Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mapping of the human and other eukaryotic genomes has provided the pharmacological industry with excellent models for drug discovery. Control of cell proliferation, differentiation, activation and cell removal is crucial for the development and existence of multicellular organisms. Each cell cycle progression, with sequences of DNA replication, mitosis, and cell division, is a tightly controlled and complicated process that, when deregulated, may become dangerous not only to a single cell, but also to the whole organism. Regulation and the proper control of the cell cycle and of programmed cell death (apoptosis) is therefore essential for mammalian development and the homeostasis of the immune system. The molecular networks that regulate these processes are critical targets for drug development, gene therapy, and metabolic engineering. In addition to the primary, intracellular apoptotic suicide machinery, components of the immune system can detect and remove cells and tissue fragments that no longer serve their defined functions. In this review we will focus on apoptotic pathways converging on caspase family proteases, summarizing pharmacological attempts that target genes, proteins, and intermolecular interactions capable of modulating apoptosis and the inflammatory response. The upcoming pharmacological development for treatment of acute pathologies, such as sepsis, SIRS, stroke, traumatic brain injury, myocardial infarction, spinal cord injury, acute liver failure, as well as chronic disorders such as Huntington's disease, Parkinson's disease, ALS, and rheumatoid arthritis, will be discussed in details. We also suggest new potential molecular targets that may prove to be effective in controlling apoptosis and the immune response in vivo.
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PMID:Stroke, myocardial infarction, acute and chronic inflammatory diseases: caspases and other apoptotic molecules as targets for drug development. 1524 81

The authors provide an extensive review of new data related to the role of glutamate in CNS disorders, describing new aspects in glutamate and glutamatergic receptors-NMDA receptors, NR2B-selective antagonists, non-NMDA ionotropic glutamate receptors, N-acetylaspartylglutamate, and glutamate and glycine transporters. New findings in animal models and in human diseases-stroke, traumatic brain injury, Alzheimer's, Parkinson's and Huntington's diseases, tardive dyskinesia, ALS, olivopontcerebellar degeneration, AIDS, allergic encephalomyelitis, epilepsy, anxiety, depression, schizophrenia, liver disease, aminoglycoside antibiotic-induced hearing loss, hemiplegia, chronic pain and drug tolerance and abuse-are presented. Finally, the authors cite the progress achieved in the development of agents that interact with the glutamatergic system: NMDA channel blockers, competitive NMDA receptor antagonists, NR2B-selective antagonists, glutamate release inhibitors, glycineB antagonists, AMPA and kainate receptor antagonists, AMPA receptor-positive modulators and agents that act by modifying endogenous kynurenic acid metabolism.
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PMID:Glutamate in CNS disorders as a target for drug development: an update. 1561 69

Neural cell transplantation is an emerging therapy that may provide an effective treatment for neurodegenerative disorders. The most extensive work with neural transplants has been carried out for Parkinson's and Huntington's diseases. However, intensive efforts are also being made for the treatment of other neurological indications, such as spinal cord repair, stroke, epilepsy, multiple sclerosis (MS), Alzheimer's disease and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), to name just a few. The major barrier for the successful application of cells as therapeutics is achieving long-term survival and function. The CNS has proven to be ideal for transplantation, in part because immune rejection is attenuated in the CNS compared to peripheral locations. However, some form of immunosuppression is desirable for optimal allograft survival and required for xenograft survival. This review will focus on the challenges of restoring function to something as intricate as the CNS and on the limitations imposed by this complexity on any cellular therapeutic.
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PMID:Treatment of neurodegenerative diseases with neural cell transplantation. 1599 90

We conducted a retrospective chart review of all ALS patients seen at our institution over four years to determine the incidence of venous thromboembolism and to identify risk factors in this population. Events occurred in 13 of 438 patients (2.97%), yielding an annual incidence rate of 33.1 events per 1,000 patients (95% CI 17.5-55.3). ALS patients have a risk of venous thromboembolism that is higher than the general population but lower than the population of patients with acute stroke or spinal cord injury. Immobility was significantly associated with increased risk of venous thrombosis (RR = 4.96; 95% CI 1.39-17.78).
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PMID:Venous thrombosis in an ALS population over four years. 1631 29

GCP II inhibition decreases extracellular excitotoxic glutamate and increases extracellular NAAG, both of which provide neuroprotection. We have demonstrated with our potent and selective GCP II inhibitors efficacy in models of stroke, ALS and neuropathic pain. GCP II inhibition may have significant potential benefits over existing glutamate-based neuroprotection strategies. The upstream mechanism seems selective for excitotoxic induced glutamate release, as GCP II inhibitors in normal animals induced no change in basal glutamate. This suggestion has recently been corroborated by Lieberman and coworkers24 who found that both NAAG release and increase in GCP II activity appear to be induced by electrical stimulation in crayfish nerve fibers and that subsequent NAAG hydrolysis to glutamate contributes, at least in part, to subsequent NMDA receptor activation. Interestingly, even at relatively high doses of compounds, GCP II inhibition did not appear to be associated with learning/memory deficits in animals. Additionally, quantitative neurophysiological testing data and visual analog scales for 'psychedelic effects' in Phase I single dose and repeat dose studies showed GCP II inhibition to be safe and well tolerated by both healthy volunteers and diabetic patients. GCP II inhibition may represent a novel glutamate regulating strategy devoid of the side effects that have hampered the development of postsynaptic glutamate receptor antagonists.
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PMID:Glutamate carboxypeptidase II (NAALADase) inhibition as a novel therapeutic strategy. 1680 24

Neural stem cells (NSCs)of the central nervous system (CNS) have recently received a great deal of attention and interest for their therapeutic potential for neurological disorders. NSCs are defined as CNS progenitor cells that have the capacity for self-renewal and multipotent potential to become neurons or glial cells. Recent studies have shown that NSCs isolated from mammalian CNS including human can be propagated in vitro and then implanted into the brain of animal models of human neurological disorders. Recently, we have generated clonally derived immortalized human NSC cell lines via a retroviral vector encoded with v-myc oncogene. One of the human NSC lines, HB1.F3, was utilized in stem-cell based therapy in animal models of human neurological disorders. When F3 human NSCs were implanted into the brain of murine models of lysosomal storage diseases, stroke, Parkinson disease, Huntington disease or stroke, implanted F3 NSCs were found to migrate to the lesion sites, differentiate into neurons and glial cells, and restore functional deficits found in these neurological disorders. In animal models of brain tumors, F3 NSCs could deliver a bioactive therapeutically relevant molecules to effect a significant anti-tumor response intracranial tumor mass. Since these genetically engineered human NSCs are immortalized and continuously multiplying, there would be limitless supply of human neurons for treatment for patients suffering from neurological disorders including stroke, Parkinson disease, Huntington disease, ALS, multiple sclerosis and spinal cord injury. The promising field of stem cell research as it applies to regenerative medicine is still in infancy, but its potential appears limitless, and we are blessed to be involved in this exciting realm of research.
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PMID:Genetically engineered human neural stem cells for brain repair in neurological diseases. 1730 60

Influx of Ca(2+) ions through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors contributes to neuronal damage in stroke, epilepsy, and neurodegenerative disorders such as ALS. The Ca(2+) permeability of AMPA receptors is largely determined by the glutamate receptor 2 (GluR2) subunit, receptors lacking GluR2 being permeable to Ca(2+) ions. We identified a difference in GluR2 expression in motor neurons from two rat strains, resulting in a difference in vulnerability to AMPA receptor-mediated excitotoxicity both in vitro and in vivo. Astrocytes from the ventral spinal cord were found to mediate this difference in GluR2 expression in motor neurons. The presence of ALS-causing mutant superoxide dismutase 1 in astrocytes abolished their GluR2-regulating capacity and thus affected motor neuron vulnerability to AMPA receptor-mediated excitotoxicity. These results reveal a mechanism through which astrocytes influence neuronal functioning in health and disease.
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PMID:Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. 1780 92

Cell death plays an important role both in shaping the developing nervous system and in neurological disease and traumatic injury. In spite of their name, death receptors can trigger either cell death or survival and growth. Recent studies implicate five death receptors--Fas/CD95, TNFR1 (tumor necrosis factor receptor-1), p75NTR (p75 neurotrophin receptor), DR4, and DR5 (death receptors-4 and -5)--in different aspects of neural development or degeneration. Their roles may be neuroprotective in models of Parkinson's disease, or pro-apoptotic in ALS and stroke. Such different outcomes probably reflect the diversity of transcriptional and posttranslational signaling pathways downstream of death receptors in neurons and glia.
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PMID:Signaling by death receptors in the nervous system. 1872 96

The corticospinal tract provides the most direct pathway over which the cerebral cortex controls movement. In rodents and marsupials this influence is exerted largely upon interneurons in the dorsal horn of the spinal gray matter. However, ascending the phylogenetic scale through carnivores and primates, the number of corticospinal axons grows and corticospinal terminations shift progressively toward the interneurons of the intermediate zone and ventral horn, ultimately forming increasing numbers of synaptic terminations directly on the motoneurons themselves. Based on this phylogenetic trend, humans are believed to have more direct corticomotoneuronal synapses than any other species, consistent with observations that humans suffer more extensive loss of motility from lesions of the corticospinal tract than do other mammals. Beyond this phylogenetic trend, studies of the corticospinal system in animals have provided insight into the motor abnormalities that result from corticospinal lesions in humans. Corticospinal lesions impair many functionally related muscles and movements in parallel, both because of the divergent output from single corticomotoneuronal cells to multiple motoneuron pools, and because of the convergent input to different motoneuron pools from large, overlapping cortical territories. Furthermore, the weakness, slowness and inflexible, stereotyped movements that remain after corticospinal lesions reflect the loss of input to spinal interneurons and motoneurons from corticospinal neurons, the discharge frequency of which varies with the force, direction and speed of both gross and fine movements. That these deficits resulting from corticospinal lesions are more prominent in humans than in animals indicates, moreover, that animals make greater use of additional descending pathways to control movement. Animal studies have shown that although the bulk of the corticospinal tract arises from the primary motor cortex, this projection is not the only route via which the brain controls movement. Adjacent areas in the frontal and parietal lobes also contribute axons to the corticospinal tract, as well as having corticocortical connections with the motor cortex. Furthermore, the motor cortex and premotor cortex both project to the red nucleus and to the pontomedullary reticular formation, from which the rubrospinal and reticulospinal tracts arise. However, given the limitations on experimental studies in humans, comparative animal studies of the distributed descending system through which the brain controls movement continue to provide deeper understanding and insight into the deficits resulting from human corticospinal lesions, whether caused by stroke, tumor, multiple sclerosis, trauma or ALS.
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PMID:Chapter 2 Comparative anatomy and physiology of the corticospinal system. 1880 87

Reactive oxygen species (ROS) are produced at low levels in mammalian cells by various metabolic processes, such as oxidative phosphorylation by the mitochondrial respiratory chain, NAD(P)H oxidases, and arachidonic acid oxidative metabolism. To maintain physiological redox balance, cells have endogenous antioxidant defenses regulated at the transcriptional level by Nrf2/ARE. Oxidative stress results when ROS production exceeds the cell's ability to detoxify ROS. Overproduction of ROS damages cellular components, including lipids, leading to decline in physiological function and cell death. Reaction of ROS with lipids produces oxidized phospholipids, which give rise to 4-hydroxynonenal, 4-oxo-2-nonenal, and acrolein. The brain is susceptible to oxidative damage due to its high lipid content and oxygen consumption. Neurodegenerative diseases (AD, ALS, bipolar disorder, epilepsy, Friedreich's ataxia, HD, MS, NBIA, NPC, PD, peroxisomal disorders, schizophrenia, Wallerian degeneration, Zellweger syndrome) and CNS traumas (stroke, TBI, SCI) are problems of vast clinical importance. Free iron can react with H(2)O(2) via the Fenton reaction, a primary cause of lipid peroxidation, and may be of particular importance for these CNS injuries and disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Atherosclerosis, the major risk factor for ischemic stroke, involves accumulation of oxidized LDL in the arteries, leading to foam cell formation and plaque development. This review will discuss the role of lipid oxidation/peroxidation in various CNS injuries/disorders.
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PMID:Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. 1962 72


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