New prospects and strategies for drug target discovery in neurodegenerative disorders.
TL;DR: A general experimental paradigm is described that is being employed across several mouse models of neurodegenerative disease to elucidate molecular determinants of selective neuronal vulnerability and key elements of the target discovery program are outlined.
Abstract: The future of neurodegenerative therapeutics development depends upon effective disease modification strategies centered on carefully investigated targets. Pharmaceutical research endeavors that probe for a much deeper understanding of disease pathogenesis, and explain how adaptive or compensatory mechanisms might be engaged to delay disease onset or progression, will produce the needed breakthroughs. Below, we discuss the prospects for new targets emerging out of the study of brain disease genes and their associated pathogenic pathways. We describe a general experimental paradigm that we are employing across several mouse models of neurodegenerative disease to elucidate molecular determinants of selective neuronal vulnerability. We outline key elements of our target discovery program and provide examples of how we integrate genomic technologies, neuroanatomical methods, and mouse genetics in the search for neurodegenerative disease targets.
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TL;DR: Neurochemical results in FTD indicate degeneration and loss of pyramidal neurones in frontotemporal neocortex, yet 5-HT afferents and5-HT concentration, which are inhibitory on pyramid neurones, were relatively preserved, which could lead to an excess of extraneural 5- HT causing underactivity of surviving pyramides.
Abstract: Rationale
Information is sparse on neurotransmitter deficiencies in frontotemporal dementia (FTD), in particular with reference to distinct histological subgroups and Alzheimer’s disease (AD).
63 citations
TL;DR: 3-HB and derivatives enhance learning and memory, possibly through a signaling pathway requiring PUMA-G that increases protein synthesis and gap junctional intercellular communication.
58 citations
Cites background from "New prospects and strategies for dr..."
...Silent synapses, containing N-methyl-D-aspartate receptors, are highly plastic and may present a target for axons augmented with gap junctions [46]....
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TL;DR: In this review, the authors intend to survey new drugs in different clinical phases but not in the preclinical or discovery stages nor already in the market, with new molecules aimed at interrupting or at attenuating different pathogenic pathways of neurodegeneration and/or at ameliorating symptoms.
Abstract: Neurodegenerative diseases are now generally considered as a group of disorders that seriously and progressively impair the functions of the nervous system through selective neuronal vulnerability of specific brain regions. Alzheimer's disease is the most common neurodegenerative disease, followed in incidence by Parkinson's disease; much less common are frontotemporal dementia, Huntington's disease, amyothrophic lateral sclerosis (Lou Gehrig's disease), progressive supranuclear palsy, spinocerebellar ataxia, Pick's disease and, lastly, prion disease. In this review, the authors intend to survey new drugs in different clinical phases but not in the preclinical or discovery stages nor already in the market, with new molecules aimed at interrupting or at attenuating different pathogenic pathways of neurodegeneration and/or at ameliorating symptoms. Drugs in different pharmacological phases are under study or are ready to be introduced into therapy for Alzheimer's disease, which display anti-beta-amyloid activity or nerve growth factor-like activity or anti-inflammatory properties. Other drugs possess mixed mechanisms of action, such as acetylcholinesterase inhibition and impairment of beta-amyloid formation through inhibition of beta-amyloid precursor protein synthesis and/or modulation of secretase activity. Other therapeutic approaches are based on immunotherapy, control of metal ions interactions with beta-amyloid and ensuing oxidative reactions as well as metabolic or hormonal regulation. The symptomatic therapy of motor behaviour in Parkinson's disease, based on l-DOPA, is registering adenosine A(2A) receptor antagonists, monoamine oxidase B inhibitors and ion channel modulators, as well as dopamine uptake inhibitors and glutamate AMPA receptor antagonists. There are also many other drugs involved, including astrocyte-modulating agents, 5-HT(1A) agonists and alpha(2)-adrenergic receptor antagonists, which are targeted at preventing or ameliorating Parkinson's disease-related or l-DOPA-induced dyskinesias. Huntington's disease therapy envisages a Phase III drug, LAX-101, which displays antiapoptotic properties by promoting membrane stabilisation and mitochondrial integrity. Other drugs with antioxidant and antiapoptotic steroid-like and neuroprotective activity are under investigation for the therapy of the less common neurodegenerative diseases.
58 citations
TL;DR: The molecular docking results revealed five ligands that showed high docking scores and optimal protein-ligand interactions of p-tau, which showed the best pharmacokinetic and physicochemical properties, including good absorption, distribution, metabolism, and excretion and admetSAR toxicity tests.
Abstract: The purpose of our study is to identify phosphorylated tau (p-tau) inhibitors. P-tau has recently received great interest as a potential drug target in Alzheimer’s disease (AD). The continuous failure of Aβ-targeted therapeutics recommends an alternative drug target to treat AD. There is increasing evidence and growing awareness of tau, which plays a central role in AD pathophysiology, including tangles formation, abnormal activation of phosphatases/kinases, leading p-tau aggregation in AD neurons. In the present study, we performed computational pharmacophore models, molecular docking, and simulation studies for p-tau in order to identify hyperphosphorylated sites. We found multiple serine sites that altered the R1/R2 repeats flanking sequences in the tau protein, affecting the microtubule binding ability of tau. The ligand molecules exhibited the p-O ester scaffolds with inhibitory and/or blocking actions against serine residues of p-tau. Our molecular docking results revealed five ligands that showed high docking scores and optimal protein-ligand interactions of p-tau. These five ligands showed the best pharmacokinetic and physicochemical properties, including good absorption, distribution, metabolism, and excretion (ADME) and admetSAR toxicity tests. The p-tau pharmacophore based drug discovery models provide the comprehensive and rapid drug interventions in AD, and tauopathies are expected to be the prospective future therapeutic approach in AD.
52 citations
Cites background from "New prospects and strategies for dr..."
...This current challenging situation makes considering the rational therapeutic development for AD and other tauopathy diseases an urgent matter [19,20]....
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TL;DR: Administration of the test formulation for a period of 12 months was effective in improving cognitive functions in the SDAT patients, when compared to the donepezil-treated group, as determined by the DSS.
Abstract: The enigmatic etiology of neurodegenerative diseases poses a challenge for the development of novel and efficient drugs The objective of the present study was to evaluate the efficacy of a polyherbal (test) formulation on cognitive functions, inflammatory markers and oxidative stress in healthy elderly as well as senile dementia of Alzheimer’s type (SDAT) patients A randomized double-blind placebo- and active-controlled clinical trial was performed in healthy elderly subjects and SDAT patients with an age range of 60–75 years The polyherbal test formulation along with a placebo was given to healthy elderly subjects while the SDAT patients received either the test formulation containing extracts of Bacopa monnieri (whole plant), Hippophae rhamnoides (leaves and fruits) and Dioscorea bulbifera (bulbils) at a dose of 500 mg or donepezil drug (Aricept) at a dose of 10 mg, twice daily, for a period of 12 months After every three months, cognitive functions were assessed by determining the mini mental state examination (MMSE) score, digital symbol substitution (DSS; subtest of the Wechsler Adult Intelligence Scale—Revised), immediate and delayed word recall (digital memory apparatus—Medicaid systems, Chandigarh, India), attention span (Attention Span Apparatus—Medicaid systems, Chandigarh, India), functional activity questionnaire (FAQ) and depression (geriatric depression scale) scores Further inflammatory markers and level of oxidative stress were analyzed using standard biochemical tests The trial was performed in 109 healthy subjects and 123 SDAT patients of whom 97 healthy subjects and 104 SDAT patients completed the study Administration of the test formulation for a period of 12 months was effective in improving cognitive functions in the SDAT patients, when compared to the donepezil-treated group, as determined by the DSS (38984 ± 3016 vs 35852 ± 4906, P = 00001), word recall immediate (3594 ± 1003 vs 2794 ± 0593, P < 00001) and attention span (4918 ± 1239 vs 4396 ± 0913, P = 00208) scores A significant improvement in the FAQ (11873 ± 2751 vs 9801 ± 1458, P < 00001) and depression (16387 ± 2116 vs 21006 ± 2778, P < 00001) scores was also observed, whereas no significant differences were observed in the MMSE and word recall delayed scores The level of inflammation and oxidative stress was markedly reduced in the SDAT patients treated with the test formulation when compared to the donepezil-treated group indicating a likely mechanism of action of the test formulation (homocysteine 3022 ± 387 vs 4473 ± 711 nmol/L, P < 00001; C-reactive protein [CRP] 4751 ± 1149 vs 5887 ± 1049 mg/L, P < 00001; tumour necrosis factor alpha [TNF–α] 113945 ± 19887 vs 159877 ± 29852 pg/ml, P < 00001; superoxide dismutase [SOD] 114592 ± 22875 vs 1296 ± 22572 U/g Hb, P = 00013; glutathione peroxidase [GPx] 2078 ± 314 vs 2599 ± 411 U/g Hb, P < 00001; glutathione [GSH] 9358 ± 2139 vs 6831 ± 1139 U/g Hb, P < 00001; thiobarbituric acid reactive substances [TBARS] 13162 ± 2968 vs 17640 ± 6811 nmol/g Hb, P < 00001) Similarly, when healthy elderly subjects treated with the test formulation for 12 months were compared to the placebo group, a significant (P < 0001) improvement in cognitive measures (MMSE, DSS, word recall delayed but not immediate, attention span, FAQ and depression scores) and a reduction in inflammation (reduction in homocysteine, CRP, IL-6 and TNF-α levels) and oxidative stress levels (reduction in SOD, GPx and TBARS and increase in GSH) was observed This indicated a protective effect of the test formulation in managing cognitive decline associated with the ageing process The results of this study demonstrate the therapeutic potential of this novel polyherbal formulation for the management and treatment of SDAT
41 citations
Cites background from "New prospects and strategies for dr..."
...The pharmaceutical industry is facing a serious challenge in the drug discovery and development process for neurodegenerative diseases [44]....
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References
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TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
Abstract: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer9s disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance.
12,652 citations
"New prospects and strategies for dr..." refers background in this paper
...However, little consensus exists as to what constitutes the toxic A species, how or where (or if?) the aberrant peptide initiates a toxic disease process, or what serves as its primary target.(3) Candidates for mechanism-based targets in neurodegenerative disorders have arisen chiefly out of the initial identification of disease genes through genetic linkage and mapping approaches....
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TL;DR: The APOE-epsilon 4 allele is associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD) in 42 families with late onset AD.
Abstract: The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
8,669 citations
TL;DR: Strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease, indicates that the LewY bodies from these two diseases may have identical compositions.
Abstract: Lewy bodies, a defining pathological characteristic of Parkinson's disease and dementia with Lewy bodies (DLB)1,2,3,4, constitute the second most common nerve cell pathology, after the neurofibrillary lesions of Alzheimer's disease. Their formation may cause neurodegeneration, but their biochemical composition is unknown. Neurofilaments and ubiquitin are present5,6,7,8, but it is unclear whether they are major components of the filamentous material of the Lewy body9,10. Here we describe strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease11. α-Synuclein may be the main component of the Lewy body in Parkinson's disease. We also show staining for α-synuclein of Lewy bodies from DLB, indicating that the Lewy bodies from these two diseases may have identical compositions.
6,923 citations
TL;DR: A purified protein derived from the twisted beta-pleated sheet fibrils in cerebrovascular amyloidosis associated with Alzheimer's disease has been isolated and Amino acid sequence analysis and a computer search reveals this protein to have no homology with any protein sequenced thus far.
4,795 citations
TL;DR: A new term "prion" is proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids.
Abstract: After infection and a prolonged incubation period, the scrapie agent causes a degenerative disease of the central nervous system in sheep and goats. Six lines of evidence including sensitivity to proteases demonstrate that this agent contains a protein that is required for infectivity. Although the scrapie agent is irreversibly inactivated by alkali, five procedures with more specificity for modifying nucleic acids failed to cause inactivation. The agent shows heterogeneity with respect to size, apparently a result of its hydrophobicity; the smallest form may have a molecular weight of 50,000 or less. Because the novel properties of the scrapie agent distinguish it from viruses, plasmids, and viroids, a new term "prion" is proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids. Knowledge of the scrapie agent structure may have significance for understanding the causes of several degenerative diseases.
4,753 citations
"New prospects and strategies for dr..." refers background in this paper
...In prion diseases, the mutant protein, termed PrP, fibrillizes and forms numerous amyloid deposits.(13) The protein -synuclein is found in inclusions called Lewy bodies in PD(14) and mutant SOD1 is found in intraneuronal inclusions in some forms of familial amyotrophic lateral sclerosis (ALS)....
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