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)

Basic fibroblast growth factor (bFGF) is a polypeptide with potent survival-promoting and protective effects on brain cells. In previous studies, we showed that intravenous administration of bFGF reduced infarct volume in models of focal cerebral ischemia in rats, mice, and cats. In these previous studies, infarct volume was measured within 1-7days of the onset of ischemia. The current study was undertaken to determine whether the reduction in infarct volume by bFGF was persistent beyond the first week after stroke. Mature male Sprague-Dawley rats received an intravenous infusion of bFGF (50 microg/kg per h) or vehicle during 0.5-3.5h after permanent proximal middle cerebral artery occlusion. We found a 27% reduction in infarct volume in bFGF- compared to vehicle-treated animals at three months after infarction (P<0.05). The data show that intravenous bFGF treatment produces a persistent reduction in infarct volume, at least up to three months following focal stroke.
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PMID:Intravenous basic fibroblast growth factor produces a persistent reduction in infarct volume following permanent focal ischemia in rats. 1117 28

Basic fibroblast growth factor (bFGF) has minimal pharmacological effects in the central nervous system in the absence of blood-brain barrier (BBB) disruption. BBB transport of bFGF occurs via an absorptive-mediated transcytosis mechanism, which is relatively inefficient. To enhance the BBB transport of bFGF, this neurotrophin was reformulated to enable receptor-mediated transport across the BBB via the transferrin receptor. bFGF was monobiotinylated and coupled to a BBB drug-delivery vector comprised of streptavidin (SA) and the OX26 monoclonal antibody to the rat transferrin receptor. The entire conjugate of biotinylated bFGF bound to the OX26-SA is designated bio-bFGF/OX26-SA. The bFGF retains receptor-binding affinity and has increased brain uptake following conjugation to OX26-SA. The bio-bFGF/OX26-SA conjugate protects cortical cell cultures against hypoxia/reoxygenation insult in a dose-dependent manner in vitro. A single intravenous injection of bio-bFGF/OX26-SA, equivalent to a dose of 25 microg/kg bFGF, produces an 80% reduction in infarct volume in the brain of rats subjected to permanent occlusion of the middle cerebral artery in parallel with a significant improvement of neurologic deficit. The neuroprotection is time-dependent, and there is a 67% reduction in stroke volume if the conjugate is administered at 60 min after arterial occlusion, whereas no significant reduction in stroke volume is observed if treatment is delayed 2 h. In conclusion, neuroprotection in regional brain ischemia is possible following the delayed intravenous injection of low doses of bFGF providing the neurotrophin is conjugated to a BBB drug-targeting system.
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PMID:Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood-brain barrier delivery vector. 1196 Oct 63

Basic fibroblast growth factor (bFGF) is a polypeptide with potent trophic and protective effects on the brain. bFGF has been reported to exert neuroprotection against a wide variety of insults, including ischemic neuronal injury. To date, animal models of focal ischemia have not been translated to efficacy in stroke clinically with respect to testing of neuroprotective agents. Because functional outcome is the measurement of efficacy for putative neuroprotective agents in the clinic, we sought to evaluate the functional consequences of bFGF administration in rats subjected to focal ischemia. In this study, we assessed the effects of bFGF on functional outcome as well as infarct size in rats subjected to severe cerebral ischemia by permanent occlusion of the middle cerebral artery (MCAO). Male Sprague-Dawley rats were subjected to permanent MCAO by the intraluminal filament technique. Two hours following occlusion, rats were infused intravenously with either bFGF, at a dose of 150 microg/kg, or vehicle alone. Functional sensorimotor impairment, which was assessed by the accelerating rotarod test, was recorded at baseline and compared to performance assessed at 24 h after MCAO. Permanent occlusion of the MCA caused marked impairment in rotarod performance in both groups. Treatment of rats with bFGF showed a significant 46% improvement in rotarod fall latency when compared with that from the animals treated with vehicle alone. The volume of cortical infarction was significantly reduced by 32% as a function of bFGF treatment. These results suggest that the delayed intravenous administration of bFGF improves sensorimotor function as well as reduces infarct size following permanent focal ischemia in rat.
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PMID:Postischemic administration of basic fibroblast growth factor improves sensorimotor function and reduces infarct size following permanent focal cerebral ischemia in the rat. 1242 98

Several members of the FGF family, in particular FGF2, are intimately involved in neuronal protection and repair after ischemic, metabolic or traumatic brain injury. Expression of Fgf2 mRNA and protein is strongly upregulated after neuronal damage, with glial cells as the predominant source. Given its survival-promoting effects on cultured neurons, exogenous FGF2 was tested in several animal models of stroke and excitotoxic damage, in which it consistently proved protective against neuronal loss. FGF2 affords neuroprotection by interfering with a number of signaling pathways, including expression and gating of NMDA receptors, maintenance of Ca2+ homeostasis and regulation of ROS detoxifying enzymes. FGF2 prevents apoptosis by strengthening anti-apoptotic pathways and promotes neurogenesis in adult hippocampus after injury. The protective action of FGF2 has been linked to its augmenting effect on the lesion-induced upregulation of activin A, a member of the TGF-beta superfamily. Despite the well-documented benefits of FGF2 in animal models of stroke, there is currently no clinical development in stroke, after a phase II/III trial with FGF2 in acute stroke patients was discontinued because of an unfavorable risk-to-benefit ratio. As the molecular targets of FGF2 are going to be unraveled over the next years, new therapeutic strategies will hopefully emerge that enable us to influence the various protective mechanisms of FGF2 in a more specific fashion.
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PMID:Fibroblast growth factors and neuroprotection. 1257 27

More than 30 neurotrophins have been identified, and many of them have neuroprotective effects in brain ischemia or injury. However, all the clinical trials with several neurotrophins for the treatment of acute ischemic stroke or neurodegenerative diseases have failed so far, primarily because of their poor blood-brain barrier (BBB) permeability. This article is an overview of recent progress in the research focused on BBB targeted neurotrophins using a chimeric peptide approach, in which antitransferrin receptor antibody was used as a BBB delivery vector, and neurotrophin peptide was conjugated to the antibody via the avidin/biotin technology. Vasoactive intestinal peptide was the first model chimeric peptide to show an enhanced CNS effect after noninvasive peripheral administration. Brain-derived neurotrophic factor (BDNF) chimeric peptide was neuroprotective in rats subjected to transient forebrain ischemia, permanent focal ischemia, or transient focal ischemia. Delayed treatments with the BDNF chimeric peptide showed an effective time window of 1-2 h after ischemia. Basic FGF chimeric peptide was highly effective in the reduction of infarct volume in the rat model of permanent focal ischemia, with lowest effective dose of 1 mug per rat. Future studies in this exciting area include genetically engineered fusion proteins or humanized antibodies for BBB drug targeting with less immunogenicity and reduced working burden in the chemical conjugation, the use of antihuman insulin receptor antibody for higher BBB delivery efficiency, and combination therapies using chimeric neurotrophins plus other neuroprotectants to achieve additive or synergistic effects.
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PMID:Neuroprotection in experimental stroke with targeted neurotrophins. 1571 63

Basic fibroblast growth factor (bFGF) has been reported to be involved in the pathophysiological changes following cerebral infarction. Basic fibroblast growth factor is upregulated in the brain and conduces to neuroprotection and angiogenesis in experimental brain ischemia, but the change of serum bFGF in cerebral infarction patients has not been reported. In the present study, we investigated the dynamic changes of serum bFGF in 30 patients with acute cerebral infarction and found that serum bFGF increased significantly after cerebral infarction compared with the control group (p<0.05). Serum bFGF peaked on day 3 (15.46 +/- 5.58 pg/ml; p<0.01) and remained significantly elevated on day 14 following cerebral infarction. In this study, it was also found that the levels of bFGF with large infarction were higher at each time point than those with moderate or small infarction (p<0.05). There was a positive correlation between the peak level of bFGF and improvement of clinical neurological deficits scored by Scandinavian Stroke Scale (SSS) (r=0.596; p<0.05). These results suggest that the serum bFGF level increased significantly after cerebral infarction and the level of serum bFGF could be of value to estimate the infarction size and clinical prognosis.
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PMID:Serial measurement of serum basic fibroblast growth factor in patients with acute cerebral infarction. 1622 51

Basic fibroblast growth factor (FGF-2) has been reported to protect against ischemic injury in the brains of young adult rodents. However, little is known about whether FGF-2 retains this capability in the aged ischemic brain. Since stroke in human is much more common in older people than among younger adults, to address this question is clinically important. In this study, aged (24-month-old) rats were treated with intracerebroventricular infusion of FGF-2 or vehicle for 3 days, beginning 48 h before (pre-ischemia), 24 h after (early post-ischemia), or 96 h after (late post-ischemia) 60 min of middle cerebral artery occlusion, and were killed 10 days after ischemia. Aged rats given FGF-2 pre-ischemia showed better symmetry of movement and forepaw outstretching, and reduced infarct volumes, compared to rats treated with vehicle, but no significant improvement was found in aged rats given FGF-2 after focal ischemia. In contrast, young adult (3-month-old) rats treated with FGF-2 for 3 days beginning 24 h post-ischemia showed significant neurobehavioral improvement and better histological outcome. In addition, we also found that newborn neurons in the rostral subventricular zone (SVZ) were increased in aged rats treated with FGF-2 prior to ischemia. However, unlike in young adult ischemic rats, only a few of newly generated cells migrated into the damaged region in aged brain after focal ischemia. These findings point to differences in the response of aged versus young adult rats to FGF-2 in cerebral ischemia, and suggest that such differences need to be considered in the development of neuroprotective agents for stroke.
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PMID:Influence of age on the response to fibroblast growth factor-2 treatment in a rat model of stroke. 1706 73

Basic fibroblast growth factor (bFGF) is a very important mitogenic factor with proved neurogenesis effects in the central nervous system. Intranasal administration can bypass blood-brain barrier and deliver drugs into the brain directly. We investigated whether intranasal administration of bFGF at later time points after ischemia could promote adult neurogenesis and improve neurologic functions. Rats received bFGF or saline intranasally once daily for 6 consecutive days, starting at 1 day after transient middle cerebral artery occlusion (MCAO). Bromodeoxyuridine (BrdU) was injected at 5 and 6 days after MCAO. Rats were killed at 7 or 28 days after MCAO. Neurogenesis was assessed by immunostaining for BrdU and cell type-specific markers. Neurological functions were evaluated by the modified Neurological Severity Scores. Compared with the control animals, intranasal administration of bFGF improved behavioral recovery without affecting infarct size, and enhanced proliferation of progenitor cells in the subventricular zone and the subgranular zone of the dentate gyrus (DG). Furthermore, the new proliferated cells could differentiate into neurons (BrdU+NeuN+ cells) in the striatum and DG at 28 days after MCAO. Intranasal administration of bFGF offers a non-invasive alternative for the treatment of stroke.
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PMID:Intranasally delivered bFGF enhances neurogenesis in adult rats following cerebral ischemia. 1882 50

Basic fibroblast growth factor (bFGF) is a potent endothelial and smooth muscle cell mitogen that does not normally circulate. Plasma bFGF-like bioactivity was increased in association with persistent microalbuminuria (a risk marker for cardiovascular disease) in adult type 2 diabetes mellitus. In the present study, we tested whether baseline plasma bFGF immunoreactivity (IR) predicts the occurrence of a subset of cardiovascular disease outcomes in adults with advanced type 2 diabetes mellitus from the Veterans Affairs Diabetes Trial (mean: age, 59 years; diabetes duration, 11 years; baseline hemoglobin A(1c), 9.5%). Plasma bFGF-IR was determined with a sensitive and specific 2-site enzyme-linked immunoassay in 399 patients at the baseline visit. These results were then evaluated as possible predictors of the occurrence of prespecified cardiovascular or coronary heart disease end points. There was a borderline-significant association (P = .07) between plasma bFGF-IR and the main study cardiovascular disease outcome (myocardial infarction, congestive heart failure, cerebrovascular accident, amputation, cardiovascular death, coronary, cerebrovascular or peripheral revascularization, and inoperable coronary artery disease). Plasma bFGF-IR was significantly associated with the occurrence of coronary heart disease (P = .01). After adjusting for clinical risk factors, bFGF (hazard ratio [HR], 1.013; 95% confidence interval [CI], 1.007-1.019; P < .0001), prior macrovascular event (HR, 3.55; 95% CI, 2.154-5.839; P < .0001), and duration of diabetes (HR, 1.041; 95% CI, 1.012-1.071; P = .0055) were all significantly associated with time to first postrandomization coronary heart disease occurrence. These results suggest that increased plasma bFGF-IR may be a novel risk marker for coronary heart disease occurrence in adult men with advanced type 2 diabetes mellitus.
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PMID:Increased plasma basic fibroblast growth factor is associated with coronary heart disease in adult type 2 diabetes mellitus. 2020 49

Ischemic stroke is one of the most frequent pathologies with high invalidating potential and a leading cause of death. The brain tissue adjacent to the central necrotic core, defined as penumbra, was extensively characterized mostly by imaging techniques and in animal models. Our goal was to identify a large panel of molecules in this particular area on human brains harvested at autopsy. Twenty-one patients with ischemic stroke and seven control cases were taken into study. We used immunohistochemistry to characterize necrotic lesions. Metalloproteinases, mostly MMP-9, seem to be involved in brain ischemia, but as a protective and not as a deleterious factor. Apoptotic molecules are not increasingly expressed in stroke compared to control cases. Mast cell enzymes chymase and tryptase are described for the first time in neurons and glia, even with unclear significance. Microglia appears active in stroke and stimulating methods directed to it could be useful. Nitric oxide synthases and cyclooxygenase-2 were also involved in stroke cases but not in control ones. Other factors as VEGF and its receptors, PDGF, b-FGF or TNF-alpha showed no significant expression related to ischemic brain injury. Animal study of penumbra and human tissue findings are distinct and research should be focused on the latter approach in order to find valuable and safe therapeutic methods.
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PMID:Clinico-pathological correlations in fatal ischemic stroke. An immunohistochemical study of human brain penumbra. 2142 29


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