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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The occurrence of sprouting by fibre systems in the neocortex following lesion is still a controversial issue. In previous studies, we showed a nerve growth factor (NGF)-induced sprouting and hypertrophy of presynaptic terminals in the cholinergic fibres of the rat neocortex following stroke-type lesions, effects that were potentiated by the monosialoganglioside GM1. The present study investigated whether exogenous NGF and/or GM1 treatment could also affect the noradrenergic and somatostinergic systems in the neocortex. Immediately following unilateral vascular decortication, adult rats received, via minipump, a 7-day infusion of vehicle, NGF (12 microg/day) and/or GM1 (1.5 mg/day) into the cerebroventricular space. Thirty days postlesion, the animals were perfused with histological fixatives, the brains were removed, and relevant sections were processed for dopamine beta-hydroxylase and somatostatin immunocytochemistry at the light and electron microscopic levels. A Quantimet 920 image analysis system was used for the quantification of fibre length and size of presynaptic boutons. The lesion caused a reduction in the dopamine beta-hydroxylase-immunoreactive fibre length, which was not attenuated by either NGF or GM1 treatment or both. The somatostatin-immunoreactive network, in contrast, was unaffected by the lesion, and there was no sprouting of somatostatin fibres following trophic factor therapy. We also found no significant differences in the size and number of synapses of both the dopamine beta-hydroxylase-immunoreactive and somatostatin-immunoreactive boutons following lesion and drug treatments. These results indicate that NGF and/or GM1 therapies do not cause regrowth in the noradrenergic and somatostatinergic cortical fibre networks or their presynaptic elements following a cortical devascularizing lesion.
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PMID:Responses of cortical noradrenergic and somatostinergic fibres and terminals to adjacent strokes and subsequent treatment with NGF and/or the ganglioside GM1. 940 24

Ischemic insults to the brain result in a time-dependent increase in neuronal death that is responsible for some of the functional deficits associated with stroke. Our working hypothesis is that ischemia results in a prompt depletion of high energy phosphate species resulting in decreased pH and glutathione levels in brain in a temporal and spatial pattern that disrupts nerve growth factor homeostasis and increases neuronal apoptosis. Here we show hemispheric depletion of active phosphate species after ischemia. Also, we observed that the striatum is an early target for oxidative stress that is followed by energy metabolic impairment and altered neurotrophin levels that were detected by noninvasive magnetic resonance imaging (MRI) measurements of cytotoxicity and conventional biochemical determinations of apoptosis, glutathione, and nerve growth factor (NGF) protein levels in a pattern distinct from that observed in the hippocampus. Furthermore, early assessment of intracellular pH by 31P-magnetic resonance spectroscopy (31P-MRS) was a predictor of later infarct development as determined by MRI. We also show that pretreatment with pharmacological doses of NGF did not have overall significant beneficial consequences on irreversible ischemia in an intraluminal unilateral irreversible model of stroke in rat brain.
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PMID:Effect of NGF treatment on outcome measures in a rat model of middle cerebral artery occlusion. 1034 67

Housing rats in an enriched environment after focal brain ischemia improves functional outcome without changes in infarct volume, suggesting neuroplastic changes outside the lesion. In this study, permanent occlusion of the middle cerebral artery was followed by housing in an enriched or a standard environment. Nerve growth factor-induced gene A and glucocorticoid receptor messenger RNA expression were determined by in situ hybridization two to 30 days after middle cerebral artery occlusion. Stroke induced a decrease in nerve growth factor-induced gene A messenger RNA expression in cortical areas outside the ischemic lesion and in the CA1 subregion of the hippocampus two to three days after ischemia. This decrease was more prolonged with environmental enrichment, lasting until 20 days. However, 30 days after focal cerebral ischemia, environmental enrichment increased nerve growth factor-induced gene A expression compared to standard housing. A reduction of hippocampal glucocorticoid receptor (type II) messenger RNA two to 12 days after stroke in standard housed rats was restored by environmental enrichment. These data suggest that improved functional outcome induced by environmental enrichment after middle cerebral artery occlusion is associated with dynamically altered expression of nerve growth factor-induced gene A messenger RNA in brain regions outside the ischemic lesion, and sustained levels of hippocampal glucocorticoid receptor messenger RNA expression.
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PMID:Environmental enrichment alters nerve growth factor-induced gene A and glucocorticoid receptor messenger RNA expression after middle cerebral artery occlusion in rats. 1046 36

The proinflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha are produced within the CNS, and, similar to the periphery, they have pleotrophic and overlapping functions. We have shown previously that TNF-alpha increases neuronal survival to a toxic influx of calcium mediated through neuronal N-methyl-d -aspartic acid (NMDA) glutamate-gated ion channels. This process, termed excitotoxicity, is a major contributor to neuronal death following ischemia or stroke. Neuroprotection by this cytokine requires both activation of the p55/TNF receptor type I and the release of TNF-alpha from neurons, and it is inhibited by the plant alkaloid nicotine. Here, we report that other inflammatory cytokines (IL-1 alpha, IL-1 beta, and IL-6) are also neuroprotective to excessive NMDA challenge in our system. Neuroprotection provided by IL-1 is distinct from TNF-alpha because it is inhibited by IL-1 receptor antagonist; it is not antagonized by nicotine, but it is inhibited by a neutralizing Ab to nerve growth factor (NGF). Similar to IL-1, IL-6-mediated neuroprotection is also antagonized by pretreatment with IL-1 receptor antagonist and it is not affected by nicotine. However, neutralizing anti-NGF only partially blocks IL-6-mediated protection. These studies support an important role for distinct but overlapping neuroprotective cytokine effects in the CNS.
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PMID:Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways. 1049 Sep 98

Neurotrophins and other neurotrophic factors have been shown to support the survival and differentiation of many neuronal populations of the central and peripheral nervous system. Therefore, administering neurotrophic factors could represent an alternative strategy for the treatment of acute and chronic brain disorders. However, the delivery of neurotrophic factors to the brain is one of the largest obstacles in the development of effective therapy for neurodegenerative disorders, because these proteins are not able to cross the blood-brain barrier. The induction of growth factor synthesis in the brain tissue by systemically administered lipophilic drugs, such as beta-adrenoceptor agonists, shown to increase endogenous nerve growth factor (NGF) synthesis in the brain, would be an elegant way to overcome these problems of application. Stimulation of beta-adrenoceptors with clenbuterol led to increased NGF synthesis in cultured central nervous system (CNS) cells and rat brain tissue. Clenbuterol-induced NGF expression was reduced to the control levels by coadministration of beta-adrenoceptor antagonist propranolol. Furthermore, clenbuterol protected rat hippocampal neurons subjected to excitotoxic damage. The neuroprotective effect of clenbuterol in vitro depended on increased NGF synthesis, since the neuroprotection was abolished by NGF antisense oligonucleotide as well as by antibodies directed against NGF itself. In vivo, clenbuterol protected rat hippocampus in a model of transient forebrain ischemia and reduced the infarct volume in a rat model of permanent middle cerebral artery occlusion (MCAo). The neuroprotective effect of clenbuterol in vivo was accompanied by enhanced NGF synthesis in brain tissue. These findings support our hypothesis that orally active NGF inducers may have a potential as therapeutic agents for the treatment of neurodegenerative disorders and stroke.
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PMID:Neuroprotection mediated via neurotrophic factors and induction of neurotrophic factors. 1052 74

Previous studies have shown that several different neurotrophic factors can prevent death of cortical and hippocampal neurons induced by excitotoxic and oxidative insults in cell culture and in vivo. Because neuronal degeneration may be initiated by alterations occurring in synaptic compartments in disorders ranging from Alzheimer's disease to stroke, we tested the hypothesis that neurotrophic factors can exert direct protective actions at the level of the synapse. We now report that a nine amino acid bioactive fragment of activity-dependent neurotrophic factor (ADNF-9) enhances basal glucose and glutamate transport, and attenuates oxidative impairment of glucose and glutamate transport induced by amyloid beta-peptide and Fe(2+), in neocortical synaptosomes. Preservation of transporter function required only short-term (1-2 h) pretreatments. Basic fibroblast growth factor (bFGF) was also effective in suppressing oxidative impairment of synaptic transporter functions, while nerve growth factor (NGF) was less effective. Additional analyses showed that ADNF-9, bFGF and NGF suppress oxidative stress and mitochondrial dysfunction induced by amyloid beta-peptide and Fe(2+) in synaptosomes. Our data suggest that ADNF-9 can act locally in synaptic compartments to suppress oxidative stress and preserve function of glucose and glutamate transporters. Such synapto-protective actions suggest roles for activity-dependent trophic signaling in preventing degeneration of neuronal circuits, and indicate possible therapeutic applications of agents that stimulate local synaptic (transcription-independent) neurotrophic factor signaling pathways.
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PMID:Neurotrophic factors protect cortical synaptic terminals against amyloid and oxidative stress-induced impairment of glucose transport, glutamate transport and mitochondrial function. 1063 95

Bax-mediated apoptosis in neurons is involved in many pathologic conditions affecting the central nervous system, including degenerative diseases, stroke, and trauma. Two molecules belonging to the Bcl-2 family, Bcl-2 and Bcl-X(L), protect cells from Bax-induced apoptosis and show distinct expression patterns in adult neurons, with downregulated Bcl-2 and highly upregulated Bcl-X(L) expression. To investigate the biological functions of these two molecules in Bax-mediated apoptosis in neurons, we transduced various levels of Bcl-X(L) or Bcl-2 via adenoviral vectors into nerve growth factor (NGF)-treated PC12 cells. Overexpression of Bax induced drastic apoptosis in NGF-treated PC12 cells. Bcl-X(L) expressed at a wide range of levels conferred a high level of protection against Bax-mediated apoptosis. In contrast, Bcl-2 at various levels conferred far less protection against apoptosis. Moreover, Bcl-X(L) protected PC12 cells from apoptosis induced by NGF withdrawal. These data indicate that Bcl-X(L)-mediated protection is the major pathway that suppresses apoptosis in NGF-treated PC12 cells and that Bcl-X(L) would be a more relevant target of manipulation in future treatment strategies, including gene therapies.
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PMID:Adenovirus-mediated transfer of Bcl-X(L) protects neuronal cells from Bax-induced apoptosis. 1064 Apr 20

Apoptotic cell death has been implicated in Alzheimer's disease pathology and amyloid peptide induced neurotoxicity. We investigated the survival promoting effects of Propentofylline in two models of apoptotic cell death, nerve growth factor withdrawal and beta-amyloid mediated cell death in nerve growth factor differentiated rat pheochromocytoma cell lines. The increase in cell death as measured by lactate dehydrogenase release in response to nerve growth factor withdrawal was suppressed by nitric oxide donor S-nitroso-N-acetylpenicillamine (12.5 to 200 microM) and by 8-bromoguanosine-3',5'-cyclic monophosphate (1.25 to 10mM). Both agents decreased cell death mediated by 25 microM beta-amyloid, suggesting that the protective mechanism involves guanosine -3', 5'-cyclic monophosphate. In support of this hypothesis we can show that S-nitroso-N-acetylpenicillamine increases intracellular levels of guanosine -3',5'-cyclic monophosphate in pheochromocytoma cell lines 3 to 8 fold.Propentofylline, a phosphodiesterase inhibitor, has previously demonstrated neuroprotective activity in stroke models and is a potential candidate for therapeutic treatment in neurodegenerative diseases. The present findings support this claim by providing evidence that Propentofylline has protective effects in both nerve growth factor withdrawal and beta-amyloid mediated cell death. Lactate dehydrogenase release was significantly reduced and caspase-3-like activity was attenuated after cotreatment with Propentofylline. Furthermore Propentofylline dose responsively increases intracellular guanosine-3',5'-cyclic monophosphate levels over the same dose range that provided protection. We hypothesized that guanosine-3',5'-cyclic monophosphate is a key mediator of neuroprotection under these conditions.
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PMID:Guanosine 3',5'-cyclic monophosphate mediated inhibition of cell death induced by nerve growth factor withdrawal and beta-amyloid: protective effects of propentofylline. 1097 37

This study aimed at evaluating changes in expression of immediate early genes in a new photothrombotic focal ischemia model that exhibits late spontaneous reperfusion and morphological restoration in the region-at-risk within the cerebral cortex. Gene expression was studied with Northern blots, in situ hybridization and immunohistochemistry. At early time points (1-4 h), nerve growth factor-induced gene A and B, and c-fos mRNAs, were quickly induced throughout the ipsilateral cortex, with no obvious differences between the region-at-risk and remote cortical areas. High concentrations of nerve growth factor-induced gene A and c-Fos proteins were present within the region-at-risk even when cortical cerebral blood flow was as low as 40% of control values. At 4 h the nerve growth factor-induced gene A mRNA and protein expression was significantly decreased in the hippocampus vs. naive controls. However, a small decrease was also found in sham-operated and anaesthetized controls. A late induction, at 5 days, of c-fos and nerve growth factor-induced gene B mRNAs was seen bilaterally in the hippocampus and also, in the case of nerve growth factor induced-gene B, in the contralateral cortex. A complex pattern of changes in immediate early gene expression occurs after reversible focal cortical ischemia. This may be important for tissue recovery as well as neuropsychiatric symptoms after stroke.
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PMID:Early and delayed induction of immediate early gene expression in a novel focal cerebral ischemia model in the rat. 1102 32

A major government-sponsored study of nerve growth factor for treating HIV-related neuropathy has recently been revived after it was canceled earlier this year by Genentech, Inc. of South San Francisco, which holds a patent for the use of the drug. Human nerve growth factor has been shown to be the most promising therapy for treating HIV-related neuropathy, the most common neurological complication in AIDS. The AIDS Clinical Trials Group (ACTG) of the National Institute of Allergy and Infectious Disease and the National Institute of Neurological Disorders and Stroke have, for three years, been developing a study of 180 randomly assigned volunteers to receive low-dose nerve growth factor, high-dose nerve growth factor, or placebo. However, in January 1995, Genentech informed the government that it would not provide the drug--although almost all of the financial cost of the study was to be paid for by the ACTG. After major protests by experts and community organizations, Genentech reinstated its earlier agreement to provide the drug for the ACTG study. The trial, known as ACTG 291, is expected to go forward.
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PMID:Nerve growth factor: major trial canceled, revived after protest. 1136 4


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