Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Neurotrophins such as brain-derived neurotrophic factor (BDNF) are potential neuroprotective agents that could be used in the treatment of acute stroke, should these proteins be made transportable through the blood-brain barrier (BBB) in vivo. One approach to the BBB problem is to attach the nontransportable peptide to a brain targeting vector, which is a peptide or peptidomimetic monoclonal antibody (MAb), that is transported into brain from blood via an endogenous BBB transport system. The present studies describe a conjugate of BDNF and the OX26 monoclonal antibody (MAb) to the transferrin receptor. Avidin-biotin technology is used to link the BDNF and the MAb. The surface of the BDNF is conjugated with 2000 Da polyethylene glycol at carboxyl residues to optimize the plasma pharmacokinetics of the neurotrophin. Adult rats subjected to 24 h of permanent middle cerebral artery occlusion (MCAO) were treated intravenously with either unconjugated BDNF, unconjugated MAb, or the BDNF-OX26 conjugate at a dose of 1, 5 and 50 microg/rat of the BDNF. These doses decreased the infarct volume by 6% (not significant), 43% (P<0.01), and 65% (P<0.01), respectively. Significant reduction in stroke volume was still observed if the administration of the BDNF conjugate was delayed for 1-2 h after MCAO, although the pharmacological effect was progressively diminished in proportion to the time delay between MCAO and treatment. In conclusion, these studies demonstrate that large reductions in stroke volume can be achieved with the noninvasive intravenous administration of neurotrophins such as BDNF, providing the peptide is conjugated to a BBB drug targeting system.
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PMID:Conjugation of brain-derived neurotrophic factor to a blood-brain barrier drug targeting system enables neuroprotection in regional brain ischemia following intravenous injection of the neurotrophin. 1116 85

Iron is the most abundant transition metal in the brain, where it functions as an important cofactor in a host of vital metabolic processes and plays an absolutely essential role in cell viability. Free iron is also very toxic when present in high concentrations, thus placing this essential metal at the core of neurotoxic injury in a number of neurological disorders. The pivotal role of iron in cellular homeostasis, including its latent toxicity, necessitates a tight regulation of iron metabolism. Oxygen and iron appear to play an important role in iron homeostasis. They appear to exert their homeostatic role by modulating the proteins involved in a complex interplay between iron sensing, transport, and storage. These key regulatory proteins include ferritin (intracellular storage), transferrin (extracellular transport), transferrin receptor, and iron regulatory protein (sensor of intracellular iron concentration). The interplay of iron and oxygen is most intriguing in the setting of stroke, where hypoxia and free iron appear to interact in causing the subsequent neuronal death.
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PMID:Ironing-out mechanisms of neuronal injury under hypoxic-ischemic conditions and potential role of iron chelators as neuroprotective agents. 1122 56

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

The blood-brain barrier (BBB) is the rate-limiting step in the translation of neurotrophin neuroscience into clinically effective neurotherapeutics. Since neurotrophins do not cross the BBB, these proteins cannot be used for neuroprotection following intravenous administration, and it is not feasible to administer these molecules by intra-cerebral injection in human stroke. The present studies describe the development of the chimeric peptide brain drug targeting technology and the use of brain-derived neurotrophic factor (BDNF) chimeric peptides in either global or regional brain ischemia. The BDNF chimeric peptide is formed by conjugation of BDNF to a monoclonal antibody (MAb) to the BBB transferrin receptor, and the MAb acts as a molecular Trojan Horse to ferry the BDNF across the BBB via transport on the endogenous BBB transferrin receptor. High degrees of neuroprotection in transient forebrain ischemia, permanent middle cerebral artery occlusion, or reversible middle cerebral artery occlusion are achieved with the delayed intravenous administration of BDNF chimeric peptides. In contrast, no neuroprotection is observed following the intravenous administration of unconjugated BDNF, because the neurotrophin does not cross the BBB in vivo.
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PMID:Blood-brain barrier drug targeting enables neuroprotection in brain ischemia following delayed intravenous administration of neurotrophins. 1257 30

Pretreatment with a low intracerebral dose of thrombin reduces brain edema after hemorrhagic and thrombo-embolic stroke. We have termed this phenomena thrombin preconditioning (TPC) or thrombin-induced brain tolerance. Red blood cell lysis and iron overload contribute to delayed edema formation after intracerebral hemorrhage. The present study examined whether TPC can attenuate the brain edema induced by lysed red blood cells or iron. It also examined whether TPC is associated with increasing hypoxia inducible factor-1alpha (HIF-1alpha) levels and alterations in two HIF-1alpha target genes, transferrin (Tf) and transferrin receptor (TfR), within the brain. Brain edema was measured by wet/dry weight method. HIF-1alpha, Tf, and TfR were measured by Western blot analysis and immunohistochemistry. We found that TPC reduces the edema induced by infusion of lysed red blood cells and iron. Thrombin increases HIF-1alpha levels through p44/42 mitogen activated protein kinases pathway. Thrombin also increases Tf and TfR levels in the brain. These results indicate that HIF-1alpha and its target genes may be involved in thrombin-induced brain tolerance.
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PMID:Thrombin preconditioning attenuates brain edema induced by erythrocytes and iron. 1466 40

Pretreatment with a low dose of thrombin reduces brain edema after both hemorrhagic and ischemic stroke. We call this phenomenon thrombin preconditioning (TPC) or thrombin-induced brain tolerance. The present study examines whether TPC can attenuate the brain edema induced by lysed red blood cells (RBCs) to determine whether thrombin production early in an intracerebral hemorrhage (ICH) might alter potentially injurious events associated with clot resolution. It also examines whether TPC might be protective by altering iron handling within the brain, particularly through modulating transferrin (Tf) and transferrin receptor (TfR) levels. Brain edema was measured by wet/dry weight. Western blot analysis and immunohistochemistry were used for Tf and TfR measurements. We found that TPC reduces lysed RBC-induced brain edema and upregulates both Tf and TfR levels in the brain. Thrombin formation after an ICH may be part of a signaling cascade that acts to limit potentially injurious events associated with clot resolution through altering iron-handling proteins.
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PMID:Thrombin preconditioning upregulates transferrin and transferrin receptor and reduces brain edema induced by lysed red blood cells. 1475 84

Historically, in vivo imaging methods have largely relied on imaging gross anatomy. More recently it has become possible to depict biological processes at the cellular and molecular level. These new research methods use magnetic resonance imaging (MRI), positron emission tomography (PET), near-infrared optical imaging, scintigraphy, and autoradiography in vivo and in vitro. Of primary interest is the development of methods using MRI and PET with which the progress of gene therapy in glioblastoma (herpes simplex virus-thymidine kinase) and Parkinson's disease can be monitored and graphically displayed. The distribution of serotonin receptors in the human brain and the duration of serotonin-receptor antagonist binding can be assessed by PET. With PET, it is possible to localize neurofibrillary tangles (NFTs) and beta-amyloid senile plaques (APs) in the brains of living Alzheimer disease (AD) patients. MR tracking of transplanted oligodendrocyte progenitors is feasible for determining the extent of remyelinization in myelin-deficient rats. Stroke therapy in adult rats with subventricular zone cells can be monitored by MRI. Transgene expression (beta-galactosidase, tyrosinase, engineered transferrin receptor) can also be visualized using MRI. Macrophages can be marked with certain iron-containing contrast agents which, through accumulation at the margins of glioblastomas, ameliorate the visual demarcation in MRI. The use of near-infrared optical imaging techniques to visualize matrix-metalloproteinases and cathepsin B can improve the assessment of tumor aggressiveness and angiogenesis-inhibitory therapy. Apoptosis could be detected using near-infrared optical imaging representation of caspase 3 activity and annexin B. This review demonstrates the need for neurohistological research if further progress is to be made in the emerging but burgeoning field of molecular imaging.
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PMID:Molecular imaging: Bridging the gap between neuroradiology and neurohistology. 1502 22

The high level of expression of transferrin receptors (Tf-R) on the surface of endothelial cells of the blood-brain-barrier (BBB) had been widely utilized to deliver drugs to the brain. The primary aim of this study was to use transferrin receptor mediated endocytosis as a pathway for the rational development of holo-transferrin coupled liposomes for drug targeting to the brain. Citicoline is a neuroprotective agent used clinically to treat for instance Parkinson disease, stroke, Alzheimer's disease and brain ischemia. Citicoline does not readily cross the BBB because of its strong polar nature. Hence, citicoline was used as a model drug. (Citicoline liposomes have been prepared using dipalmitoylphosphatidylcholine (DPPC) or distearoylphosphatidylcholine (DSPC) by dry lipid film hydration-extrusion method). The effect of the use of liposomes composed of DPPC or DSPC on their citicoline encapsulation efficiency and their stability in vitro were studied. Transferrin was coupled to liposomes by a technique which involves the prevention of scavenging diferric iron atoms of transferrin. The coupling efficiency of transferrin to the liposomes was studied. In vitro evaluation of transferrin-coupled liposomes was performed for their radioprotective effect in radiation treated cell cultures. In this study, OVCAR-3 cells were used as a model cell type over-expressing the Tf-R and human umbilical vein endothelial cells (HUVEC) as BBB endothelial cell model. The average diameter of DPPC and DSPC liposomes were 138 +/- 6.3 and 79.0 +/- 3.2 nm, respectively. The citicoline encapsulation capacity of DPPC and DSPC liposomes was 81.8 +/- 12.8 and 54.9 +/- 0.04 microg/micromol of phospholipid, respectively. Liposomes prepared from DSPC showed relatively better stability than DPPC liposomes at 37 degrees C and in the presence of serum. Hence, DSPC liposomes were used for transferrin coupling and an average of 46-55 molecules of transferrin were present per liposome. Free citicoline has shown radioprotective effect at higher doses tested. Interestingly, encapsulation of citicoline in pegylated liposomes significantly improved the radioprotective effect by 4-fold compared to free citicoline in OVCAR-3 but not in HUVEC. Further, citicoline encapsulation in transferrin-coupled liposomes has significantly improved the radioprotective effect by approximately 8-fold in OVCAR-3 and 2-fold in HUVEC cells with respect to the free drug. This is likely due to the entry of citicoline into cells via transferrin receptor mediated endocytosis. In conclusion, our results suggest that low concentrations of citicoline encapsulated in transferrin-coupled liposomes could offer therapeutic benefit in treating stroke compared to free citicoline.
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PMID:Radioprotective effect of transferrin targeted citicoline liposomes. 1660 47

Intravenous brain-derived neurotrophic factor (BDNF) causes a 65-70% reduction in stroke volume in rats with the middle cerebral artery occlusion (MCAO), provided the BDNF is conjugated to a blood-brain barrier (BBB) molecular Trojan horse. The latter may be a peptidomimetic monoclonal antibody (MAb) to the transferrin receptor. The present studies determine whether the effects on stroke volume correlate with an improvement in neuro-behavior using the rotarod test. The rotarod latency was >200 s at 16 RPM in all rats pre-MCAO. The latency was 30+/-7 s and 103+/-9 s at 24 h post-MCAO in the animals treated with BDNF alone and the BDNF-MAb conjugate, respectively. These studies show that when BDNF is formulated to enable transport across the BBB, the intravenous administration of the neurotrophin results in a reduction in stroke volume that is associated with a parallel improvement in functional outcome.
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PMID:Blood-brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion. 1688 98

The essential metals iron, zinc and copper deposit near the Abeta (amyloid beta-peptide) plaques in the brain cortex of AD (Alzheimer's disease) patients. Plaque-associated iron and zinc are in neurotoxic excess at 1 mM concentrations. APP (amyloid precursor protein) is a single transmembrane metalloprotein cleaved to generate the 40-42-amino-acid Abetas, which exhibit metal-catalysed neurotoxicity. In health, ubiquitous APP is cleaved in a non-amyloidogenic pathway within its Abeta domain to release the neuroprotective APP ectodomain, APP(s). To adapt and counteract metal-catalysed oxidative stress, as during reperfusion from stroke, iron and cytokines induce the translation of both APP and ferritin (an iron storage protein) by similar mechanisms. We reported that APP was regulated at the translational level by active IL (interleukin)-1 (IL-1-responsive acute box) and IRE (iron-responsive element) RNA stem-loops in the 5' untranslated region of APP mRNA. The APP IRE is homologous with the canonical IRE RNA stem-loop that binds the iron regulatory proteins (IRP1 and IRP2) to control intracellular iron homoeostasis by modulating ferritin mRNA translation and transferrin receptor mRNA stability. The APP IRE interacts with IRP1 (cytoplasmic cis-aconitase), whereas the canonical H-ferritin IRE RNA stem-loop binds to IRP2 in neural cell lines, and in human brain cortex tissue and in human blood lysates. The same constellation of RNA-binding proteins [IRP1/IRP2/poly(C) binding protein] control ferritin and APP translation with implications for the biology of metals in AD.
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PMID:Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer's disease. 1902 41


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