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

We have developed a cytoplasmic replicating virus vector of Sendai virus (SeV) that infects and replicates in most mammalian cells, including neurons, and directs high-level gene expression. To investigate the protective effect of SeV vector-mediated gene transfer of glial cell line-derived neurotrophic factor (GDNF) on the delayed neuronal death caused by transient global ischemia in gerbils, SeV vectors carrying either GDNF (SeV/GDNF) or enhanced green fluorescent protein gene (SeV/GFP) were stereotaxically microinjected into the lateral ventricle. Four days after injection, occlusion of the bilateral common carotid arteries for 5 min produced transient global forebrain ischemia. Treatment with SeV/GDNF significantly decreased the delayed neuronal death of the hippocampal CA1 pyramidal neurons observed 6 days after the operation. TUNEL staining demonstrated that SeV/GDNF treatment markedly reduced the number of apoptotic cells in the hippocampal CA1 neurons, indicating that SeV/GDNF treatment prevented apoptosis. Furthermore, delayed neuronal death on the contralateral side of the hippocampal CA1 was also prevented to a similar extent as that on the ipsilateral side. These results suggest that SeV/GDNF prevents the delayed neuronal death induced by ischemia and is potentially useful for gene therapy for stroke.
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PMID:Sendai virus vector-mediated gene transfer of glial cell line-derived neurotrophic factor prevents delayed neuronal death after transient global ischemia in gerbils. 1280 86

Direct intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) is neuroprotective against ischemia-induced cerebral injury. Utilizing viral vectors to deliver and express therapeutic genes presents an opportunity to produce GDNF within localized regions of an evolving infarct. We investigated whether a herpes simplex virus (HSV) amplicon-based vector encoding GDNF (HSVgdnf) would protect neurons against ischemic injury. In primary cortical cultures HSVgdnf reduced oxidant-induced injury compared to the control vector HSVlac. To test protective effects in vivo, HSVgdnf or HSVlac was injected into the cerebral cortex 4 days prior to, or 3 days, after a 60-min unilateral occlusion of the middle cerebral artery. Control stroke animals developed bradykinesia and motor asymmetry; pretreatment with HSVgdnf significantly reduced such motor deficits. Animals receiving HSVlac or HSVgdnf after the ischemic insult did not exhibit any behavioral improvement. Histological analyses performed 1 month after stroke revealed a reduction in ischemic tissue loss in rats pretreated with HSVgdnf. Similarly, these animals exhibited less immunostaining for glial fibrillary acidic protein and the apoptotic marker caspase-3. Taken together, our data indicate that HSVgdnf pretreatment provides protection against cerebral ischemia and supports the utilization of the HSV amplicon for therapeutic delivery of trophic factors to the CNS.
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PMID:HSV amplicon delivery of glial cell line-derived neurotrophic factor is neuroprotective against ischemic injury. 1295 87

Previous studies have indicated that administration of glial cell line-derived neurotrophic factor (GDNF) counteracts neuronal death after stroke. However, in these studies damage was evaluated at most a few days after the insult. Here, we have explored the long-term consequences of two routes of GDNF delivery to the rat striatum prior to stroke induced by 30 min of middle cerebral artery occlusion (MCAO): striatal transduction with a recombinant lentiviral vector or transduction of the substantia nigra with a recombinant adeno-associated viral vector and subsequent anterograde transport of GDNF to striatum. Despite high GDNF levels, stereological quantification of striatal neuron numbers revealed no protection at 5 or 8 weeks after MCAO. In fact, anterograde GDNF delivery exacerbated neuronal loss. Moreover, supply of GDNF did not alleviate the striatum-related behavioral deficits. Thus, we demonstrate that the actions of GDNF after stroke are more complex than previously believed and that high levels of this factor, which are neuroprotective in models of Parkinson's disease, can increase ischemic damage. Our findings also underscore the need for quantitative assessment of long-term neuronal survival and behavioral changes to evaluate the therapeutic potential of factors such as GDNF.
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PMID:Elevated GDNF levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats. 1467 70

Sendai virus (SeV) vector-mediated gene delivery of glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) prevented the delayed neuronal death induced by transient global ischemia in gerbils, even when the vector was administered several hours after ischemia. Intraventricular administration of SeV vector directed high-level expression of the vector-encoded neurotrophic factor genes, which are potent candidates for the treatment of neurodegenerative diseases. After occlusion of the bilateral carotid arteries of gerbils, SeV vector carrying GDNF (SeV/GDNF), NGF (SeV/NGF), brain-derived neurotrophic factor (SeV/BDNF), insulin-like growth factor-1 (SeV/IGF-1) or vascular endothelial growth factor (SeV/VEGF) was injected into the lateral ventricle. Administration of SeV/GDNF, SeV/NGF or SeV/BDNF 30 min after the ischemic insult effectively prevented the delayed neuronal death of the hippocampal CA1 pyramidal neurons. Furthermore, the administration of SeV/GDNF or SeV/NGF as late as 4 or 6 h after the ischemic insult also prevented the death of these neurons. These results indicate that SeV vector-mediated gene transfer of neurotrophic factors has high therapeutic potency for preventing the delayed neuronal death induced by transient global ischemia, and provides an approach for gene therapy of stroke.
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PMID:Postischemic administration of Sendai virus vector carrying neurotrophic factor genes prevents delayed neuronal death in gerbils. 1496 Oct 67

Recent studies have indicated that proteins in the transforming growth factor-beta superfamily alter damage induced by various neuronal injuries. Of these proteins, glial cell line-derived neurotrophic factor (GDNF) and bone morphogenetic protein-7 (BMP-7) have unique protective and regenerative effects in stroke animals. Delivery of GDNF or BMP-7 to brain tissue reduced cerebral infarction and improved motor functions in stroke animals. Pretreatment with these factors reduced caspase-3 activity and DNA fragmentation in the ischemic brain region, suggesting that antiapoptotic effects are involved. Beside the protective effects, BMP-7 given after stroke improves locomotor function. These regenerative effects of BMP-7 may involve the enhancement of dendritic growth and remodeling. In this review, we illustrate the neuroprotective and neuroregenerative properties of GDNF and BMP-7 and emphasize their therapeutic potential for stroke.
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PMID:Stroke and TGF-beta proteins: glial cell line-derived neurotrophic factor and bone morphogenetic protein. 1567 Jun 22

Glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-beta superfamily. Over the last decade, GDNF has been shown to promote regenerative and restorative effects on dopaminergic neurons. Accumulating evidence also demonstrates that administration of GDNF to areas of ischemic brain injury limits cerebral infarction and reduces damage to motor functions in animal models of stroke. Neurotrophic factor and anti-apoptotic mechanisms, among others, have been proposed to underlie the therapeutic effects of GDNF. A major obstacle for GDNF therapy is the protein delivery to the brain, as well as its sustained bioavailability over time. Gene therapy and the use of viral vectors offer a technique for longevity of GDNF expression within the brain. In this review, we consider the risks and benefits of GDNF gene therapy as it relates to the treatment of stroke.
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PMID:Viral vector strategy for glial cell line-derived neurotrophic factor therapy for stroke. 1614

In the present study, the underlying protective mechanism of melatonin on kainic acid (KA)-induced excitotoxicity was examined in the hippocampus of mice. KA, administered intracerebroventricularly (i.c.v.), induced marked neuronal cell death with concurrent microglial activation and subsequent induction of inducible nitric oxide synthase (iNOS) in the hippocampus. Histopathological analysis demonstrated that melatonin (10 mg/kg), administered 1 hr prior to KA, attenuated KA-induced death of pyramidal neurons in the CA3 region. Melatonin obviously suppressed KA-induced microglial activation and consequent iNOS expression that were determined by increased immunoreactivities of microglial marker OX-6 and iNOS, respectively. Increased phosphorylation of Akt in pyramidal neurons was observed as early as 2 hr after administration of melatonin. Further, melatonin resulted in increased expression of astroglial glial cell line-derived neurotrophic factor (GDNF), which started to appear approximately 6 hr after administration of melatonin. The results of the present study demonstrate that melatonin exerts its neuroprotective action against KA-induced excitotoxicity both through the activation of neuronal Akt and via the direct action on hippocampal neurons and through the increased expression of astroglial GDNF, which subsequently activates neuronal PI3K/Akt pathway. Therefore, the present study suggests that melatonin, pineal secretory product, is potentially useful in the treatment of acute brain pathologies associated with excitotoxic neuronal damage such as epilepsy, stroke, and traumatic brain injury.
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PMID:Sustained activation of Akt by melatonin contributes to the protection against kainic acid-induced neuronal death in hippocampus. 1631 2

The tetracycline derivatives minocycline (MINO) and doxycycline (DOXY) have been shown to be neuroprotective in in vivo and in vitro models of stroke. This neuroprotection is thought to be due to the suppression of microglial activation. However, the specific molecular parameters in microglia of the tetracyclines' effect are not understood. We subjected cultured rat microglial and neuronal cells to in vitro hypoxia and examined the effects of MINO and DOXY pre-treatments. Our data showed that MINO and DOXY protect against hypoxia-induced neuronal death by a mechanism dependent on regulation of microglial factors, but likely unrelated to regulation of microglial proliferation/viability. Both MINO and DOXY suppressed the hypoxic activation of ED-1, a marker for microglial activation. Morphological analyses of hypoxic microglia using the microglial marker Iba1 revealed that treatment with MINO and DOXY caused a higher percentage of microglia to remain in a non-activated state. MINO suppressed the hypoxic upregulation of pro-inflammatory agents nitric oxide (NO), interleukin-1 beta (IL-1beta), and tumor necrosis factor alpha (TNF-alpha), while DOXY down-regulated only NO and IL-1beta. In contrast, the hypoxic activation of pro-survival/neuroprotective microglial proteins, such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), were unaffected by tetracycline treatments. Taken together, these results suggest that MINO and DOXY may provide neuroprotection against stroke by selectively down-regulating microglial toxic factors while maintaining functional pro-survival factors.
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PMID:Hypoxia-activated microglial mediators of neuronal survival are differentially regulated by tetracyclines. 1654 36

Intravenous administration of human mesenchymal stem cells (hMSCs) prepared from adult bone marrow has been reported to ameliorate functional deficits after cerebral artery occlusion in rats. Several hypotheses to account for these therapeutic effects have been suggested, and current thinking is that neuroprotection rather than neurogenesis is responsible. To enhance the therapeutic benefits of hMSCs potentially, we transfected hMSCs with the glial cell line-derived neurotrophic factor (GDNF) gene using a fiber-mutant F/RGD adenovirus vector and investigated whether GDNF gene-modified hMSCs (GDNF-hMSCs) could contribute to functional recovery in a rat permanent middle cerebral artery occlusion (MCAO) model. We induced MCAO by using intraluminal vascular occlusion, and GDNF-hMSCs were intravenously infused into the rats 3 hr later. MRI and behavioral analyses revealed that rats receiving GDNF-hMSCs or hMSCs exhibited increased recovery from ischemia compared with the control group, but the effect was greater in the GDNF-hMSC group. Thus, these results suggest that intravenous administration of hMSCs transfected with the GDNF gene using a fiber-mutant adenovirus vector may be useful in the cerebral ischemia and may represent a new strategy for the treatment of stroke.
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PMID:Intravenous administration of glial cell line-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in the adult rat. 1699 18

Ammonium trichloro(dioxoethylene-0,0') tellurate (AS101) is a non-toxic organotellurium compound with pleiotropic activities. It was recently shown to induce production of the neurotrophic factor glial cell line-derived neurotrophic factor and to rescue neuronal-like PC-12 cells from neurotrophic factor deprivation-induced apoptosis. In this study, we show that AS101 improves functional outcome and reduces brain damage in a mouse model of focal ischemic stroke. Both pre-stroke and post-stroke intraperitoneal treatments with AS101 reduced infarct size and edema and improved the neurological function of the animals. AS101 treatments reduced both apoptotic and inflammatory caspase activities, and also inhibited protein tyrosine nitration suggesting that AS101 suppresses oxidative stress. Studies of cultured neurons showed that AS101 confers protection against apoptosis induced by either glucose deprivation or the lipid peroxidation product 4-hydroxynonenal. Moreover, AS101 treatment reduced glutamate-induced intracellular calcium elevation, a major contributor to neuronal death in stroke. As AS101 has an excellent safety profile in humans, our pre-clinical data suggest a potential therapeutic benefit of AS101 in patients suffering from stroke and other neurodegenerative conditions.
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PMID:The organotellurium compound ammonium trichloro(dioxoethylene-0,0') tellurate enhances neuronal survival and improves functional outcome in an ischemic stroke model in mice. 1754 9


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