Current drug targets. CNS and neurological disorders最新文献

Aggregation of Abeta plays a key role in the pathogenesis of Alzheimer's disease. Although the highly structured Abeta aggregates (fibrils) have long been thought to be the toxic form of Abeta, recent evidence suggests that smaller, soluble intermediates in Abeta aggregation are the real culprit. Because these oligomeric aggregates are already formed in the secretory pathway, this raises another issue: Is intra- or extracellular Abeta involved in the pathogenic cascade? Because aggregated proteins are very toxic, cells have developed quality control responses to deal with such proteins. A prime site for quality culum. Here, aberrant proteins are recognized and can be targeted for degradation to the cytosolic quality control system. In addition, there is accumulating evidence for quality control in other subcellular compartments in the cell. All quality control mechanisms are initially protective, but will become destructive after prolonged accumulation of aggregated proteins. This is enhanced by decreased efficiency of these systems during aging and therefore, these responses may play an important role in the pathogenesis of Alzheimer's disease. In this review, we will discuss the role of protein quality control in the neurotoxicity of Abeta.

Alzheimer's disease is a chronic neurodegenerative disorder characterised by typical pathological hallmarks such as amyloid deposition, neurofibrillary tangles and disturbances in the expression of various cell cycle proteins. A current pathogenetic hypothesis suggests that neurons, forced by external and internal factors, leave the differentiated G(0) phase and re-enter the cell cycle. This process results in neuronal de-differentiation and apoptosis and might contribute to an increased phosphorylation of the tau protein. There are a number of reports, however, describing the expression of cell cycle proteins in rodent or human brain under normal non-disease conditions. This might indicate that cell cycle expression of proteins in neurons is of physiological rather than pathophysiological relevance. Therefore, it needs to be carefully analysed whether the expression of cell cycle regulators such as cyclin-dependent kinases, cyclins or cyclin-dependent kinase inhibitors in neurons is a pathological hallmark that allows to discriminate between normal and disease condition. Here we attempt to summarise recent evidence for a dysfunction of cell cycle regulators in Alzheimer's disease, considering the potential functions of these molecules beyond cell cycle regulation.

Glutamate is the main excitatory neurotransmitter in the central nervous system and it plays a significant role not only in synaptic transmission but also in acute and chronic neuropathologies including stroke. Presently, four receptors for glutamate have been identified and the NMDA receptor family is the most intensively studied. A number of NMDA receptor antagonists have been developed and used for treatment of neurological diseases in patients. However, all of these drugs have been failed in clinical trials either because of intolerable side effects or lack of medical efficacy. Recently, the understanding of molecular structure of NMDA receptors has been advanced and this finding thus provides information for designing subtype-selective antagonists. Using NR2B subunit selective antagonists, ifenprodil and eliprodil, as basic structure models, second and third generation congeners have been developed. Several NR2B-selective compounds showed neuroprotective actions at doses that did not produce measurable side effects in preclinical studies. Some of NR2B subunit selective antagonists have also been tested for the treatment of ischemic brain injury. The present review describes the role of glutamate in ischemic brain injury with an emphasis on the NR2B containing NMDA receptors.

Signal transduction via ionotropic glutamate receptors is found in many life forms, from protozoa to mammals. Glutamate is the main excitatory neurotransmitter in the mammalian CNS, were fast postsynaptic depolarisation is induced by the activation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. In addition to their important physiological role, excessive AMPA receptor stimulation is also a hallmark of excitotoxicity-related diseases, like ischaemic stroke. Conversely, AMPA receptor inhibitors were proposed to be useful neuroprotective drugs. First generation AMPA receptor blockers were competitive antagonists, like NBQX, which showed robust neuroprotection in a variety of disease-related animal models. Its clinical use, however, was restricted by the very low solubility, inducing kidney precipitaton in vivo. Second generation competitive antagonists are available, which do not possess this property. None of those, however, up to now is in clinical use. Competitive AMPA receptor antagonists are not the first choice for neuroprotective drugs, since due to receptor kinetics they preferently suppress the physiological relevant component of the postsynaptic glutamate response. Non-competitive blockers, like 2,3-benzodiazepines or the novel neuroprotectant BIIR 561 should be suited better for the treatment of stroke. The latter compound is also described as blocker of voltage-gated sodium channels. Targetting more than one mechanism in the excitotoxicity cascade might be a fruitful approach for the development of neuroprotective drugs.

Locomotion results from the activity in neural networks in the spinal cord that together with sensory and descending inputs generate coordinated motor outputs. Descending inputs include glutamatergic, monoaminergic, and peptidergic pathways. Spinal injuries interrupt these descending pathways, resulting in the disruption or loss of function. Drugs that target these endogenous transmitter systems have been used to improve function after spinal injury. However, individual drugs can have beneficial or deleterious effects in different studies and thus there is little consensus on optimal pharmacological strategies. The variability may be influenced by changes introduced by the type of lesion (complete or partial), time after injury, or the lack of specific ligands that target specific transmitter systems. It is now recognised that these transmitter systems do not necessarily act in isolation, but can interact to evoke additive, inhibitory, or novel metamodulatory effects. Meta interactions mean that differing chemical environments in lesioned spinal cords could influence drug effects. The spinal cord also exhibits injury-induced changes, which could alter the chemical environment and functional properties over time. While they have not been considered in pharmacological approaches to spinal injury, interactive and adaptive changes could influence the effects of spinal lesions and therapeutic interventions. The properties of endogenous transmitter systems in spinal locomotor networks before and after spinal lesions need to be understood, and pharmacological tools that target specific functional aspects need to be developed.

Poly (ADP-ribose) polymerase-1 (PARP-1) is a DNA-binding protein that is primarily activated by nicks in the DNA molecule. It regulates the activity of various enzymes - including itself- that are involved in the control of DNA metabolism. Upon binding to DNA breaks, activated PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins including histones, transcription factors and PARP itself. Poly(ADP-ribosylation) contributes to DNA repair and to the maintenance of genomic stability. Evidence obtained with pharmacological PARP inhibitors of various structural classes, as well as animals lacking the PARP-1 enzyme indicate that PARP plays an important role in cerebral ischemia/reperfusion, stroke and neurotrauma. Overactivation of PARP consumes NAD+ and ATP culminating in cell dysfunction and necrosis. PARP activation can also act as a signal that initiates cell death programs, for instance through AIF (apoptosis inducing factor) translocation. PARP has also been shown to associate with and regulate the function of several transcription factors. Of special interest is the enhancement by PARP of NF-kappaB-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules and inflammatory mediators. Via this mechanism, PARP is involved in the up-regulation of numerous pro-inflammatory genes that play a pathogenetic role in the later stage of stroke and neurotrauma. Here we review the roles of PARP in DNA damage signaling and cell death, and summarize the pathogenetic role of PARP in stroke and neurotrauma.

After focal cerebral ischemia, the infarct volume increases rapidly within acute infarct expansion (initial 12 to 24 h) and continues slowly during delayed infarct expansion (25 to 168 h). While acute infarct expansion represents progressive necrosis within the ischemic core, delayed infarct expansion starts as disseminated apoptotic cell death in a narrow rim surrounding the infarct border, which gradually coalesces to form a larger infarct. Discovery of a distinct correlation between reactive astrogliosis along the infarct border and delayed infarct expansion in the rodent ischemia model led us to investigate the possible causal relationship between the two events. Specifically, the calcium binding protein S100B exerts detrimental effects on cell survival through activation of various intracellular signaling pathways, resulting in altered protein expression. Arundic acid [(R)-(-)-2-propyloctanoic acid, ONO-2506] is a novel agent that inhibits S100B synthesis in cultured astrocytes. In the rodent ischemia model, this agent was shown to inhibit both the astrocytic overexpression of S100B and the subsequent activation of signaling pathways in the peri-infarct area. Concurrently, delayed infarct expansion was prevented, and neurologic deficits were promptly ameliorated. The results of subsequent studies suggest that the efficacy of arundic acid is mediated by restoring the activity of astroglial glutamate transporters via enhanced genetic expression.

Serotonin agonists can reduce glutamate-induced excitotoxicity in cerebral ischemia. The potent 5-HT1A agonist BAY x 3702, or repinotan, has reduced cortical infarct volume in pre-clinical models even when given 5 hours after injury. Early clinical trials showed that the drug was safe, and displayed primarily serotonergic side effects such as nausea and vomiting. A phase IIb trial in moderate to moderately severe strokes completed enrollment in June 2004.

This review discusses the potential usefulness of several selected polypeptide growth factors as treatments for stroke. Distinctions between global vs. focal cerebral ischemia, permanent vs. temporary focal ischemia, and acute stroke vs. stroke recovery are first discussed. Potential routes of administration of growth factors are also considered. The growth factors basic fibroblast growth factor (bFGF), osteogenic protein-1 (OP-1), vascular endothelial growth factor (Veg-f), erythropoietin (EPO), and granulocyte colony stimulating factor (G-CSF) all show potential usefulness in animal models of acute stroke and stroke recovery. Two of these factors, bFGF and EPO, have reached human clinical trials for acute stroke, and the data are discussed. Future directions in this field are also discussed.