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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NGF and bFGF have recently been shown to have biological activity in central neurons, but their normal functions and mechanisms of action are unknown. Since central neurons are particularly vulnerable to hypoglycemia that occurs with ischemia or insulin overdose, we tested the hypothesis that growth factors can protect neurons against hypoglycemic damage. NGF and bFGF each prevented glucose deprivation-induced neuronal damage in human cerebral cortical and rat hippocampal cell cultures (EGF was ineffective). Protection was afforded when the growth factors were administered before (NGF and bFGF) or up to 12 hr following (NGF) the onset of hypoglycemia. Direct measurements of intracellular calcium levels and manipulations of calcium influx demonstrated that sustained elevations in intracellular calcium levels mediated the hypoglycemic damage. NGF and bFGF each prevented the hypoglycemia-induced elevations of intracellular calcium. These findings indicate that growth factors can stabilize neuronal calcium homeostasis in central neurons and thereby protect them against environmental insults.
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PMID:NGF and bFGF protect rat hippocampal and human cortical neurons against hypoglycemic damage by stabilizing calcium homeostasis. 166 17

Selective neuronal death in the CA1 sector of the hippocampus [delayed neuronal death (DND)] develops several days after transient global cerebral ischemia in rodents. Because NGF plays a potential role in neuronal survival, it was decided to study its effect in DND. We report here that intraventricular injection of NGF either before or after 5 min forebrain ischemia in the Mongolian gerbil significantly reduced the occurrence of DND. The tissue content of NGF in the hippocampus was decreased 2 d after ischemia and recovered to the preischemic level by 1 week. By the Golgi staining technique, changes first began in the dendrites of affected neurons as early as 3 hr. Such changes could be ameliorated by NGF treatment. Although previous knowledge of NGF is limited to the survival of cholinergic neurons in the CNS, it is assumed that other mechanisms must be operating in the hippocampus, for example, postsynaptic modification at dendrites or aberrant expression of NGF receptors possibly at the initial excitation period by glutamate. Furthermore, because previous work has shown that inhibition of protein synthesis reduces the occurrence of DND, a program leading to cell death might also be operating via de novo synthesis of certain protein(s), collectively termed "killer protein," because of a lack of NGF.
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PMID:Amelioration of delayed neuronal death in the hippocampus by nerve growth factor. 188 May 56

Throughout evolution the brain has acquired elegant strategies to protect itself against a variety of environmental insults. Prominent among these are signals released from injured cells that are capable of initiating a cascade of events in neurons and glia designed to prevent further damage. Recent research has identified a remarkably large number of neuroprotection factors (NPFs), whose expression is increased in response to brain injury. Examples include the neurotrophins (NGF, NT-3, NT-5, and BDNF), bFGF, IGFs, TGFs, TNFs and secreted forms of the beta-amyloid precursor protein. Animal and cell culture studies have shown that NPFs can attenuate neuronal injury initiated by insults believed to be relevant to the pathophysiology of traumatic brain injury (TBI) including excitotoxins, ischemia, and free radicals. Studies of the mechanism of action of these NPFs indicate that they enhance cellular systems involved in maintenance of Ca2+ homeostasis and free radical metabolism. Recent work has identified several low-molecular-weight lipophilic compounds that appear to mimic the action of NPFs by activating signal transduction cascades involving tyrosine phosphorylation. Such compounds, alone or in combination with antioxidants and calcium-stabilizing agents, have proved beneficial in animal studies of ischemic brain injury and provide opportunities for development of preventative/therapeutic approaches for TBI.
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PMID:Endogenous neuroprotection factors and traumatic brain injury: mechanisms of action and implications for therapy. 820 25

Cerebral hypoxia-ischemia was produced in 7 day old rats by right common carotid artery occlusion combined with systemic hypoxia. In the hypoxic-ischemic group animals, striatal ACh contents on both sides were reduced to a significant extent in commensurate to AChE histochemical image analysis. All these changes could be restored to normal control by a protection dose (50 micrograms) of NGF intraventricularly injected.
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PMID:[Protective effect of nerve growth factor on cholinergic neurons corpus striatum of new born rat subjected to hypoxia-ischemia]. 829 6

Several cellular signaling systems have been implicated in the neuronal death that occurs both in development ("natural" cell death) or in pathological conditions such as stroke and Alzheimer's disease (AD). Here we consider the possibility that neuronal degeneration in an array of disorders including stroke and AD arises from one or more alterations in calcium-regulating systems that result in a loss of cellular calcium homeostasis. A long-standing hypothesis of neuronal injury, the excitatory amino acid (EAA) hypothesis, is revisited in light of new supportive data concerning the roles of EAAs in stroke and the neurofibrillary degeneration in AD. Two quite new concepts concerning mechanisms of neuronal injury and death are presented, namely: 1) growth factors normally "stabilize" intracellular free calcium levels ([Ca2+]i) and protect neurons against ischemic/excitotoxic injury, and 2) aberrant processing of beta-amyloid precursor protein (APP) can cause neurodegeneration by impairing a neuroprotective function of secreted forms of APP (APPs) which normally regulate [Ca2+]i. Altered APP processing also results in the accumulation of beta-amyloid peptide which contributes to neuronal damage by destabilizing calcium homeostasis; in AD beta-amyloid peptide may render neurons vulnerable to excitotoxic conditions that accrue with increasing age (e.g., altered glucose metabolism, ischemia). Growth factors may normally protect neurons against the potentially damaging effects of calcium influx resulting from energy deprivation and overexcitation. For example, bFGF, NGF and IGFs can protect neurons from several brain regions against excitotoxic/ischemic insults. Growth factors apparently stabilize [Ca2+]i by several means including: a reduction in calcium influx; enhanced calcium extrusion or buffering; and maintenance or improvement of mitochondrial function. For example, bFGF can suppress the expression of a N-methyl-D-aspartate (NMDA) receptor protein that mediates excitotoxic damage in hippocampal neurons. Growth factors may also prevent the loss of neuronal calcium homeostasis and the increased vulnerability to neuronal injury caused by beta-amyloid peptide. Since elevated [Ca2+]i can elicit cytoskeletal alterations similar to those seen in AD neurofibrillary tangles, we propose that neuronal damage in AD results from a loss of calcium homeostasis. The data indicate that a variety of alterations in [Ca2+]i regulation may contribute to the neuronal damage in stroke and AD, and suggest possible means of preventing neuronal damage in these disorders.
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PMID:Altered calcium signaling and neuronal injury: stroke and Alzheimer's disease as examples. 851 77

We studied the temporal profile of nerve growth factor-like immunoreactivity (NGF-LI) in the rat brains following 30 min of middle cerebral artery occlusion. The rats were decapitated at 4 h, 1, 3, 7, and 14 days of recirculation. Brain sections at the level of striatum were immunostained against NGF as well as a stress protein, HSP70. Also, double immunostaining of NGF and glial fibrillary acidic protein was performed. In the sham-control rats, NGF-LI was normally present in the cortical and striatal neurons. However, at 4 h of recirculation, there was a significant decrease of NGF-LI in the ischemic cortex and striatum. From 1 day, NGF-LI was absent completely in the ischemic striatum. However, in the ischemic cortex, NGF-LI decreased to the lowest level at 1 day, but it recovered gradually from 3 days and increased significantly to above sham-control level at 7 days. At 14 days of recirculation, NGF-LI returned to a near sham-control level. In the non-ischemic cortex, NGF-LI increased gradually from 4 h with a peak at 7 days, and returned to the sham-control level at 14 days of recirculation. A HSP70 was induced in the ischemic cortex at 1 and 3 days, when there was a significant reduction of NGF-LI. The number of reactive astrocytes increased gradually and NGF-LI in the reactive astrocytes became gradually intense after ischemia. The present finding showing that NGF-LI can be recovered in the stressed cortical neurons suggests a possible involvement of NGF in the process of neuronal survival after focal cerebral ischemia. The expression of NGF in reactive astrocytes indicates that astrocyte may also play a role in supporting neuronal survival after ischemia.
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PMID:Temporal profile of nerve growth factor-like immunoreactivity after transient focal cerebral ischemia in rats. 872 92

It has been shown previously that clenbuterol, a beta 2-adrenergic receptor agonist, enhances NGF synthesis in adult rat brain. Since NGF is able to protect neurons against damage, we tried to find out whether clenbuterol can rescue cultured hippocampal neurons from excitotoxic damage by induction of NGF. The neuroprotective activity of clenbuterol on neurons in the vulnerable CA1 subfield of the hippocampus was tested in a rat model of transient forebrain ischemia. Additionally, in the mouse model of focal cerebral ischemia the ability of clenbuterol to reduce the infarct size was examined. Exposure of mixed neuronal/glial hippocampal cultures to clenbuterol (1 to 100 microM) enhanced significantly the content of NGF measured in the culture medium by two-site ELISA. The excitotoxic injury was induced in the same type of cells after 14 days in vitro by exposure to 1 mM L-glutamate for 1 h in serum-free medium. NGF itself (0.15 to 100 ng/ml) added to the growth medium 4 h before until 18 h after induction of injury (the point of glutamate-toxicity measurement), protected hippocampal neurons from excitotoxic damage. Clenbuterol (1 to 100 microM) provided similar neuroprotection as NGF under the same experimental conditions. The neuroprotective activity of clenbuterol (100 microM) against glutamate-induced damage in hippocampal cultures was blocked by anti-NGF monoclonal antibodies (0.5 microgram/ml) added to the medium during the clenbuterol exposure, demonstrating that the neuronal rescue is mediated by NGF. Propranolol, a beta-adrenergic receptor antagonist (10 microM) added 20 min before and kept in the medium during exposure of the cultures to clenbuterol (1 microM) reversed the neuroprotective activity, suggesting that the induction of NGF and neuroprotection caused by clenbuterol are mediated via beta-adrenergic receptor activation. The capacity of clenbuterol to protect hippocampal neurons was also demonstrated in vivo in a rat model of transient forebrain ischemia. Clenbuterol (4 x 1 mg/kg) administered intraperitoneally increased the number of viable neurons in CA1 subfield of the rat hippocampus. Furthermore, clenbuterol (0.3 and 1 mg/kg, i.p. and 1 mg/kg, s.c.) reduced significantly the infarct area on the mouse brain surface after occlusion of the middle cerebral artery. The present data demonstrate that clenbuterol induces NGF synthesis in cultured hippocampal cells and protects hippocampal neurons from excitotoxic damage. The neuroprotective activity of clenbuterol is also demonstrated in vivo in two rodent models of cerebral ischemia. The results offer strong evidence that the neuroprotective activity of clenbuterol is caused by activation of beta-adrenergic receptors and the subsequent increased expression of NGF.
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PMID:Clenbuterol protects mouse cerebral cortex and rat hippocampus from ischemic damage and attenuates glutamate neurotoxicity in cultured hippocampal neurons by induction of NGF. 873 52

Treatment strategies based on transfer of genes, molecules, or cells to the central nervous system are summarized. When neurons are already degenerated, functional compensation can be effected by grafts of syngeneic or allogenic tissue to the target area. This technique is undergoing clinical trials in Parkinson's disease. Before degeneration has occurred, it may be possible to rescue "stressed" neurons, and stimulate terminal outgrowth using treatment with neurotrophic factors. Such approaches, with an emphasis on the NGF family of neurotrophins and their receptors, are reviewed. Finally, new molecular biology techniques may permit the transfer of genes directly into non-dividing cells of the central nervous system. These three approaches may have a more general applicability, and become important not only in neurodegenerative diseases, but also in other afflictions of the nervous system such as ischemia, stroke and injury.
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PMID:Treatment strategies for neurodegenerative diseases based on trophic factors and cell transplantation techniques. 926 9

The neurotrophins NGF, BDNF, NT-3 and NT-4 have a wide range of effects in the development and regeneration of neural circuits in the visual system of vertebrates. This review focuses on the localization and functions of neurotrophins in the retina, lateral geniculate nucleus, suprachiasmatic nucleus, superior colliculus/optic tectum, and isthmic nuclei. Research of the past 20 years has shown that neurotrophins and their receptors are localized in numerous visual centers from the retina to the visual cortex, and that neurotrophins influence proliferation, neurite outgrowth and survival of cells in the visual system in vitro and in vivo. A relationship between electrical activity and neurotrophic functions has been established in several visual centers in the CNS, and neurotrophins have been implicated in synaptic plasticity in the visual cortex. Besides functions of neurotrophins as retrograde, target-derived trophic factors, recent data indicate that neurotrophins may have anterograde, afferent as well as local, paracrine actions in the retina, optic nerve and the visual cortex. Some neurotrophins appear to regulate proliferation and survival of glial cells in the optic pathways. Neurotrophins increase the survival of retinal ganglion cells after axotomy or ischemia and they promote the regeneration of retinal ganglion cell axons in some vertebration. Neurotrophins also rescue photoreceptors from degeneration. These findings implicate the neurotrophins not only as important regulators during development, but also as potential therapeutic agents in degenerative retinal diseases and after optic nerve injury.
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PMID:Neurotrophins in the developing and regenerating visual system. 958 2

We examined the uptake and distribution of an antisense phosphorothioated oligodeoxynucleotide (s-ODN) to c-fos, rncfosr115, infused into the left cerebral ventricle of male Long-Evans rats and the effect of this s-ODN on subsequent Fos, NGF, neurotrophin-3 (NT-3), and actin expression. To establish the uptake and turnover of s-ODN in the brain, we studied the copurification of the immunoreactivity of biotin with biotinylated s-ODN that was recovered from different regions of the brain. A time-dependent diffusion and the localization of s-ODN were further demonstrated by labeling the 3'-OH terminus of s-ODN in situ with digoxigenin-dUTP using terminal transferase and detection using anti-digoxigenin IgG-FITC. Cellular uptake of the s-ODN was evident in both the hippocampal and cortical regions, consistent with a gradient originating at the ventricular surface. Degradation of the s-ODN was observed beginning 48 hr after delivery. The effectiveness of c-fos antisense s-ODN was demonstrated by its suppression of postischemic Fos expression, which was accompanied by an inhibition of ischemia-induced NGF mRNA expression in the dentate gyrus. Infusion of saline, the sense s-ODN, or a mismatch antisense s-ODN did not suppress Fos expression. That this effect of c-fos antisense s-ODN was specific to NGF was demonstrated by its lack of effect on the postischemic expression of the NT-3 and beta-actin genes. Our results demonstrate that c-fos antisense s-ODN blocks selected downstream events and support the contention that postischemic Fos regulates the subsequent expression of the NGF gene and that Fos expression may have a functional component in neuroregeneration after focal cerebral ischemia-reperfusion.
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PMID:Suppression of postischemic hippocampal nerve growth factor expression by a c-fos antisense oligodeoxynucleotide. 995 11


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