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)

Previous studies of neuronal degeneration induced by the neurotoxin, kainic acid, employed silver stain techniques that are non-quantitative or ELISA measurement of the non-neuronal protein, glial fibrillary acidic protein. As previous studies employed biomarkers that were either non-quantitative or non-neuronal, the present study employed a new neuronally localized biomaker of neuronal damage, cleaved microtubule-associated protein (MAP)-tau (C-tau). The time course of kainate neurotoxicity was quantitatively determined in several brain regions in the present study employing a C-tau specific ELISA. Differences in ELISA determined regional brain levels of C-tau were compared with the density of somatodendritic C-tau labeling qualitatively determined in immunohistochemical anatomical mapping studies of kainic acid-treated animals. Immunoblot studies revealed that the C-tau antibodies employed in the present study were highly specific for proteolytic cleaved C-tau. Immunolabeling of 45 kD-50 kD C-tau proteins was observed only in brain samples from kainic acid-treated but not vehicle-treated rats. Time course studies revealed that C-tau levels determined by ELISA were maximal 3 days after kainic acid with C-tau levels increasing 26-fold in hippocampus, 16-fold in cortex and four-fold in both striatum and hypothalamus. These statistical differences in maximal C-tau levels observed in the ELISA studies were similar to differences qualitatively observed in C-tau immunohistochemical studies. C-tau immunohistochemistry revealed extensive damage in hippocampal regions CA1 and 3, moderate damage in several cortical regions and mild damage in striatum and hypothalamus. Similar cleavage of rat MAP-tau to C-tau has been reported after neuronal degeneration induced by neurotoxic doses of methamphetamine and neuronal degeneration resulting from bacterial meningitis. In humans, C-tau proteolysis has been demonstrated to be a reliable biomarker of neuronal damage in traumatic brain injury and stroke where cerebrospinal C-tau levels are correlated with patient clinical outcome. These data suggest that C-tau proteolysis may prove a reliable species independent biomarker of neuronal degeneration regardless of source of injury.
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PMID:Quantification and localization of kainic acid-induced neurotoxicity employing a new biomarker of cell death: cleaved microtubule-associated protein-tau (C-tau). 1452 98

Moderate hypothermia and application of brain-derived neurotrophic factor (BDNF) have separately been identified as neuroprotective strategies in experimental cerebral ischemia. To assess their separate and combined effects on striatal glutamate release in the hyperacute phase of stroke, we inserted microdialysis probes into the striatum of rats 2 h before permanent middle cerebral artery occlusion (MCAO). The animals (N = 28) were randomly assigned to one of four treatment strategies commencing 30 min after MCAO: (1) hypothermia at 33 degrees C (n = 7); (2) intravenous BDNF infusion [300 microg/(kg/h) for 2 h, n = 7]; (3) combination of hypothermia and BDNF (n = 7); (4) control group (saline, n = 7). Infarct size at 5 h after MCAO was assessed with the silver-staining method. Total infarct volume was significantly reduced in the hypothermia (202.7 +/- 3.5 mm(3), P = 0.0002) and BDNF group (206.5 +/- 6.9 mm(3), P = 0.0006) as compared to control group (254.4 +/- 9.3 mm(3)). In the combination group, infarct size was further reduced with overall significance in post hoc tests (157.3 +/- 6.2 mm(3), P < 0.0001). Postischemic glutamate concentrations in the control group constantly remained significantly higher than in all other treatment groups. At 255 and 270 min after MCAO, striatal glutamate in the combination group decreased significantly more than in animals treated with hypothermia or BDNF alone.Combining hypothermia and BDNF therapy in the acute stage of ischemia has a synergistic effect in attenuating striatal glutamate release and reducing early infarct size.
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PMID:Hypothermia and brain-derived neurotrophic factor reduce glutamate synergistically in acute stroke. 1473 12

The regenerative capacity of the CNS is extremely limited. The reason for this is unclear, but glial cell involvement has been suspected, and oligodendrocytes have been implicated as inhibitors of neuroregeneration (Chen et al., 2000, GrandPre et al., 2000; Fournier et al., 2001). The role of astrocytes in this process was proposed but remains incompletely understood (Silver and Miller, 2004). Astrocyte activation (reactive gliosis) accompanies neurotrauma, stroke, neurodegenerative diseases, or tumors. Two prominent hallmarks of reactive gliosis are hypertrophy of astrocytic processes and upregulation of intermediate filaments. Using the entorhinal cortex lesion model in mice, we found that reactive astrocytes devoid of the intermediate filament proteins glial fibrillary acidic protein and vimentin (GFAP-/-Vim-/-), and consequently lacking intermediate filaments (Colucci-Guyon et al., 1994; Pekny et al., 1995; Eliasson et al., 1999), showed only a limited hypertrophy of cell processes. Instead, many processes were shorter and not straight, albeit the volume of neuropil reached by a single astrocyte was the same as in wild-type mice. This was accompanied by remarkable synaptic regeneration in the hippocampus. On a molecular level, GFAP-/-Vim-/- reactive astrocytes could not upregulate endothelin B receptors, suggesting that the upregulation is intermediate filament dependent. These findings show a novel role for intermediate filaments in astrocytes and implicate reactive astrocytes as potent inhibitors of neuroregeneration.
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PMID:Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. 1516 94

Early diagnosis and immediate therapeutic interventions are crucial factors to reduce the damage extent and the risk of death. Currently, the diagnosis of stroke relies on neurological assessment of the patient and neuro-imaging techniques including computed tomography and/or magnetic resonance imaging scan. An early diagnostic marker of stroke, ideally capable to discriminate ischemic from hemorrhagic stroke would considerably improve patient acute management. Using surface-enhanced laser desorption/ionization (SELDI) technology, we aimed at finding new early diagnostic plasmatic markers of stroke. Strong anionic exchange (SAX) SELDI profiles of plasma samples from 21 stroke patients were compared to 21 samples from healthy controls. Seven peaks appeared to be differentially expressed with significant p values (p < 0.05). Proteins were stripped from the SAX chips, separated on a one-dimensional electrophoresis (1-DE) gel and stained using mass spectrometry (MS)-compatible silver staining. Following in-gel tryptic digestion, the peptides were analyzed by MS. Four candidate proteins were identified as apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), serum amyloid A (SAA), and antithrombin-III fragment (AT-III fragment). Assessment of ApoC-I and ApoC-III levels in plasma samples using a sandwich enzyme-linked immunosorbent assay (ELISA) allowed to distinguish between hemorrhagic (n = 15) and ischemic (n = 16) stroke (p < 0.001). To the best of our knowledge, ApoC-I and ApoC-III are the first reported plasmatic biomarkers capable to accurately distinguish between ischemic and hemorrhagic stroke in a small number of patients. It requires further investigation in a large cohort of patients.
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PMID:ApoC-I and ApoC-III as potential plasmatic markers to distinguish between ischemic and hemorrhagic stroke. 1527 18

Thrombolysis (T) is limited by reperfusion-associated injury and the short therapeutic window after stroke onset. The present study investigates whether hypothermia alone or in combination with thrombolysis has beneficial effects after experimental thromboembolic stroke. Wistar rats (n = 60) were subjected to thromboembolic occlusion (TE) of the middle cerebral artery (MCA). Thrombolysis (T) was performed with intravenous recombinant tissue-plasminogen activator (rt-PA) 1 h (early T) or 3 h (late T) after TE. Hypothermia (Hy) was applied for 4 h at 33 degrees C started 1 h after TE. Experimental groups included control (C), early thrombolysis (ET), late thrombolysis (LT), hypothermia (Hy), early thrombolysis plus hypothermia (ET+Hy), and late thrombolysis plus hypothermia (LT+Hy). Animals were investigated by MRI and silver infarct staining (SIS) to assess the cerebral infarct size. All animals of group Hy survived, in contrast to 40% in group C (P < 0.05). ET+HY and LT+Hy showed a trend towards better survival as compared to ET and LT alone. PWI parameters were not significantly different between ET versus ET+HY and LT versus LT+Hy, but rt-PA administration led to improved cerebral perfusion in MRI. Significant differences in infarct volumes (T2/SIS) were found after 24 h in all treatment groups versus the control group (P < 0.05). The lesion volume calculated from T2 was significantly smaller in ET (16% +/- 5%), ET+Hy (10 +/- 4%), and LT+Hy (20% +/- 9%) after 5.5 h (10.8% +/- 4.8%) versus C (42% +/- 15%), (P < 0.05). These data indicate that hypothermia improves survival and decreases infarct volume. However, there were no significant differences between the use of rt-PA alone or in combination with hypothermia. Further studies are needed to confirm these effects, also several days after stroke onset.
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PMID:Combination therapy of moderate hypothermia and thrombolysis in experimental thromboembolic stroke--an MRI study. 1547 93

Hip fracture is the most serious complication of osteoporosis and has been recognized as a major public health problem. The prevention of hip fractures is an high-priority issue because of the rapid increase of the number of elderly people in Japan. The General Research Committee for the Prevention and Treatment of Osteoporosis in Silver Health Science Researches sponsored by the Ministry of Health and Welfare (Director, Hajime Orimo) first undertook a nationwide survey of femoral neck fracture in 1987. This nationwide survey has been continued every 5 years, in 1992, 1997, and 2002. The total number of new cases was nearly 120,000 in the latest survey, and has been rising in every survey. Total number of new cases was about 1.4 times the baseline 1987 figures in 1992, 1.7 times in 1997, and 2.2 times in 2002. The total number of new female patients was about three times higher than that of new male patients, a finding identical to those of the previous surveys. The incidences of hip fracture (per 10,000) according to sex and age was increased in both men and women, particularly among individuals 80 years old or over. The Epidemiological Research Group on Osteoporosis, Ministry of Health and Welfare (Chairman; Hajime Orimo) undertook a nation-wide case-control study to clarify the risk factors for hip fractures among Japanese in 1994. Cases of hip fracture in people aged 65-89 were selected from 21 hospitals in seven areas of Japan. Two sex- and age-matched controls were selected from the same residential area for each case using resident registration lists. During this 1-year survey, 249 cases of hip fractures (43 men and 206 women) were reported. The following risk factors for hip fractures were identified using multivariate analysis: past history of stroke with hemiplegia, sleep disturbance, sleeping in a Western-style bed, and drinking more than 3 cups of coffee daily.
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PMID:Epidemiology of hip fracture in Japan: incidence and risk factors. 1598 19

Voluntary physical activity and exercise training can favorably influence brain plasticity by facilitating neurogenerative, neuroadaptive, and neuroprotective processes. At least some of the processes are mediated by neurotrophic factors. Motor skill training and regular exercise enhance executive functions of cognition and some types of learning, including motor learning in the spinal cord. These adaptations in the central nervous system have implications for the prevention and treatment of obesity, cancer, depression, the decline in cognition associated with aging, and neurological disorders such as Parkinson's disease, Alzheimer's dementia, ischemic stroke, and head and spinal cord injury. Chronic voluntary physical activity also attenuates neural responses to stress in brain circuits responsible for regulating peripheral sympathetic activity, suggesting constraint on sympathetic responses to stress that could plausibly contribute to reductions in clinical disorders such as hypertension, heart failure, oxidative stress, and suppression of immunity. Mechanisms explaining these adaptations are not as yet known, but metabolic and neurochemical pathways among skeletal muscle, the spinal cord, and the brain offer plausible, testable mechanisms that might help explain effects of physical activity and exercise on the central nervous system.
Obesity (Silver Spring) 2006 Mar
PMID:Neurobiology of exercise. 1664 3

A new paradigm is emerging in the targeting of multiple disease aetiologies that collectively lead to neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, post-stroke neurodegeneration and others. This paradigm challenges the widely held assumption that 'silver bullet' agents are superior to 'dirty drugs' when it comes to drug therapy. Accumulating evidence in the literature suggests that many neurodegenerative diseases have multiple mechanisms in their aetiologies, thus suggesting that a drug with at least two mechanisms of action targeted at multiple aetiologies of the same disease may offer more therapeutic benefit in certain disorders compared with a drug that only targets one disease aetiology. This review offers a synopsis of therapeutic strategies and novel investigative drugs developed in the authors' own and other laboratories that modulate multiple disease targets associated with neurodegenerative diseases.
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PMID:Multifunctional neuroprotective drugs targeting monoamine oxidase inhibition, iron chelation, adenosine receptors, and cholinergic and glutamatergic action for neurodegenerative diseases. 1685 91

The multiple disease etiologies that lead to neuropsychiatric disorders, such as Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis, Huntington disease, schizophrenia, depressive illness and stroke, offer significant challenges to drug discovery efforts aimed at preventing or even reversing the progression of these disorders. Transcriptomic tools and proteomic profiling have clearly indicated that such diseases are multifactorial in origin. Further, they are thought to be initiated by a cascade of molecular events that involve several neurotransmitter systems. In response to this complexity, a new paradigm has recently emerged that challenges the widely held assumption that 'silver bullet' agents are superior to 'dirty drugs' in therapeutic approaches aimed at the prevention or treatment of neuropsychiatric diseases. A similar pattern of drug development has occurred in strategies for the treatment of cancer, AIDS and cardiovascular diseases. In this review, we offer an overview of therapeutic strategies and novel investigative drugs discovered or developed in our own and other laboratories, that address multiple CNS etiological targets associated with an array of neuropsychiatric disorders.
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PMID:Multifunctional drugs with different CNS targets for neuropsychiatric disorders. 1705 41

As body composition in Asian populations is largely different from Western populations, a healthy BMI could also differ between the two populations. Thus, further study is needed to determine whether a healthy BMI in Asians should be lower than Western populations, as recommended by the World Health Organization (WHO). We investigated the relationship between BMI and mortality in a sample of 8,924 Japanese men and women without stroke or heart disease. During 19 years of follow-up, 1,718 deaths were observed. We found a U-shaped relationship between BMI and fatal events. Risk of total mortality was highest in participants with BMI <18.5 kg/m(2) and lowest in participants with BMI 23.0-24.9 kg/m(2). These findings persisted even after excluding the first 5 years of follow-up with a focus on healthy participants who never smoked, were aged <70 years, and had total cholesterol (TC) levels >or=4.1 mmol/l (N=3712). For both the full sample and healthy participants, all-cause mortality risk did not differ between BMI ranges 21.0-22.9 and 23.0-24.9 kg/m(2). Our findings do not support the recent WHO implications that BMIs <23.0 kg/m(2) is healthy for Asians. Therefore, further studies are needed to identify an optimal BMI range for Asia.
Obesity (Silver Spring) 2008 Jul
PMID:Relationship between BMI and all-cause mortality in Japan: NIPPON DATA80. 1842 Dec 64


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