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)

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

We tested the hypothesis that intravenous infusion of human marrow stromal cells (hMSC) with a nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio] diazen-1-ium-1,2-diolate (DETA/NONOate), enhances angiogenesis, neurogenesis and neurological functional recovery after stroke in rats compared to individual therapy. Experimental groups consist of rats subjected to 2 h of middle cerebral artery occlusion (MCAo) and at 24 h after MCAo intravenous injection of (n=10/group): Group 1: phosphate buffered saline (PBS 1 ml) for control. Group 2: NONOate alone (0.4 mg/kg). Group 3: hMSCs (1 x 10(6)) alone. Group 4: hMSCs (1 x 10(6)) with NONOate (0.4 mg/kg). Functional tests and immunohistochemical staining were performed. Marginal functional recovery after treatment of stroke was found with 1 x 10(6) hMSCs alone (p=0.06) and no benefit was detected with NONOate alone (0.4 mg/kg, p=0.64). However, NONOate+hMSCs in combination significantly induced functional recovery (p<0.05). Treatment using hMSC in combination with NONOate significantly increased vessel perimeter and endothelial cell proliferation compared with hMSC or NONOate alone treatment (p<0.05). Cell proliferation and neurogenesis were assessed with bromodeoxyuridine (BrdU) labeling and immunostaining for cell type-specific markers. Combination treatment promoted increased, BrdU positive cell number in the subventricular zone (SVZ), migrating neuronal doublecortin immunoreactive cells and VEGF and bFGF expression in the ischemic boundary area compared to individual treatment. The functional therapeutic enhancement of combination treatment may be attributed to increased plasticity induced by the combination of a nitric oxide donor and hMSC therapy. These data suggest that pharmacological and cellular therapy may provide an additive therapeutic benefit after stroke.
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PMID:Combination therapy of stroke in rats with a nitric oxide donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis. 1504 60

Angiogenesis is a critical component of stroke, head injury, cerebral vascular malformation development, and brain tumor growth. An understanding of the mechanisms of adult cerebral angiogenesis is fundamental to therapeutic vessel modulation for these diseases. To study angiogenesis in the central nervous system, we injected an adenoviral vector engineered to express vascular endothelial growth factor (VEGF-A164) into adult murine striatum. Vector-infected astrocytes expressed VEGF-A164 resulting in vascular permeability, hemorrhage, and the formation of greatly enlarged "mother" vessels. Subsequently, endothelial cells and pericytes lining mother vessels proliferated and assembled into glomeruloid bodies, complex cellular arrays interspersed by small vessel lumens. As VEGF-A164 expression declined, glomeruloid bodies involuted through apoptotic processes to engender numerous small daughter vessels. Characterized by modestly enlarged lumens with prominent pericyte coverage, daughter vessels were distributed with a density greater than normal cerebral vessels. Daughter vessels remained stable and patent to 16 months and represented the final stage of VEGF-A-induced cerebral angiogenesis. Together, these findings provide a mechanistic understanding of angiogenesis in cerebral disease processes. Furthermore, the long-term stability of daughter vessels in the absence of exogenous VEGF-A164 expression suggests that VEGF-A may enable therapeutic angiogenesis in brain.
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PMID:VEGF-A angiogenesis induces a stable neovasculature in adult murine brain. 1533 Mar 39

Valuable clues about how axons degenerate in MS can be gained from axon pathology in other disorders and experimental models. We discuss the similarities in mechanism and morphology of axon pathology in diverse circumstances revealed using mutant mice. The slow Wallerian degeneration mutation, Wld(S), delays three types of axon degeneration previously considered distinct: Wallerian degeneration of injured axons, 'dying-back' of axons in peripheral nervous system disease, and axonal spheroid pathology in gracile axonal dystrophy (gad) mice. Therefore, axon degeneration mechanisms are more uniform than previously thought and, in gad at least, axonal swelling is either related to or a consequence of Wallerian degeneration. Both axonal swelling and the accumulation of amyloid precursor protein through impaired axonal transport are common to MS, gad, and many other CNS disorders, indicating a degree of shared mechanism. YFP-H transgenic mice express YFP in a representative subset of neurons enabling unprecedented imaging of axon morphology and pathology over considerable longitudinal distances. Using this method, we have observed unbroken axons with multiple constrictions and dilatations in VEGF(delta/delta) mice, a model of amyotrophic lateral sclerosis (ALS). Similar morphologies have been described in MS, stroke, and other disorders, again suggesting a uniformity of axon degeneration mechanisms.
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PMID:Neuroprotective strategies in MS: lessons from C57BL/Wld(S) mice. 1589 98

Vascular endothelial growth factor (VEGF, occurring in several isoforms: VEGF-A, -B, -C, -D) is a well-known endothelial cell mitogen and vascular growth and permeability factor. Recent work done over the last few years has elucidated the important role of VEGF, which participates in the regulation of normal (physiological or therapeutic) and pathological angiogenesis (VEGF-A, VEGF-B) and lymphangiogenesis (VEGF-C, VEGF-D). VEGF has also been implicated in practically every stage of angiogenesis, yet its role in the initiation of new blood vessel creation appears to be the most important. In addition to its role as a key angiogenic factor, VEGF also possesses neurotrophic and neuroprotective activity both in the peripheral and in the central nervous system, exerting a direct action on neurons, Schwann cells, astrocytes, neural stem cells, and microglia. VEGF interacts with three subtypes of VEGF receptors occurring on the cellular membrane known as VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/KDR), and VEGFR-3 (Flt-4). All these receptor types possess an internal tyrosin kinase domain. Interaction of VEGF with particular subtypes of receptors activates a circuit of signaling pathways, e.g. PI3K/Akt, Ras/Raf-MEK/Erk, eNOS/NO, and IP3/Ca2+. These participate in the generation of specific biological responses connected with proliferation, migration, increasing vascular permeability, or promoting endothelial cell survival. Recent findings from experiments performed on animals with experimentally evoked focal cerebral ischemia suggest that the neuroprotective activity of VEGF runs in parallel with its ability to promote neurogenesis and angiogenesis and that these effects may operate independently through multiple mechanisms. The above-mentioned three major features characterizing the neurobiological activity of VEGF, i.e. neuroprotection, neurogenesis, and angiogenesis, together with their possible functional link(s), provide the rationale for considering VEGF-based therapy as a promising future avenue for a more effective treatment of at least some neurodegenerative disorders and stroke. Moreover, the possibility of using neutralizing factors of VEGF or VEGF receptor antagonists may reveal a way of preventing many dangerous pathologies, including post-ischemic disturbances in cardiac and neurological disorders, tumor growth, or hypervascularization in avascular structures of the eye.
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PMID:[VEGF as an angiogenic, neurotrophic, and neuroprotective factor]. 1640 96

Matrix metalloproteinases (MMPs) are zinc-endopeptidases with multifactorial actions in central nervous system (CNS) physiology and pathology. Accumulating data suggest that MMPs have a deleterious role in stroke. By degrading neurovascular matrix, MMPs promote injury of the blood-brain barrier, edema and hemorrhage. By disrupting cell-matrix signaling and homeostasis, MMPs trigger brain cell death. Hence, there is a movement toward the development of MMP inhibitors for acute stroke therapy. But MMPs may have a different role during delayed phases after stroke. Because MMPs modulate brain matrix, they may mediate beneficial plasticity and remodeling during stroke recovery. Here, we show that MMPs participate in delayed cortical responses after focal cerebral ischemia in rats. MMP-9 is upregulated in peri-infarct cortex at 7-14 days after stroke and is colocalized with markers of neurovascular remodeling. Treatment with MMP inhibitors at 7 days after stroke suppresses neurovascular remodeling, increases ischemic brain injury and impairs functional recovery at 14 days. MMP processing of bioavailable VEGF may be involved because inhibition of MMPs reduces endogenous VEGF signals, whereas additional treatment with exogenous VEGF prevents MMP inhibitor-induced worsening of infarction. These data suggest that, contrary to MMP inhibitor therapies for acute stroke, strategies that modulate MMPs may be needed for promoting stroke recovery.
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PMID:Role of matrix metalloproteinases in delayed cortical responses after stroke. 1659 83

Ranibizumab therapy is the first treatment for neovascular AMD to improve vision for most patients. The benefits apply to all angiographic subtypes of neovascular AMD and across all lesion sizes. Although the pivotal phase III trials (MARINA and ANCHOR) used monthly injections of ranibizumab for 2 years, the ongoing PIER, PrONTO, and SAILOR trials are investigating less frequent dosing regimens, and preliminary results from the PrONTO study suggest that fewer injections will most likely result in visual acuity improvements similar to the results from the phase III trials. When comparing the ANCHOR results with the FOCUS results, it also becomes apparent that the combination of ranibizumab with PDT does not necessarily result in better visual acuity outcomes, and the use of PDT may even reduce the visual acuity benefits achieved with ranibizumab alone (see Figs. 1-3). It seems unlikely that combination therapy provides any significant advantage over ranibizumab alone unless the combination of PDT and ranibizumab can decrease the need for frequent retreatment. The results from the PrONTO Study already suggest that less frequent treatment with ranibizumab is possible by using a variable dosing regimen with OCT. Ranibizumab also seems to be safe, with the 2-year MARINA data showing no increase in the incidence of systemic adverse events that could be associated with anti-VEGF therapy, such as myocardial infarction and stroke. There was a hint of a safety concern, however, in the pooled 1-year safety results from the MARINA and ANCHOR trials. Although the combined rate of myocardial infarction and stroke during the first year of the ANCHOR and MARINA trials was similar in the control and the 0.3-mg ranibizumab arms (1.3% and 1.6% respectively), these adverse events were slightly higher in the 0.5-mg ranibizumab arm (2.9%). These differences are not statistically significant, however, and probably do not represent a dose-dependent increase in risk because the 2-year results from the MARINA trial with the same monthly injection regimen showed no increased risk of thromboembolic events. In December 2005, Genentech submitted a Biologics License Application to the FDA for the use of ranibizumab in the treatment of neovascular wet AMD based on 1-year clinical efficacy and safety data from the two pivotal phase III trials, ANCHOR and MARINA, and the phase I-II FOCUS trial. Genentech has been granted a 6-month Priority Review from the FDA with a decision anticipated 6 months from the December submission date or by the end of June 2006 [29]. By the summer of 2006, this revolutionary therapy should be available for the treatment of neovascular AMD. At that time, the major dilemma facing most retina specialists will be whether to use intravitreal ranibizumab or intravitreal bevacizumab, the low cost alternative, for the treatment of neovascular AMD.
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PMID:Ranibizumab: Phase III clinical trial results. 1693 11

Increased vascular permeability causing vasogenic brain edema is characteristic for many acute neurological diseases such as stroke, brain trauma, and meningitis. Src family kinases, especially c-Src, play an important role in regulating blood-brain barrier permeability in response to VEGF, but also mediate leukocyte function and cytokine signalling. Here we demonstrate that pharmacological inhibition of Src or c-Src deficiency does not influence cerebrospinal fluid (CSF) pleocytosis, brain edema formation, and bacterial outgrowth during experimental pneumococcal meningitis despite the increased cerebral expression of inflammatory chemokines, such as IL-6, CCL-9, CXCL-1, CXCL-2 and G-CSF as determined by protein array analysis. In contrast, inhibition of Src significantly reduced brain edema formation, lesion volume, and clinical worsening in cold-induced brain injury without decreasing cytokine/chemokine expression. While brain trauma was associated with increased cerebral VEGF formation, VEGF levels significantly declined during pneumococcal meningitis. Therefore, we conclude that in brain trauma blood-brain barrier tightness is regulated by the VEGF/Src pathway whereas c-Src does not influence brain edema formation and leukocyte function during bacterial meningitis.
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PMID:Differential regulation of blood-brain barrier permeability in brain trauma and pneumococcal meningitis-role of Src kinases. 1701 Mar 40

The ovarian hyperstimulation syndrome (OHSS) is still a difficult diagnostic and therapeutic problem. OHSS is associated with significant hypertrophy of the ovaries associated with the loss of the intravascular fluid to the third space which results in hypovolaemia, oliguria, electrolyte imbalance, and a rise in haematocrit. The endogenous OHSS is rare. Most often OHSS appears as a complication of induction of ovulation. The fundamental issue in pathophysiology of OHSS is an increase of capillary permeability which results in the leakage of fluid to the third space. The vascular endothelial growth factor--VEGF--is considered to be the factor directly responsible for the processes involved. The most common are the mild and moderate forms of the syndrome. The severe form of OHSS is a life-threatening condition. The following symptoms may be present: ascites, pleural and pericardial effusion, oliguria, dyspnoea with tachypnoe, tachycardia, adult respiratory distress syndrome, renal failure, venous thrombosis, ischaemic stroke, haemorrhage from a ruptured ovary. Therapy should be based on the correction of hypovolaemia, hypotension and oliguria. Antithrombotic prophylaxis is an integral part of the OHSS management. Some interesting attempts have been undertaken to re-infuse the protein-rich ascites fluid directly to the systemic circulation, so called continuous auto-transfusion system of the ascites (CATSA).
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PMID:[The ovarian hyperstimulation syndrome--diagnostic criteria, management procedures]. 1737 30

Stroke-prone spontaneously hypertensive rats (SHRSP) often suffer from spontaneous stroke, in part, due to abnormalities in the cerebrovasculature. Here, we investigate the profile of key angiogenic factors and their basic signaling molecules in the brain of SHRSP during the age-dependent stages of hypertension. The profile of VEGF and its receptor, Flk-1, was dependent on age and stage of hypertension (i.e., down regulated at pre-hypertensive and malignant hypertensive stages, but up regulated at typical hypertensive stage), while that of its downstream components, pAkt and eNOS, were down regulated in a time-dependent manner in the frontal cortex of SHRSP compared to age-matched genetic control, normotensive WKY rats. On the other hand, the expression of endothelin-1 and its type A receptor (endothelin ETA receptor) were up regulated, depending on age and stage of hypertension. In contrast, levels of endothelin type B receptor were down regulated. The regional cerebral blood flow decreased during the development of malignant hypertension. Thus, subsequent experiments were designed to investigate whether endothelin-1 receptor antagonism, using endothelin-A/-B dual receptor antagonist SB209670, could normalize the molecular profile of these factors in SHRSP brain. Interestingly, blockage of endothelin-1 receptor restored to normal, levels of cerebral endothelin-1, endothelin ETA receptor and endothelin ETB receptor; VEGF and Flk-1; endothelial nitric oxide synthase (eNOS) and pAkt, in SHRSP, compared to age-matched WKY. Endothelin receptor blocker might be important to prevent the progression in the defect in VEGF and its angiogenic signaling cascade in the pathogenesis of hypertension-induced vascular remodeling in frontal cortex of SHRSP rats.
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PMID:Antagonism of endothelin action normalizes altered levels of VEGF and its signaling in the brain of stroke-prone spontaneously hypertensive rat. 1768 27


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