐survival factors such as Akt, and the inhibition of pro‐apoptotic factors such as glycogen synthase kinase 3 beta (GSK3β). Because stimulation of the α7 nicotinic acetylcholine receptors (α7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD.     

Activation of the α-secretase processing of AβPP as a therapeutic approach in Alzheimer's disease

Alzheimer's disease (AD) is by far the main cause of dementia in the aged population. Because the amyloid-β peptide (Aβ) is the main component of senile plaques that develop in the brain of affected patients, numerous studies aimed at preventing its production or aggregation were conducted during the past 25 years. The inhibition of Aβ production via pharmacological inhibition of β- and γ-secretases is, with vaccination, one of the two main current challenges aimed at curing AD. However, the fact that there exist numerous substrates of these two activities renders this approach problematic since treatments with β- or γ-secretase inhibitors can cause deleterious effects. An alternative to the inhibition of the amyloidogenic enzymes would be to activate the α-secretase processing of AβPP. This cleavage is performed by two members of the disintegrin family of metalloproteases (ADAM10 and ADAM17). It is noteworthy that this cleavage can be seen as doubly beneficial regarding AD since it both occurs in the middle of the Aβ sequence and triggers the release of the neuroprotective sAβPPα product. However, similarly to β- and γ-secretases, ADAM10 and ADAM17 are responsible for the cleavage of a large number of proteins, the processing of some of them being tightly associated with important physiological functions but also with severe pathologies. This review focuses on our current knowledge of the various natural or synthetic compounds able to trigger α-secretase activities and on the possible ways to circumvent the deleterious side effects that would result from their broad activation.     

Mechanisms of tau self-aggregation and neurotoxicity

Pathological tau protein aggregates can be found in brain of patients with some of the neurodegenerative diseases collectively known as tauopathies, which include Alzheimer's disease (AD). Since tau post-translational modifications including phosphorylations, glycosylations, truncation and the subsequent aggregation in oligomers, paired helical filaments (PHFs) and neurofibrillary tangles (NFTs), correlate with cognitive impairment and neurodegeneration in AD, a pathogenic role for tau and its modifications has been raised. Here we summarize the current status of knowledge about tau modifications under pathologic conditions and the evidence supporting neurotoxic - or neuroprotective - roles of the diverse forms of modified and aggregated tau. Finally, we analyze the structural and functional tau alterations found in different tauopathies and how these modifications are related to the pathophysiologic mechanisms of neurodegeneration.     

Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer's and other neurodegenerative diseases

Latrepirdine (Dimebon^TM) was originally marketed as a non-selective antihistamine in Russia. It was repurposed as an effective treatment for patients suffering from Alzheimer''s disease (AD) and Huntington''s disease (HD) following preliminary reports showing its neuroprotective functions and ability to enhance cognition in AD and HD models. However, latrepirdine failed to show efficacy in phase III trials in AD and HD patients following encouraging phase II trials. The failure of latrepirdine in the clinical trials has highlighted the importance of understanding the precise mechanism underlying its cognitive benefits in neurodegenerative diseases before clinical evaluation. Latrepirdine has shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx and intracellular catabolic pathways; however, it is unclear how these properties contribute to its clinical benefits. Here, we review the studies investigating latrepirdine in cellular and animal models to provide a complete evaluation of its mechanisms of action in the central nervous system. In addition, we review recent studies that demonstrate neuroprotective functions for latrepirdine-related class of molecules including the β-carbolines and aminopropyl carbazoles in AD, Parkinson''s disease and amyotrophic lateral sclerosis models. Assessment of their neuroprotective effects and underlying biological functions presents obvious value for developing structural analogues of latrepirdine for dementia treatment.     

Overcoming cell death and tau phosphorylation mediated by PI3K-inhibition: a cell assay to measure neuroprotection

Few targets for neuroprotection have been defined in Alzheimer's disease (AD). Recent data from the role of Wnt, insulin-like growth factor-1 and estradiol pathways in AD suggest some therapeutic targets for disease treatment, and have led us to evaluate the "common factors" in these pathways as further candidate targets. These data have led us to propose that glycogen synthase kinase-3 (GSK-3) inhibition appears to be a common feature of these pathways. Besides, considering that GSK-3 activation seems to be correlated with neurodegeneration, its selection as a relevant target appears obvious. The capacity of different GSK-3 inhibitors to prevent amyloid β-peptide neurotoxicity and tau phosphorylation has been evaluated in order to develop novel clinical and therapeutic approaches. Different approaches could be used to search for new neuroprotective compounds. The most classical of these is to first define the target and then design a specific in vitro screening assay for it. Alternatively, a cell model of cell culture could be used as a "primary screen". Following this rationale, we have used a combined approach in which we first used an in vitro system to select compounds able to inhibit recombinant GSK3β. Subsequently, we subjected the candidate compounds to three consecutive cell-based complementary screening assays. First, cell viability was assessed using a neuroblastoma cell line before assaying the capacity of the compounds to reduce tau phosphorylation. Finally, we designed a neuronal cell model of apoptosis using the phosphatidylinositol kinase-3 inhibitor LY294002. Finally, we summarize several new compounds with "neuroprotective" properties.     

TGF‐β1 Pathway as a New Target for Neuroprotection in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder that affects more than 37 million people worldwide. Current drugs for AD are only symptomatic, but do not interfere with the underlying pathogenic mechanisms of the disease. AD is characterized by the presence of ß‐amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. The identification of the molecular determinants underlying AD pathogenesis is a fundamental step to design new disease‐modifying drugs. Recently, a specific impairment of transforming‐growth‐factor‐β1 (TGF‐β1) signaling pathway has been demonstrated in AD brain. The deficiency of TGF‐β1 signaling has been shown to increase both Aβ accumulation and Aβ‐induced neurodegeneration in AD models. The loss of function of TGF‐ß1 pathway seems also to contribute to tau pathology and neurofibrillary tangle formation. Growing evidence suggests a neuroprotective role for TGF‐β1 against Aβ toxicity both in vitro and in vivo models of AD. Different drugs, such as lithium or group II mGlu receptor agonists are able to increase TGF‐β1 levels in the central nervous system (CNS), and might be considered as new neuroprotective tools against Aβ‐induced neurodegeneration. In the present review, we examine the evidence for a neuroprotective role of TGF‐β1 in AD, and discuss the TGF‐β1 signaling pathway as a new pharmacological target for the treatment of AD.     

Uncaria rhynchophylla, a Chinese medicinal herb, has potent antiaggregation effects on Alzheimer's beta-amyloid proteins

Because the deposition of beta-amyloid protein (Abeta) is a consistent pathological hallmark of Alzheimer's disease (AD) brains, inhibition of Abeta generation, prevention of Abeta fibril formation, or destabilization of preformed Abeta fibrils would be attractive therapeutic strategies for the treatment of AD. We examined the effects of several medicinal herbs used in traditional Chinese medical formulae on the formation and destabilization of Abeta fibrils by using the thioflavin T binding assay, atomic force microscopic imaging, and electrophoresis. Our study demonstrates that several of these herbs have potent inhibitory effects on fibril formation of both Abeta(1-40) and Abeta(1-42) in concentration-dependent manners; in particular, Uncaria rhynchophylla inhibited Abeta aggregation most intensively. Significant destabilization of preformed Abeta(1-40) and Abeta(1-42) fibrils was also induced by Uncaria rhynchophylla as well as some other herb extracts. Three-dimensional HPLC analysis indicated that the water extract of this herb contains several different chemical compounds, including oxindole and indol alkaloids, which have been regarded as neuroprotective. Our results suggest that Uncaria rhynchophylla has remarkably inhibitory effects on the regulation of Abeta fibrils, and we conclude that this medicinal herb could have the potency to be a novel therapeutic agent to prevent and/or cure AD.     

Smoking and Parkinson's and Alzheimer's disease: review of the epidemiological studies

The relationship between smoking and neurological diseases has always been controversial. Even the expected association between smoking and increased risk for cerebrovascular disease has been debated for years. It was at the end of the 1980s that smoking became definitively accepted as a risk factor for ischemic stroke. More recently, two other neurological diseases have been studied in relation to smoking: Parkinson's disease (PD) and Alzheimer's disease (AD). Many epidemiological studies have found a highly significant negative association between cigarette smoking and these two neurodegenerative disorders. The risk of AD or PD in nonsmokers has generally been about twice that of smokers. That is, patients with AD or PD are approximately 50% less likely to have smoked cigarettes during their lifetime than are age- and gender-matched controls. Alternatively, cigarette smokers are 50% less likely to have PD or AD than are age- and gender-matched nonsmokers. This statistically significant negative association has been interpreted as suggesting that cigarette smoking exerts an undefined, biologic, neuroprotective influence against the development of PD and AD. A review of all studies that either support or refute this hypothesis is presented separately for PD and AD.     

Memantine for the treatment of dementia

BACKGROUND: The use of cholinesterase inhibitors to correct the cholinergic deficit in patients with mild to moderate Alzheimer's disease (AD) is well established. However, the treatment is only effective in about half of the patients for whom it is prescribed. Vascular dementia may respond, at least to some extent, to these drugs (T Erkinjuntti and colleagues, Lancet 2002; 359: 1283-90). In 2002, the Committee of Proprietary Medicinal Products recommended that memantine-a drug that acts on the glutamatergic system rather than the cholinergic system-be approved by the European Commission for the treatment of moderately severe to severe AD. Clinical trials have shown some effectiveness of memantine in the treatment of vascular dementia, although it has not been approved for use in this disorder. RECENT DEVELOPMENTS: The results of a study of the effects of memantine on moderate to severe AD have recently been published (B Reisberg and colleagues, N Engl J Med 2003; 348: 1333-41). Reisberg and colleagues treated their patients for 28 weeks, assessed several outcome variables, and found that memantine reduced clinical deterioration without significant adverse effects. This study is important as memantine is the only treatment licensed for patients with more advanced AD. WHERE NEXT? Several questions about the use of memantine as a treatment for AD remain to be answered. How beneficial is memantine treatment in routine clinical practice compared with clinical trials? What is the best way to assess treatment effects? How long do the beneficial effects last? Does memantine have neuroprotective, rather than just symptomatic, effects? In addition, we need to know when to switch from cholinesterase inhibitors to memantine or when to co-prescribe memantine with cholinesterase inhibitors. The efficacy of memantine in vascular dementia also requires further investigation.     

Molecular mechanisms and therapeutic application of NSAIDs and derived compounds in Alzheimer's disease

Alzheimer's disease (AD) is the most common form of neurodegenerative dementias worldwide. Amyloid-β deposition, neurofibrillary tangle formation and Neuroinflammation are the major pathogenetic mechanisms that in concert lead to memory dysfunction and decline of cognition. To date, there is no curative treatment for AD. Epidemiological analysis support the notion that sustained intake of non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk and delay the onset of AD. In contrast, therapeutic studies testing NSAID efficacy in AD patients have not yielded positive results. This suggests that either the investigated drugs have not addressed the mechanism of action required for mediating beneficial effects or that NSAIDs are effective at stages way before clinical onset of symptoms. The NSAIDs concerned are pleiotrophic in nature and interact with more than one pathomechanism. Therefore evidence for more than one neuroprotective action of NSAIDs has been put forward and it seems likely that some of the drugs act at multiple levels through more than one molecular mechanism. Some, even may not only be beneficial, but negative actions may be overruled by protective effects. Within these mechanisms, modulation of γ-secretase activity, the activation of the peroxisome proliferator-activated receptor-γ, binding to prostaglandin receptors or interactions at the blood-brain barrier may account for the observed protection from AD. This article reviews the current knowledge and views on the above mechanisms and critically discusses current obstacles and the potential as future AD therapeutics.     

A placebo-controlled trial of valproate for agitation and aggression in Alzheimer's disease

BACKGROUND/AIMS: To assess the efficacy and tolerability of valproate for the treatment of agitation and aggression in moderate-to-severe Alzheimer's disease (AD). METHODS: This was a randomized, double-blind, placebo-controlled crossover trial of valproate in institutionalized AD patients. Patients were assessed with the Neuropsychiatric Inventory (NPI) and Cohen-Mansfield Agitation Inventory at baseline and after 6 weeks of treatment with valproate and placebo, with 2 weeks between phases to allow for placebo washout and tapering. RESULTS: Fourteen patients (8 male/6 female) aged 85.6 +/- 4.5 years with baseline Mini Mental State Examination scores of 4.5 +/- 4.6 and NPI agitation/aggression scores of 6.4 +/- 3.5 were randomized to treatment. NPI agitation/aggression treatment change scores significantly worsened during valproate treatment compared with placebo (Z = -2.03, p = 0.04). Tolerability of valproate was also poor, with patients experiencing a significantly greater mean number of adverse events during valproate therapy compared to placebo (Z = -2.82, p = 0.005). CONCLUSION: Valproate is not effective for the management of agitation in moderate-to-severe AD, and may be poorly tolerated in this population.     

��Untangling�� Alzheimer's Disease and Epilepsy

There is a substantial body of evidence that spontaneous recurrent seizures occur in a subset of patients with Alzheimer disease (AD), especially the familial forms that have an early onset. In transgenic mice that simulate these genetic forms of AD, seizures or reduced seizure threshold have also been reported. Mechanisms underlying the seizures or reduced seizure threshold in these mice are not yet clear and are likely to be complex, because the synthesis of amyloid β (Aβ) involves many peptides and proteases that influence excitability. Based on transgenic mouse models of AD where Aβ and its precursor are elevated, it has been suggested that seizures are caused by the downregulation of the Nav1.1 sodium channel in a subset of GABAergic interneurons, leading to a reduction in GABAergic inhibition. Another mechanism of hyperexcitability appears to involve tau, because deletion of tau reduces seizures in some of the same transgenic mouse models of AD. Therefore, altered excitability may be as much a characteristic of AD as plaques and tangles—especially for the familial forms of AD.     

Melatonin in Alzheimer's disease and other neurodegenerative disorders

Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-β toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin, its analogues and kynuric metabolites may have potential value in prevention and treatment of AD and other neurodegenerative disorders.