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:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study examines the contribution of anion transporters to the swelling and intracellular acidification of glial cells from an extracellular lactacidosis, a condition well-known to accompany cerebral ischemia and traumatic brain injury. Suspended C6 glioma cells were exposed to lactacidosis in physiological or anion-depleted media, and different anion transport inhibitors were applied. Changes in cell volume and intracellular pH (pH(i)) were simultaneously quantified by flow cytometry. Extracellular lactacidosis (pH 6.2) led to an increase in cell volume to 125.1 +/- 2.5% of baseline within 60 min, whereas the pH(i) dropped from the physiological value of 7.13 +/- 0.05 to 6.32 +/- 0.03. Suspension in Cl(-)-free or HCO(3)(-)/CO(2)-free media or application of anion transport inhibitors [0.1 mM bumetanide or 0.5 mM 4, 4'-diisothio-cyanatostilbene-2,2'-disulfonic acid (DIDS)] did not affect cell volume during baseline conditions but significantly reduced cell swelling from lactacidosis. In addition, the Cl(-)-free or HCO(3)(-)/CO(2)-free media and DIDS attenuated intracellular acidosis on extracellular acidification. From these findings it is concluded that besides the known activation of the Na(+)/H(+) exchanger, activation of the Na(+)-independent Cl(-)/HCO(3)(-) exchanger and the Na(+)-K(+)-Cl(-) cotransporter contributes to acidosis-induced glial swelling and the intracellular acidification. Inhibition of these processes may be of interest for future strategies in the treatment of cytotoxic brain edema from cerebral ischemia or traumatic brain injury.
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PMID:Contribution of anion transporters to the acidosis-induced swelling and intracellular acidification of glial cells. 1085 55

Vascular endothelial growth factor (VEGF) is most promising in therapeutic angiogenesis for ischemic vascular disease. This paper aimed to study VEGF gene therapy for the treatment of cerebral ischemia. The glial cell was chosen as the target cell for gene transfer, and the expression of VEGF was studied in vitro. VEGF plasmid/liposome complexes were constructed by mixing VEGF plasmid with liposome, and then cultured C6 glioma cells were transfected with these complexes by lipofectamine method. As control, the same kind of cells were exposed to liposome only. Immunohistochemistry was performed to both groups at 24, 48 and 72 hours after transfection. The transfected cells expressed VEGF significantly higher than the control. The present result demonstrated the feasibility of choosing the glial cell as the target cell for VEGF gene transfer, and found the rationale for the cerebral VEGF gene therapy.
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PMID:Gene transfer of vascular endothelial growth factor plasmid/liposome complexes in glioma cells in vitro: the implication for the treatment of cerebral ischemic diseases. 1132 55

The objective of this study was to investigate the effects of repeated, short-term ischemia on bradykinin-mediated permeability of the blood-brain barrier (BBB) and the blood-tumor barrier (BTB). The mechanism by which bradykinin transiently opens the BTB, involves B2 receptors, Ca2+ flux, nitric oxide (NO) and cyclic GMP (cGMP). Since global and focal cerebral ischemia are known to increase levels of brain nitric oxide synthase (bNOS) and endothelial nitric oxide synthase (eNOS) we tested the hypothesis that bradykinin may increase the BTB permeability to a greater extent under ischemic rather than nonischemic conditions. The vertebral arteries in female Wistar rats were coagulated immediately after intracerebral implantation of RG2 glioma. Short-term ischemia was produced in some rats by a modification of the four-vessel occlusion procedure for incomplete forebrain ischemia, in which the common carotid arteries were clamped daily for 15 min on days 7, 8 and 9 after tumor implantation, after which reperfusion was allowed. On day 10 after tumor implantation, bradykinin (10 microg kg(-1) min(-1)) or phosphate-buffered saline (PBS) was infused for 15 min into the right carotid artery of anesthetized, sham-operated (nonischemic controls) and ischemic rats, followed by an intravenous bolus (100 microCi kg(-1)) each of [14C]-iodo-antipyrine (IAP), [14C]-dextran or [14C]-aminoisobutyric acid (AIB) to measure regional cerebral blood flow (rCBF), blood volume, or unidirectional transfer constant Ki, respectively, by quantitative autoradiography. A single 15-min ischemic episode significantly decreased rCBF in the tumor center (158.9 +/- 17.33 in control vs. 58.78 +/- 24.45 ml 100 g(-1) min(-1) in ischemic group; p < 0.01) and in the tumor periphery (106.82 +/- 7.34 in control vs. 70.55 +/- 26.66 ml 100 g(-1) min(-1) in ischemic group; p < 0.05). Respective mean blood volume in tumors (11.7 +/- 13.3, 12.7 +/- 14.0, and 13.3 +/- 14.5 microl g(-1)) from ischemic-PBS, nonischemic-bradykinin, and ischemic-bradykinin groups, respectively, was not significantly different; mean blood volume in normal brain (3.7, 3.1 and 3.8 microl g(-1)) was not significantly different among these groups either. Intracarotid infusion of bradykinin following repeated ischemia significantly increased mean Ki, as compared to bradykinin infusion in nonischemic controls, in both the tumor center (36.60 +/- 8.4 vs. 22.90 +/- 4.61 microl g(-1) min(-1), p < 0.05) and in tumor periphery (17.70 +/- 5.93 vs. 8.50 +/- 4.42 microl g(-1) min(-1), p < 0.05). Mean Ki values for tumor center and tumor periphery of ischemic rats receiving intracarotid bradykinin were 3-fold greater than those of nonischemic rats infused with PBS. Immunohistochemical and Western blot analyses showed that repeated, short-term ischemia significantly increased the levels of bNOS in tumor cells and eNOS in tumor capillaries, but neither induced iNOS nor affected B2 receptor levels in tumor cells in vivo, as compared with nonischemic controls. Taken together, these results demonstrate for the first time that repeated, short-term ischemia augments bradykinin-mediated opening of the BTB. We conclude that the elevated intratumoral levels of bNOS and eNOS may 'prime' the NO generating capacity of tumor cells. Consequently, increased de novo synthesis and a correspondingly elevated concentration of NO within the tumor, therefore, may be one mechanistic explanation for the significantly increased, bradykinin-mediated BTB opening under ischemic conditions, reported here.
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PMID:Repeated, short-term ischemia augments bradykinin-mediated opening of the blood-tumor barrier in rats with RG2 glioma. 1154 33

Cytotoxic polyamine-derived amino aldehydes, formed during cerebral ischaemia, damage adjacent tissue (the so-called 'penumbra') not subject to the initial ischaemic insult. One such product is 3-aminopropanal (3-AP), a potent cytotoxin that accumulates in ischaemic brain, although the precise mechanisms responsible for its formation are still unclear. More relevant to the present investigations, the mechanisms by which such a small aldehydic compound might be cytotoxic are also not known, but we hypothesized that 3-AP, having the structure of a weak lysosomotropic base, might concentrate within lysosomes, making these organelles a probable focus of initial toxicity. Indeed, 3-AP leads to lysosomal rupture of D384 glioma cells, a process which clearly precedes caspase activation and apoptotic cell death. Immunohistochemistry reveals that 3-AP concentrates in the lysosomal compartment and prevention of this accumulation by the lysosomotropic base ammonia, NH(3), protects against 3-AP cytotoxicity by increasing lysosomal pH. A thiol compound, N-(2-mercaptopropionyl)glycine, reacts with and neutralizes 3-AP and significantly inhibits cytoxocity. Both amino and aldehyde functions of 3-AP are necessary for toxicity: the amino group confers lysosomotropism and the aldehyde is important for additional, presently unknown, reactions. We conclude that 3-AP exerts its toxic effects by accumulating intralysosomally, causing rupture of these organelles and releasing lysosomal enzymes which initiate caspase activation and apoptosis (or necrosis if the lysosomal rupture is extensive). These results may have implications for the development of new therapeutics designed to lessen secondary damage arising from focal cerebral ischaemia.
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PMID:3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin. 1251 95

To determine the frequency that high-field magnetic resonance (MR) imaging sequences influenced surgical decision making during intraoperative MR-guided surgery. From January 1997 to February 2001, 346 MR-guided procedures were performed using a 1.5-Tesla MR system (NT-ACS, Philips Medical Systems). This system can perform functional MR imaging (fMRI), diffusion weighted imaging (DWI), MR spectroscopy (MRS), MR angiography (MRA), and MR venography (MRV) in addition to T1-weighted, T2-weighted, and turbo FLAIR (fluid-attenuated inversion recovery) imaging. FMRI was used to determine areas of brain activation for language, motor function, and memory. DWI was utilized after tumor resection to exclude cerebral ischemia or infarction. MRS was obtained to identify areas of elevated choline that were suspected to correlate with tumor presence. MRA and MRV localized vascular structures adjacent to tumors prior to resection. The intraoperative procedures performed included 140 brain biopsies of which 82 utilized a trajectory guide and prospective stereotaxy. MRS was used in 42 biopsies (30%), of which 29 had turbo spectroscopic imaging (TSI) and 21 had single voxel spectroscopy (SVS). In all biopsy cases, diagnostic tissue was obtained. There were 103 tumor resections of which 18 (17%) had MRS. Functional MRI was used in 17 cases; 3 biopsies (2%) and 14 planned resections (14%). Speech function was localized in 3 cases, memory function in 3, and motor function in 11. In one case where the motor function of the tongue was intimately involved with a low-grade glioma, resection was not attempted. DWI was used in less than 10% of tumor resections. MRA and MRV were performed in 3 (3%) and 2 (2%) of tumor resections, respectively. The imaging capabilities (i.e., fMRI, DWI, MRA, MRV) associated with high-field intraoperative MR influenced surgical decision making primarily for tumor resections. MRS influenced target selection during brain biopsy.
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PMID:Influence of 1.5-Tesla intraoperative MR imaging on surgical decision making. 1257 Jan 35

Gene therapy involves the transfer of genes into cells with therapeutic intent. Although several methods can accomplish this, vectors based on viruses still provide the most efficient approach. For neurosurgical purposes, preclinical and clinical applications in the areas of glioma therapy, spinal neurosurgery, and neuroprotection for treatment of Parkinson's disease and cerebral ischemia are reviewed. In general, therapies applied in the neurosurgical realm have proven relatively safe, despite occasional, well-publicized cases of morbidity and death in non-neurosurgical trials. However, continued clinical and preclinical research in this area is critical, to fully elucidate potential toxicities and to generate truly effective treatments that can be applied in neurological diseases.
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PMID:Gene therapy: a primer for neurosurgeons. 1292 53

Studies have shown that ebselen is an antiinflammatory and antioxidative agent. Its protective effect has been investigated in oxidative stress related diseases such as cerebral ischemia in recent years. However, experimental evidence also shows that ebselen causes cell death in several different cell types. Whether ebselen will have a beneficial or detrimental effect on cells under ischemic condition is not known. Herein, we studied the effect of ebselen on C6 glioma cells under oxygen and glucose deprivation (OGD), an in vitro ischemic model. We found that ebselen significantly enhanced cell death after 3 h of OGD as observed by lactase dehydrogenase (LDH) release and cellular morphological changes. Further studies revealed that depletion of cellular glutathione level by the combined action of ebselen and OGD played a role in enhanced cell death as demonstrated by the following evidence: (1) cellular GSH was significantly depleted by the combined effort of ebselen and OGD, compared to that of ebselen or OGD insult alone; (2) exogenous addition of N-acetyl cysteine completely diminished the cell damage induced by ebselen and OGD; (3) supplement of glucose, which provides cellular reducing agents and thus maintains cellular GSH level, to the OGD medium diminished C6 cell damage induced by ebselen. We conclude that depleting cellular glutathione plays an important role in ebselen-induced cell death with OGD. Our results suggest that ebselen can have a beneficial or toxic effect, depending on the availability of GSH.
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PMID:Ebselen induced C6 glioma cell death in oxygen and glucose deprivation. 1669 67

In brain, levels of adenosine increase up to 100-fold during cerebral ischemia. Based on in vitro studies, both astrocytes and neurons contribute to this adenosine release. Neurons release adenosine per se whereas astrocytes release adenine nucleotides that are metabolized to adenosine extracellularly. In contrast, inosine is released from both cell types via a nucleoside transporter. C6 glioma cells, which are derived from astrocytes, release inosine but not adenosine. The present study investigated the relative expression of purine metabolizing enzymes and transporters in neurons, astrocytes and C6 glioma cells by real-time PCR analysis. In agreement with the extracellular formation of adenosine and intracellular formation of inosine by astrocytes, the present study showed high expression of ecto 5'-nucleotidase and AMP deaminase type 3 in astrocytes. The lack of adenosine release from C6 glioma cells was consistent with the absence of expression of the AMP-preferring cytosolic 5'-nucleotidase in these cells. The predominance of nitrobenzylthioinosine (NBMPR) insensitive equilibrative nucleoside transport (ENT2) in all three cell types was consistent with the greater activity of this isoform in comparison to NBMPR-sensitive ENT1 in these rat cells. Thus, cell type differences in adenosine formation and release are primarily a function of differences in expression of purinergic enzymes and transporters.
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PMID:Gene expression for enzymes and transporters involved in regulating adenosine and inosine levels in rat forebrain neurons, astrocytes and C6 glioma cells. 1686 52

Dexmedetomidine (Dexmd), a potent and highly specific alpha(2) adrenoreceptor agonist, is an efficient therapeutic agent for sedation. Dexmd has been recently reported to have a neuroprotective effect. Heat shock protein (HSP) 27, a low-molecular weight HSP has been shown to be expressed following cerebral ischemia in astrocytes but not in neurons. HSP27 expression is involved in ischemic tolerance of the brain. This study investigated the effect of Dexmd on HSP27 in rat C6 glioma cells. 12-O-tetradecanoylphorbol-13-actate (TPA), a direct activator of protein kinase C (PKC), stimulated the phosphorylation of HSP27 at Ser82, but not Ser15 in a time-dependent manner. Prostaglandin (PG) E(1) or PGE(2) which activates the adenylyl cyclase-cAMP system as well as forskolin and dibutyryl-cAMP, suppressed the TPA-induced phosphorylation of HSP27. Dexmd reversed the suppression of HSP27 phosphorylation by the adenylyl cyclase-cAMP system. Therefore, these results strongly suggest that Dexmd reverses the suppression of HSP27 phosphorylation by the adenylyl cyclase-cAMP system activation through the inhibition of its system in C6 cells. alpha(2) Adrenoreceptor agonists may therefore show a neuroprotective effect through the modification of HSP27 phosphorylation induced by PKC activation.
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PMID:Alpha2 adrenoreceptor agonist regulates protein kinase C-induced heat shock protein 27 phosphorylation in C6 glioma cells. 1838 48

The effect of hypoxia on glioma growth including pathological changes was investigated in an experimental model of brain ischemia in the rat C6 glioma model. C6 glioma cells were inoculated into the subcortex of adult Wistar rats. Focal cerebral ischemia near the implanted glioma area was induced by permanent middle cerebral artery occlusion (PMCAO). Ten days later, the rats were sacrificed to compare tumor volume of C6 glioma without PMCAO (control group) versus C6 glioma with PMCAO (hypoxia group). The histological features were also observed. The mean tumor volume in the hypoxia group was significantly larger than that in the control group. The most prominent histological finding in the hypoxia group was abundant formation of pseudopalisading around the necrotic areas. Immunohistological examinations showed intensive staining for vascular endothelial growth factor and hypoxia-inducible factor in these pseudopalisading cells. These findings suggest that cerebral ischemia positively modulates glioma mass growth by the formation of pseudopalisading necrosis, a characteristic histological finding of glioblastoma.
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PMID:Cerebral ischemia promotes rich pseudopalisading necrosis in the rat c6 glioblastoma model. 1963


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