共查询到20条相似文献,搜索用时 15 毫秒
1.
Alzheimer's disease (AD) is the most common age related neurodegenerative disease. Currently, there are no disease modifying drugs, existing therapies only offer short-term symptomatic relief. Two of the pathognomonic indicators of AD are the presence of extracellular protein aggregates consisting primarily of the Aβ peptide and oxidative stress. Both of these phenomena can potentially be explained by the interactions of Aβ with metal ions. In addition, metal ions play a pivotal role in synaptic function and their homeostasis is tightly regulated. A breakdown in this metal homeostasis and the generation of toxic Aβ oligomers are likely to be responsible for the synaptic dysfunction associated with AD. Therefore, approaches that are designed to prevent Aβ metal interactions, inhibiting the formation of toxic Aβ species as well as restoring metal homeostasis may have potential as disease modifying strategies for treating AD. This review summarizes the physiological and pathological interactions that metal ions play in synaptic function with particular emphasis placed on interactions with Aβ. A variety of therapeutic strategies designed to address these pathological processes are also described. The most advanced of these strategies is the so-called 'metal protein attenuating compound' approach, with the lead molecule PBT2 having successfully completed early phase clinical trials. The success of these various strategies suggests that manipulating metal ion interactions offers multiple opportunities to develop disease modifying therapies for AD. 相似文献
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Calcium plays a pivotal role in mediating many important biological functions. The intracellular calcium concentration is tightly regulated by a variety of systems and mechanisms. Calcium is sequestered by various organelles such as mitochondria and/or endoplasmic reticulum and extruded across the plasma membrane by energy-dependent transport systems. Different Ca2+-binding proteins are also involved in these processes. Alterations in calcium homeostasis might be critically implicated in brain aging and in the neuropathology of Alzheimer's disease (AD). In fact, one of the postulated mechanisms of beta-amyloid toxicity seems to involve a Ca2+ dysregulation accompanied with enhanced vulnerability to excitotoxic stimuli. Although brain characteristic lesions-plaques and tangles-constitute the hallmarks of AD, accumulated evidence suggests the systemic feature of this disease. Therefore peripheral cell lines may represent a useful approach to explore the cellular pathophysiology of AD, including calcium alterations and associated phenomena. 相似文献
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Mitochondrial dynamics play a crucial role in the pathobiology underlying Alzheimer's disease (AD) and Parkinson's disease (PD). Although a complete scientific understanding of these devastating conditions has yet to be realized, alterations in mitochondrial fission and fusion, and in the protein complexes that orchestrate mitochondrial fission and fusion, have been well established in AD- and PD-related neurodegeneration. Whether fission/fusion disruption in the brain is a causal agent in neuronal demise or a product of some other upstream disturbance is still a matter of debate; however, in both AD and PD, the potential for successful therapeutic amelioration of degeneration via mitochondrial protection is high. We here discuss the role of mitochondrial dynamics in AD and PD and assess the need for their therapeutic exploitation. 相似文献
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《Prescrire international》2012,21(128):150
The French Pharmacoeconomic Committee that assesses the medical benefit of new drugs and provides recommendations about reimbursement has downgraded its rating of the medical benefit (SMR, service mddical rendu) provided by cholinesterase inhibitors and memantine in Alzheimer's disease from "major" to "low". 相似文献
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Zhu X Webber KM Casadesus G Raina AK Lee HG Marlatt M Hartzler A Atwood CS Perry G Smith MA 《Current drug targets》2004,5(6):559-563
In this review, we discuss the role of cell cycle dysfunction in the pathogenesis of Alzheimer disease and propose that such mitotic catastrophe, as one of the earliest events in neuronal degeneration, may, in fact, be sufficient to initiate the neurodegenerative cascade. The question as to what molecule initiates cell cycle dysfunction is now beginning to become understood and, in this regard, the gender-predication, age-related penetrance and regional susceptibility of specific neuronal populations led us to consider luteinizing hormone as a key mediator of the abnormal mitotic process. As such, agents targeted toward luteinizing hormone or downstream sequelae may be of great therapeutic value in the treatment of Alzheimer disease. 相似文献
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A M Farghaly 《Die Pharmazie》1979,34(2):70-73
Synthesis of four different series of compounds having the phenazone moitety was accomplished, in the hope that one or more of the prepared compounds might possess pharmacological activity. These compounds may contain a hydrazone, an acid hydrazide, certain basic residues, or disubstituted urea structure. 相似文献
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Cacabelos R 《Expert opinion on pharmacotherapy》2005,6(12):1967-1987
Approximately 10-20% of the direct costs of Alzheimer's disease are attributed to pharmacological treatment. Less than 20% of Alzheimer's disease patients are moderate responders to conventional drugs (e.g., donepezil, rivastigmine, galantamine, memantine) with doubtful cost-effectiveness. In total, 15% of the Caucasian population with Alzheimer's disease are carriers of defective CYP2D6 polymorphic variants that are potentially responsible for therapeutic failures when receiving cholinesterase inhibitors and psychotropic drugs. In addition, structural genomics studies demonstrate that > 100 genes might be involved in Alzheimer's disease pathogenesis, regulating dysfunctional genetic networks leading to premature neuronal death. The Alzheimer's disease population exhibits a higher genetic variation rate than the control population, with absolute and relative genetic variations of 40-60% and 0.85-1.89%, respectively. Alzheimer's disease patients also differ from patients with other forms of dementia in their genomic architecture, possibly with different genes acting synergistically to influence the phenotypic expression of biological traits. Functional genomics studies in Alzheimer's disease reveal that age of onset, brain atrophy, cerebrovascular haemodynamics, brain bioelectrical activity, cognitive decline, apoptosis, immune function and amyloid deposition are associated with Alzheimer's disease-related genes. Pioneering pharmacogenomics studies also demonstrate that the therapeutic response in Alzheimer's disease is genotype-specific, with APOE-4/4 carriers as the worst responders to conventional treatments. It is likely that pharmacogenetic and pharmacogenomic factors account for 60-90% of drug variability in drug disposition and pharmacodynamics. The incorporation of pharmacogenomic/pharmacogenetic protocols in Alzheimer's disease may foster therapeutic optimisation by helping to develop cost-effective drugs, improving efficacy and safety, and reducing adverse events and cutting-down unnecessary cost for the industry and the community. 相似文献
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《Expert opinion on therapeutic targets》2013,17(6):585-592
Importance of the field: Fibrillar amyloid beta-protein (Aβ) is a major component of amyloid plaques in the brains of individuals with Alzheimer's disease (AD). However, a comprehensive explanation of the mechanisms leading to brain amyloidosis is still pending. Previous studies have identified the anti-amyloidogenic role of gelsolin in AD. Gelsolin can reduce amyloid burden by acting as an inhibitor of Aβ fibrillization, and as an antioxidant and anti-apoptotic protein.Areas covered in this review: Recent evidence indicates reduced brain gelsolin levels in AD. Therefore, a better understanding of the roles of gelsolin in AD pathology, particularly those related with cognition, is required.What the reader will gain: Most of the information reviewed here relates to experimental studies. However, gelsolin may progress from the present evidence to preclinical and clinical applications. In addition, a greater insight into the environmental factors contributing to abnormally reduced gelsolin function in AD brains may become crucial for the development of much needed disease-modifying strategies.Take home message: Because, the efficacy of available medicines is still poor, there is an urgent need for novel AD treatments. In this sense, gelsolin could play an important role. 相似文献
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Z S Khachaturian 《Clinical pharmacy》1984,3(5):522-523
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In Alzheimer's disease (AD), and other conditions affecting integrity of the blood-brain barrier, microglia can originate in the bone marrow, migrate into the blood and enter the brain in a chemokine-dependent manner. CCR2, a chemokine receptor that controls mononuclear phagocyte infiltration into the brain in multiple sclerosis, bacterial meningitis and neuropathic pain, also regulates microglia accumulation in mouse models of AD. CCR2 deficiency leads to lower microglia accumulation and higher brain beta-amyloid (Abeta) levels, indicating that early microglial accumulation promotes Abeta clearance. In support of this protective role, enhancing microglia accumulation delays progression of AD. AD mice that constitutively express interleukin-1 in the brain, or that are deficient in peripheral mononuclear phagocyte transforming growth factor-beta signaling, have increased microglia accumulation around beta-amyloid plaques and reduced AD-like pathology. Regulating microglia recruitment into the brain is a novel therapeutic strategy to delay or stop progression of AD. Here, we review the role of microglia in AD and the mechanisms of their accumulation and discuss implications for AD therapy. 相似文献
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The discovery of the vitamin D endocrine system and a receptor for the hormonal form, 1α,25-dihydroxyvitamin D(3), has brought a new understanding of the relationship between vitamin D and metabolic bone diseases, and has also established the functions of vitamin D beyond the skeleton. This has ushered in many investigations into the possible roles of vitamin D in autoimmune diseases, cardiovascular disorders, infectious diseases, cancers and granuloma-forming diseases. This article presents an evaluation of the possible roles of vitamin D in these diseases. The potential of vitamin D-based therapies in treating diseases for which the evidence is most compelling is also discussed. 相似文献
13.
Ototoxicity: therapeutic opportunities 总被引:7,自引:0,他引:7
Two major classes of drugs currently in clinical use can cause permanent hearing loss. Aminoglycoside antibiotics have a major role in the treatment of life-threatening infections and platinum-based chemotherapeutic agents are highly effective in the treatment of malignant disease. Both damage the hair cells of the inner ear, resulting in functional deficits. The mechanisms underlying these troublesome side effects are thought to involve the production of reactive oxygen species in the cochlea, which can trigger cell-death pathways. One strategy to protect the inner ear from ototoxicity is the administration of antioxidant drugs to provide upstream protection and block the activation of cell-death sequences. Downstream prevention involves the interruption of the cell-death cascade that has already been activated, to prevent apoptosis. Challenges and opportunities exist for appropriate drug delivery to the inner ear and for avoiding interference with the therapeutic efficacy of both categories of ototoxic drugs. 相似文献
14.
Kurt R. Brunden Yuemang Yao Justin S. Potuzak Nuria Ibarz Ferrer Carlo Ballatore Michael J. James Anne-Marie L. Hogan John Q. Trojanowski Amos B. Smith Virginia M.-Y. Lee 《Pharmacological research》2011,63(4):341-351
Tau, a protein that is enriched in neurons of the central nervous system (CNS), is thought to play a critical role in the stabilization of microtubules (MTs). Several neurodegenerative disorders referred to as tauopathies, including Alzheimer's disease and certain types of frontotemporal lobar degeneration, are characterized by the intracellular accumulation of hyperphosphorylated tau fibrils. Tau deposition into insoluble aggregates is believed to result in a loss of tau function that leads to MT destabilization, and this could cause neurodegeneration as intact MTs are required for axonal transport and normal neuron function. This tau loss-of-function hypothesis has been validated in a tau transgenic mouse model with spinal cord tau inclusions, where the MT-stabilizing agent, paclitaxel, increased spinal nerve MT density and improved motor function after drug absorption at neuromuscular junctions. Unfortunately, paclitaxel is a P-glycoprotein substrate and has poor blood–brain barrier permeability, making it unsuitable for the treatment of human tauopathies. We therefore examined several MT-stabilizing compounds from the taxane and epothilone natural product families to assess their membrane permeability and to determine whether they act as substrates or inhibitors of P-glycoprotein. Moreover, we compared brain and plasma levels of the compounds after administration to mice. Finally, we assessed whether brain-penetrant compounds could stabilize mouse CNS MTs. We found that several epothilones have significantly greater brain penetration than the taxanes. Furthermore, certain epothilones cause an increase in CNS MT stabilization, with epothilone D demonstrating a favorable pharmacokinetic and pharmacodynamic profile which suggests this agent merits further study as a potential tauopathy drug candidate. 相似文献
15.
《Drug discovery today》2014,19(11):1822-1827
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Alzheimer's disease affects nearly 5 million Americans currently and, as a result of the baby boomer cohort, is predicted to affect 14 million Americans and 22 million persons totally worldwide in just a few decades. Alzheimer's disease is present in nearly half of individuals aged 85 years. The main symptom of Alzheimer's disease is a gradual loss of cognitive function. Glutamatergic neurotransmission, an important process in learning and memory, is severely disrupted in patients with Alzheimer's disease. Loss of glutamatergic function in Alzheimer's disease may be related to the increase in oxidative stress associated with the amyloid beta-peptide that is found in the brains of individuals who have the disease. Therefore, therapeutic strategies directed at the glutamatergic system may hold promise. Therapies addressing oxidative stress induced by hyperactivity of glutamate receptors include supplementation with estrogen and antioxidants such as tocopherol (vitamin E) and acetylcysteine (N-acetylcysteine). Therapy for hypoactivity of glutamate receptors is aimed at inducing the NMDA receptor with glycine and cycloserine (D-cycloserine). Recently, memantine, an NMDA receptor antagonist that addresses the hyperactivity of these receptors, has been approved in some countries for use in Alzheimer's disease. 相似文献
17.
Alzheimer's disease is an age-related neurodegenerative disease which causes global loss of cognitive function. Drug treatment for Alzheimer's disease has been limited to agents that ameliorate behavioral symptoms but these agents are without effect on disease progression. Rational drug design for the treatment of Alzheimer's disease now seems possible. As a result of major advances in medical research in this area, knowledge of the etiology of Alzheimer's disease is rapidly being understood. This information has uncovered relevant and novel targets for treatment. At the center of the etiological progression of this disease is beta-amyloid. A substantial body of evidence strongly suggests that this small protein is critical to the development of Alzheimer's disease. The beta-amyloid protein is generated by two different proteolytic cleavages. Recently, the proteases responsible for producing the beta-amyloid protein have been identified. The proteases represent viable targets for therapeutic intervention against Alzheimer's disease. In this review, we describe the biological characteristics of the beta-amyloid-forming proteases in the context of pharmaceutical development. 相似文献
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