Multi-target-directed ligands in Alzheimer's disease treatment

Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs). This methodology has been specifically developed for treatment of disorders with complex pathological mechanisms. One such disorder is Alzheimer's disease (AD), currently the most common multifactorial neurodegenerative disease. AD is related to increased levels of the amyloid β peptide (Aβ) and the hyperphosphorylated tau protein, along with loss of neurons and synapses. Moreover, there is some evidence pointing to the role of oxidative stress, metal ion deregulation, inflammation and cell cycle regulatory failure in its pathogenesis. There are many attractive targets for the development of anti-AD drugs, and the multi-factor nature of this disease calls for multi-target-directed compounds which can be beneficial for AD treatment. This review presents the discovery of dualand multi-acting anti-AD drug candidates, focusing on the novel design strategy and the compounds it yields - particularly hybrids obtained by linking structurally active moieties interacting with different targets. The first group of compounds includes cholinesterase inhibitors acting as dual binding site inhibitors and/or inhibitors with additional properties. These compounds are characterized by increased potency against acetylcholinesterase (AChE) and Aβ plaque formation with additional properties such as antioxidant activity, neuroprotective, and metal-complexing property, voltage-dependent calcium channel antagonistic activity, inhibitory activity against glutamate-induced excitotoxicity, histamine H(3) receptor antagonism, cannabinoid CB(1) receptor antagonism and β-secretase (BACE1) inhibition. A novel class of compounds represents the combination of dual BACE1 inhibitors with metal chelators, and dual modulators of γ-secretase with peroxisome proliferator-ativated receptor γ (PPARγ). We have reviewed the latest reports (2008-2011) presenting new multi-target-directed compounds in Alzheimer's disease treatment.     

治疗阿尔茨海默病的乙酰胆碱酯酶抑制剂的分子设计: 从多位点抑制剂到一药多靶

阿尔茨海默病 (Alzheimer’s disease, AD) 是一种病因尚不明确且致病机制极为复杂的神经退行性疾病, 严重威胁老年人的健康并对整个社会发展带来沉重的负担。设计开发治疗阿尔茨海默病的药物一直是药物研发领域的热点和难点, 其中尤以乙酰胆碱酯酶 (acetylcholinesterase, AChE) 抑制剂的研究最为活跃并已在临床中成功应用。然而, 现有商品化AChE抑制剂的临床治疗效果有限, 并且都伴随不同程度的毒副作用。因此,  寻找高效、低毒的多重结合位点的AChE抑制剂和针对多重作用靶标的多功能抑制剂 (即一药多靶) 成为AChE抑制剂分子设计的主要发展方向。本文结合近年来的研究进展, 从代表性AChE抑制剂的化学结构和结合模式出发, 对AChE抑制剂分子设计的发展历程及最新成果进行了综述。     

Intranasal administration of dauricine loaded on graphene oxide: multi-target therapy for Alzheimer's disease

Alzheimer''s disease (AD) is a degenerative disease of the central nervous system characterized by progressive cognitive and memory-related impairment. However, current therapeutic treatments have not proved sufficiently effective, mainly due to the complicated pathogenesis of the disease. In this study, a nano-formulation of graphene oxide (GO) loaded with dauricine (Dau) was investigated in terms of the combined anti-inflammatory and anti-oxidative stress effects of Dau and the inhibition of misfolding and aggregation of the amyloid-β (Aβ) protein by GO. Both in vivo and in vitro models were induced using Aβ_1-42, and the formulation was administered nasally in mice. The results showed that GO loaded with Dau greatly reduced oxidative stress through increasing superoxide dismutase levels and decreasing reactive oxygen species and malondialdehyde levels in vitro; it also alleviated the cognitive memory deficits and brain glial cell activation in mice with Aβ_1-42-induced AD. This proved that GO loaded with Dau could protect against Aβ_1-42-induced oxidative damage and apoptosis in both in vitro and in vivo AD models; therefore, GO loaded with Dau has the potential to be an effective and agent for the rapid treatment of AD.     

Antiamyloid strategies for the treatment of Alzheimer's disease

Although the specific causes of Alzheimer's disease have not yet been determined, considerable circumstantial evidence implicates beta-amyloid, an insoluble polypeptide made up of 39 to 42 amino acids, in the continuing destruction of brain cells that results in the progressive deterioration of the patient's mental ability. The toxic actions of beta-amyloid appear to be due to free radicals generated by a portion of the beta-amyloid molecule. These free radicals damage various parts of the neuron and lead to increased intracellular calcium which is also toxic. beta-Amyloid is formed by the aberrant processing of a much larger precursor protein that is made when cells are damaged. The normal processing of this precursor protein not only prevents the formation of beta-amyloid, but produces a soluble protein that regulates the entry of calcium into neurons and has cytoprotective actions. Interventions to prevent the destruction of neurons and the disruption of brain function by beta-amyloid include the administration of antioxidants and free radical scavengers to reduce further neural damage from deposits of beta-amyloid, the activation of various growth factors to repair damaged cells and restore their functions, and the stimulation of the normal processing of the precursor protein not only to aid in neural repair but more importantly to prevent the formation of additional beta-amyloid.     

Evaluation of memantine for the treatment of Alzheimer's disease

Increasing evidence suggests that disturbances in glutamatergic activity play an important role in Alzheimer's disease (AD). Excessive glutamate-mediated activation of NMDA receptors, for example, may contribute to the neuronal death that characterises AD. On the other hand, physiological activation of the NMDA receptor appears necessary for normal cognitive function. Therefore, compounds that finely modulate NMDA receptor activity hold promise as treatments for AD. Memantine (Namenda, Axura, Ebixa; Forest Laboratories, Inc., Merz Pharmaceuticals GmbH, H. Lundbeck A/S) is a low-moderate affinity, uncompetitive NMDA-receptor antagonist that appears to block pathological, but not physiological, activation of the NMDA receptor. Consequently, therapeutic doses of the drug are well-tolerated and do not seem to interfere with the acquisition or processing of cognitive information. Memantine has been shown to improve symptoms and reduce the rate of clinical deterioration among patients with moderate-to-severe AD and was approved in the US for this indication in October 2003. This review provides a brief rationale for the development of memantine as a therapy for AD, as well as an overview of the pharmacology, clinical efficacy, safety and tolerability of this novel therapeutic agent.     

Emerging beta-amyloid therapies for the treatment of Alzheimer's disease

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavioral stability. AD is defined pathologically by extracellular neuritic plaques comprised of fibrillar deposits of beta-amyloid peptide (Abeta) and neurofibrillary tangles comprised of paired helical filaments of hyperphosphorylated tau. Current therapies for AD, such as cholinesterase inhibitors, treat the symptoms but do not modify the progression of the disease. The etiology of AD is unclear. However, data from familial AD mutations (FAD) strongly support the "amyloid cascade hypothesis" of AD, i.e. that neurodegeneration in AD is initiated by the formation of neurotoxic beta-amyloid (Abeta) aggregates; all FAD mutations increase levels of Abeta peptide or density of Abeta deposits. The likely link between Abeta aggregation and AD pathology emphasizes the need for a better understanding of the mechanisms of Abeta production. This review summarizes current therapeutic strategies directed at lowering Abeta levels and decreasing levels of toxic Abeta aggregates through (1) inhibition of the processing of amyloid precursor protein (APP) to Abeta peptide, (2) inhibition, reversal or clearance of Abeta aggregation, (3) cholesterol reduction and (4) Abeta immunization.     

Molecular rationale for the pharmacological treatment of Alzheimer's disease

Cerebral deposition of amyloid plaques containing amyloid beta-peptide (Abeta) has traditionally been considered the central feature of Alzheimer's disease (AD). Abeta is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: alpha-, beta- and gamma-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of alpha-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-D-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-D-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated alpha-secretase and they reduced Abeta generation and amyloid accumulation in a transgenic mouse model. beta-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for beta-secretase inhibitors. gamma-Secretase is not an easy candidate for pharmacological manipulation. Immunotherapeutic strategies have targeted Abeta directly; however, intensive investigation of indirect approaches to the management of AD with immunotherapy is now underway.     

Tau therapeutic strategies for the treatment of Alzheimer's disease

The two classical pathological hallmarks of Alzheimer's disease are deposits of aggregated beta-amyloid (Abeta) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Abeta pathology, an invariant trait of Alzheimer's disease, disruption of tau processing is a necessary event in the neurotoxic cascade which eventually leads to neuronal death and subsequent dementia. Tau is a neuronal, microtubule-bound protein which becomes hyperphosphorylated as a result of an imbalance of the kinase and phosphatase activities which normally tightly regulate its phosphorylation. In addition to this pathogenic hyperphosphorylation, tau dissociates from microtubules and self-aggregates to form insoluble oligomers which progress to the macroscopic tangles evident in post mortem Alzheimer's disease tissue. Subsequent toxicity may ensue either as a direct toxic effect of free tau oligomers or as a result of altered microtubule-dependent processes. In order to intervene pharmacologically in this disease process, much effort has been expended in order to identify and inhibit the kinases responsible for pathogenic hyperphosphorylation and many candidate kinases have been investigated including glycogen synthase kinase (GSK-3), cyclin-dependant kinase-5 (Cdk-5), MAPK family members (extracellular signal-regulated kinases 1 and 2 [Erk-1 and 2], MEK [MAP kinase kinase], c-Jun NH(2)-terminal kinases (JNKs) and p38), casein kinase, calcium calmodulin-dependant kinase II (CaMK-II), microtubule affinity regulating kinase (MARK), protein kinase A (PKA/cAMP-dependant protein kinase) and others. Focus has also fallen upon the role of the phosphatases responsible for dephosphorylation of tau. This review will describe the tau-related etiology of Alzheimer's disease and other tauopathies as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau.     

Clinical immunologic approaches for the treatment of Alzheimer's disease

Recent clinical trials of active vaccination against beta-amyloid (Abeta) have succeeded in clearing Abeta plaques; however, further understanding of immunization with regards to inflammation and other hallmarks of Alzheimer's disease pathology is required. Antibodies generated with this first-generation vaccine may not have had the desired therapeutic properties or targeted the 'correct' mechanism, but they have opened the way for new clinical approaches, which are now under consideration. Passive administration of monoclonal antibodies directed to various regions of Abeta peptide and/or administration of immunoconjugates of only small fragments of the N-terminal region may lead to the development of an improved second generation of Abeta vaccines. Amyloid immunotherapy offers genuine opportunities for disease treatment; however, such an approach towards treating and preventing Alzheimer's disease patients requires careful antigen and antibody selection to maximize efficacy and minimize adverse events.     

Emerging prospects for the disease-modifying treatment of Alzheimer's disease

The currently approved therapies for Alzheimer's disease (AD) in the US are designed to modify the function of specific neurotransmitter systems in the brain. While these palliative treatments can benefit some patients for a period of time, they do not halt the relentless cognitive and behavioral deterioration that characterize this neurodegenerative disorder. Consequently, much current research on AD is directed toward illuminating the disease process itself, particularly the abnormal accumulation of certain proteins in brain: the amyloid-beta protein (Abeta) in senile plaques and cerebral blood vessels, and the tau protein in neurofibrillary tangles. Genetic, biochemical and pathologic evidence now favors a primary role of Abeta aggregation in the Alzheimer proteopathic cascade, and studies in mice indicate that lowering the amount of this protein in brain can be beneficial. Recently, Abeta-immunization therapy has emerged as a particularly promising therapeutic option for treating Alzheimer's disease, but unexpected treatment-related side-effects are an overriding issue. These adverse events were not anticipated from preclinical studies with rodents; hence, more biologically relevant models, such as nonhuman primates, are needed to test the safety and efficacy of novel therapies for Alzheimer's disease.     

Vaccination for the prevention and treatment of Alzheimer's disease

In vitro studies showed that beta-amyloid peptide neurotoxicity correlates with the formation of fibrillar beta-amyloid and the variation in neurotoxic potency is related to the extent of peptide aggregation. Many efforts are being focused on the development of potent and selective inhibitors of amyloid formation in order to reduce the extent of their deposition and related neurotoxic effects. In our laboratory we are pioneering the idea that site-directed monoclonal antibodies (MAbs) can solubilize synthetic beta-amyloid aggregates. Production and performance of such antibodies by repeated injections of toxic human beta-amyloid fibrils into transgenic mice suggests the feasibility of vaccination against Alzheimer's disease (AD). Here we report the development of a novel immunization procedure for the production of effective antiaggregating beta-amyloid antibodies. The antigen is built from filamentous phages displaying the only four amino acids EFRH located at positions 3-6 of the beta-amyloid peptide found to be the main regulatory site of amyloid formation. Autoimmune antibodies are obtained by EFRH phage administration in guinea pigs, which exhibit human identity in the beta-amyloid peptide region. Availability of such antibodies opens up possibilities for the development of an efficient and long-lasting immunization procedure for the treatment of AD.     

Drug delivery strategies for Alzheimer's disease treatment

INTRODUCTION: Current Alzheimer's disease (AD) therapy is based on the administration of the drugs donepezil, galantamine, rivastigmine and memantine. Until disease-modifying therapies become available, further research is needed to develop new drug delivery strategies to ensure ease of administration and treatment persistence. AREAS COVERED: In addition to the conventional oral formulations, a variety of drug delivery strategies applied to the treatment of AD are reviewed in this paper, with a focus on strategies leading to simplified dosage regimens and to providing new pharmacological tools. Alternatives include extended release, orally disintegrating or sublingual formulations, intranasal or short- and long-acting intramuscular or transdermal forms, and nanotechnology-based delivery systems. EXPERT OPINION: The advent of new research on molecular mechanisms of AD pathogenesis has outlined new strategies for therapeutic intervention; these include the stimulation of α-secretase cleavage, the inhibition of γ-secretase activity, the use of non-steroidal anti-inflammatory drugs, neuroprotection based on antioxidant therapy, the use of estrogens, NO synthetase inhibitors, and natural agents such as polyphenols. Unfortunately, these compounds might not help patients with end stage AD, but might hopefully slow or stop the disease process in its early stage. Nanotechnologies may prove to be a promising contribution in future AD drug delivery strategies, in particular drug carrier nano- or microsystems, which can limit the side effects of anti-Alzheimer drugs.     

Drug delivery strategies for Alzheimer's disease treatment

Introduction: Current Alzheimer's disease (AD) therapy is based on the administration of the drugs donepezil, galantamine, rivastigmine and memantine. Until disease-modifying therapies become available, further research is needed to develop new drug delivery strategies to ensure ease of administration and treatment persistence.

Areas covered: In addition to the conventional oral formulations, a variety of drug delivery strategies applied to the treatment of AD are reviewed in this paper, with a focus on strategies leading to simplified dosage regimens and to providing new pharmacological tools. Alternatives include extended release, orally disintegrating or sublingual formulations, intranasal or short- and long-acting intramuscular or transdermal forms, and nanotechnology-based delivery systems.

Expert opinion: The advent of new research on molecular mechanisms of AD pathogenesis has outlined new strategies for therapeutic intervention; these include the stimulation of α-secretase cleavage, the inhibition of γ-secretase activity, the use of non-steroidal anti-inflammatory drugs, neuroprotection based on antioxidant therapy, the use of estrogens, NO synthetase inhibitors, and natural agents such as polyphenols. Unfortunately, these compounds might not help patients with end stage AD, but might hopefully slow or stop the disease process in its early stage. Nanotechnologies may prove to be a promising contribution in future AD drug delivery strategies, in particular drug carrier nano- or microsystems, which can limit the side effects of anti-Alzheimer drugs.     

Development of cholinergic drugs for the treatment of Alzheimer's disease

Alzheimer's Disease (AD) is characterized neurochemically by a profound loss of choline acetyl transferase activity and histologically by a selective degeneration of cholinergic neurons originating in the nucleus basalis of Meynert (nbM). The clinical relevance of this cholinergic deficit and its implications for the development of treatment strategies was explored in animal studies and in patients with carefully diagnosed AD. A hypocholinergic animal model was developed by chemical ablation of the nbM in rats. These rats demonstrated significant impairment of learning and memory as measured by long-term habituation of locomotor activity and retention of a one-trial passive avoidance task, which was substantially improved after the administration of the cholinergic drug physostigmine. In AD patients, in vivo assessment of cholinergic markers in cerebrospinal fluid showed decreased acetylcholine and choline activity in proportion to the patient's degree of cognitive impairment. Physostigmine was administered to AD patients both intravenously and orally in an attempt to enhance central cholinergic activity. Significant improvement of long-term memory encoding followed administration of intravenous physostigmine, and modest improvements in cognition and behavior resulted when oral physostigmine was given to some AD patients. These results support the hypothesis that cholinergic deficits are manifested in symptoms of AD and suggest that administration of cholinomimetic agents is a rational treatment strategy in AD.     

Herbal medicines for the prevention and treatment of Alzheimer's disease

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and is the most common cause of progressive dementia in aging. Research on AD therapy has been partly successful in terms of developing symptomatic treatments, but there have been a number of failures with regard to developing disease-modifying therapies. The pathogenesis of AD remains unclear and the present one-drug, one-target paradigm for anti-AD treatment appears to be clinically unsuccessful. In many countries, traditional herbal medicines are used to prevent or treat neurodegenerative disorders, and some have been developed as nutraceuticals or functional foods. This review briefly introduces progress in the development of anti-AD treatments and then focuses on recent advances in the research, characteristics, and development of herbal medicines. Because AD arises via multiple pathological or neurotoxic pathways, herbal medicines have the potential to be developed into optimum pharmaceuticals and nutraceuticals for AD because of their multi-function, multi-target characteristics.     

S-adenosyl-L-methionine in the treatment of Alzheimer's disease

Patients with Alzheimer's disease (AD) have an apparent abnormality possibly representing an increase in the average fluidity of their cell membranes. Changes in membrane fluidity of similar magnitude to those observed in AD have been noted to lead to marked alterations in cell function. Therefore, the changes in fluidity observed in AD may be related to the symptoms of that disorder, representing either an underlying cause of dysfunction or cellular attempts to compensate for dysfunction in AD. To test these possibilities, we administered S-adenosyl-L-methionine (SAMe), an agent shown to increase membrane fluidity in animals, to patients with AD. Treatment with SAMe led to marked increases in membrane fluidity. However, it produced neither improvement nor worsening of symptoms. The results imply that while SAMe may be useful for other conditions associated with altered membrane fluidity (such as normal aging), changing membrane fluidity per se is not likely to lead to marked changes in symptoms in AD.