Effect of dexamethasone, indomethacin, ibuprofen, and probenecid on carrageenan-induced brain inflammation

1986 ◽  
Vol 65 (5) ◽  
pp. 686-692 ◽  
Author(s):  
Daniel A. Gamache ◽  
Earl F. Ellis
Keyword(s):  
Vascular Permeability ◽  
Brain Inflammation ◽  
Intraventricular Injection ◽  
Normal Brain ◽  
Synthesis Inhibitor ◽  
Peripheral Tissues ◽  
Content Type ◽  
Carbon 14 ◽  
Brain Water ◽  
Fine Print

✓ A model of brain inflammation has recently been developed in mice using intraventricular injection of carrageenan (CAR). This model is characterized by increased brain water and vascular permeability, by neutrophil extravasation, and by evidence of increased pro-inflammatory arachidonic acid metabolites. The purpose of the current experiments was to determine the mechanism(s) by which CAR induces brain inflammation and to determine the utility of the CAR model in testing systemically administered therapeutic agents for their capacity to inhibit brain inflammation. Dexamethasone inhibited the increased brain water but not the increased vascular permeability produced by CAR. Indomethacin, an inhibitor of prostaglandin formation, suppressed peripheral inflammation produced by local injection of CAR but not brain inflammation produced by intraventricular CAR injection. Subsequent studies with carbon-14-labeled indomethacin showed that indomethacin penetrates peripheral tissues but is excluded from normal brain or brains inflamed by injection of CAR. Ibuprofen, another prostaglandin synthesis inhibitor, also had no effect on brain inflammation. Probenecid, an organic acid transport inhibitor, completely inhibited CAR-induced brain inflammation and also slowed brain elimination of intraventricularly administered prostaglandins. These experiments suggest, but do not conclusively prove, that increased prostaglandin formation contributes to brain inflammation. Also, the results with indomethacin and CAR-induced brain inflammation indicate that CAR-induced inflammation may be a useful model for screening for the ability of anti-inflammatory agents to cross the blood-brain barrier and exert their effect on brain inflammation.

Carrageenan-induced brain inflammation

1986 ◽  
Vol 65 (5) ◽  
pp. 679-685 ◽  
Author(s):  
Daniel A. Gamache ◽  
John T. Povlishock ◽  
Earl F. Ellis
Keyword(s):  
Arachidonic Acid ◽  
Vascular Permeability ◽  
Brain Inflammation ◽  
Intraventricular Injection ◽  
Arachidonic Acid Metabolite ◽  
Maximum Increase ◽  
Peripheral Tissues ◽  
Neutrophil Extravasation ◽  
Anti Inflammatory ◽  
The Brain

✓ Administration of the mucopolysaccharide, carrageenan (CAR), into the hind paw of the rat or mouse induces a local inflammation characterized by increased arachidonic acid metabolism, increased vascular permeability, edema, and neutrophil extravasation. Carrageenan-induced hind-paw inflammation is inhibited by prostaglandin synthesis inhibitors, and this assay predicts the clinical success of anti-inflammatory agents in reducing peripheral inflammation. The purpose of this study was to determine if intraventricular injection of CAR would induce brain inflammation similar to that evoked by CAR in peripheral tissues. The present study demonstrates that CAR injection into the ventricles of the mouse brain does in fact induce an inflammatory response very similar to that caused by injection of CAR into the peripheral tissues. The brain response to CAR was dose-dependent, with the maximum increase in cerebrovascular permeability to iodine-125-labeled human serum albumin and percent brain water occurring after injection of 50 µg CAR. As is seen in CAR-induced inflammation of the hind paw, the maximum increase in brain vascular permeability occurred 4 hours after CAR injection. Histological analysis of brains 4 hours after CAR administration showed global neutrophil extravasation into the subarachnoid space and evidence of focal neuronal swelling. Methotrexate-induced neutropenia, however, failed to diminish the permeability response to CAR. Gas chromatographic and mass spectrometric measurements of brain prostaglandins 4 hours after CAR injection revealed a significantly increased level of 6-keto-prostaglandin F1α. These results indicate that a significant increase in prostacyclin, the pro-inflammatory arachidonic acid metabolite, during CAR-induced brain inflammation is likely. These studies suggest that CAR-induced brain inflammation may be a useful model on which to test the efficacy of anti-inflammatory agents in the brain, as well as providing information concerning the mediators and mechanisms by which the brain may sustain inflammatory injury.

The deposition of Hg203-chlormerodrin in experimental brain tumors

1971 ◽  
Vol 35 (3) ◽  
pp. 303-308 ◽  
Author(s):  
Tatsuya Kobayashi ◽  
Louis Bakay ◽  
Joseph C. Lee
Keyword(s):  
Brain Tumors ◽  
Tumor Cells ◽  
Normal Brain ◽  
Intracranial Tumors ◽  
Electron Microscopic ◽  
Electron Microscopic Autoradiography ◽  
Content Type ◽  
Meningeal Tumors ◽  
Vacuolar System ◽  
Fine Print

✓ The deposition of Hg203-chlormerodrin was studied in intracranial tumors in mice induced by implantation of 20-methyl cholanthrene by tissue assay, as well as light microscopic and electron microscopic autoradiography. The investigations were carried out in astrocytomas, glioblastomas, and meningeal tumors. The chlormerodrin content of the tumors exceeded that of normal brain with a significant tumor/brain ratio ranging from 5.8 to 22.5. It was found that the chlormerodrin molecule becomes rapidly incorporated in the tumor cells, with a preference for that portion of the cytoplasm associated with the vacuolar system.

Quantification and pharmacokinetics of blood-brain barrier disruption in humans

1996 ◽  
Vol 85 (6) ◽  
pp. 1056-1065 ◽  
Author(s):  
Bernhard Zünkeler ◽  
Richard E. Carson ◽  
Jeff Olson ◽  
Ronald G. Blasberg ◽  
Hetty Devroom ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Normal Brain ◽  
Content Type ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
Fine Print

✓ Hyperosmolar blood-brain barrier disruption (HBBBD), produced by infusion of mannitol into the cerebral arteries, has been used in the treatment of brain tumors to increase drug delivery to tumor and adjacent brain. However, the efficacy of HBBBD in brain tumor therapy has been controversial. The goal of this study was to measure changes in vascular permeability after HBBBD in patients with malignant brain tumors. The permeability (K1) of tumor and normal brain blood vessels was measured using rubidium-82 and positron emission tomography before and repeatedly at 8- to 15-minute intervals after HBBBD. Eighteen studies were performed in 13 patients, eight with glioblastoma multiforme and five with anaplastic astrocytoma. The HBBBD increased K1 in all patients. Baseline K1 values were 2.1 ± 1.4 and 34.1 ± 22.1 µl/minute/ml (± standard deviation) for brain and tumor, respectively. The peak absolute increases in K1 following HBBBD were 20.8 ± 11.7 and 19.7 ± 10.7 µl/minute/ml for brain and tumor, corresponding to percentage increases of approximately 1000% in brain and approximately 60% in tumor. The halftimes for return of K1 to near baseline for brain and tumor were 8.1 ± 3.8 and 4.2 ± 1.2 minutes, respectively. Simulations of the effects of HBBBD made using a very simple model with intraarterial methotrexate, which is exemplary of drugs with low permeability, indicate that 1) total exposure of the brain and tumor to methotrexate, as measured by the methotrexate concentration-time integral (or area under the curve), would increase with decreasing infusion duration and would be enhanced by 130% to 200% and by 7% to 16%, respectively, compared to intraarterial infusion of methotrexate alone; and 2) exposure time at concentrations above 1 µM, the minimal concentration required for the effects of methotrexate, would not be enhanced in tumor and would be enhanced by only 10% in brain. Hyperosmolar blood-brain barrier disruption transiently increases delivery of water-soluble compounds to normal brain and brain tumors. Most of the enhancement of exposure results from trapping the drug within the blood-brain barrier, an effect of the very transient alteration of the blood-brain barrier by HBBBD. Delivery is most effective when a drug is administered within 5 to 10 minutes after disruption. However, the increased exposure and exposure time that occur with methotrexate, the permeability of which is among the lowest of the agents currently used clinically, are limited and the disproportionate increase in brain exposure, compared to tumor exposure, may alter the therapeutic index of many drugs.

The effects of glucosteroids on experimental cold-induced brain edema.

1971 ◽  
Vol 34 (4) ◽  
pp. 477-487 ◽  
Author(s):  
Robert E. Maxwell ◽  
Don M. Long ◽  
Lyle A. French
Keyword(s):  
Vascular Permeability ◽  
Brain Edema ◽  
Gray Matter ◽  
Dry Weight ◽  
Content Type ◽  
Beneficial Effects ◽  
Primary Reduction ◽  
Wet Weight ◽  
Experimental Brain Edema ◽  
Fine Print

✓ Although the beneficial effects of glucosteroids on brain edema are well documented and generally accepted clinically, investigations into their effects on experimental brain edema have been somewhat contradictory. In this study brain edema was produced by local cortical freezing in animals pretreated with glucosteroids and in untreated animals. Gross estimation of edema, wet weight-dry weight determination, and mechanical planimetry of areas of extravasated dye indicated a statistically significant reduction in edema of both white and gray matter at 24, 48, and 72 hours. Gross estimation of edema indicated a persisting effect with resolution of edema at 5 days in treated animals and from 7 to 12 days in untreated animals. These studies substantiate initial investigations and indicate a primary reduction in brain edema by glucosteroids. At least one of the effects of the glucosteroids appears to be reduction of the abnormal vascular permeability causing brain edema.

Effect of the expression of transforming growth factor-β2 in primary human glioblastomas on immunosuppression and loss of immune surveillance

1992 ◽  
Vol 76 (5) ◽  
pp. 799-804 ◽  
Author(s):  
Marius Maxwell ◽  
Theofanis Galanopoulos ◽  
Janine Neville-Golden ◽  
Harry N. Antoniades
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Immune Surveillance ◽  
Protein Product ◽  
Normal Brain ◽  
Normal Brain Tissue ◽  
Content Type ◽  
Messenger Ribonucleic Acid ◽  
Transforming Growth Factor Β2 ◽  
Fine Print

✓ Glioblastomas are malignant brain tumors that are attended by an immunosuppressed state. The authors have studied the expression of transforming growth factor-β2, which is known to have potent immunosuppressive and angiogenic properties. Transforming growth factor-β2 messenger ribonucleic acid and its protein product are both found to be greatly overexpressed in these tumors and are absent from normal brain tissue. The overexpression of this growth factor may contribute to the escape of neoplastic astrocytes from immune surveillance and, furthermore, to the immunosuppressed state that is characteristic of many of these patients.

Beagle puppy model of intraventricular hemorrhage

1983 ◽  
Vol 58 (6) ◽  
pp. 857-862 ◽  
Author(s):  
Laura R. Ment ◽  
William B. Stewart ◽  
Charles C. Duncan ◽  
David T. Scott ◽  
Richard Lambrecht
Keyword(s):  
Intraventricular Hemorrhage ◽  
The Other ◽  
Prostaglandin Synthetase ◽  
Content Type ◽  
Hemorrhagic Hypotension ◽  
Carbon 14 ◽  
Blood Pressure Responses ◽  
To Receive ◽  
Fine Print

✓ The newborn beagle puppy has been demonstrated to provide a good model for neonatal intraventricular hemorrhage (IVH). A study was designed to determine if indomethacin can prevent IVH and if indomethacin would produce changes in cerebral blood flow (CBF). Newborn beagle puppies were randomized by computer into two groups: one was pretreated with indomethacin, a known inhibitor of prostaglandin synthetase, and the other was saline. The dogs in both groups were then assigned either to undergo hemorrhagic hypotension/volume reexpansion insult or to receive no insult. Twenty percent of all pups receiving indomethacin and undergoing the insult experienced IVH, compared to 71% of the pups undergoing insult that had been pretreated with saline. Significant alterations in the blood pressure responses to the hemorrhagic hypotension/volume reexpansion insult were noted in the former group compared to the saline-pretreated pups subjected to insult. Finally, employing carbon-14 autoradiography for the determination of CBF, it was demonstrated that indomethacin decreases resting CBF of the newborn beagle pups and, in indomethacin-pretreated animals subjected to insult, prevents the increases in CBF seen in the saline-pretreated traumatized pups.

Selective blood-tumor barrier disruption by leukotrienes

1992 ◽  
Vol 77 (3) ◽  
pp. 407-410 ◽  
Author(s):  
Chung-Ching Chio ◽  
Takehiko Baba ◽  
Keith L. Black
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Normal Brain ◽  
Barrier Permeability ◽  
Content Type ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
The Mean ◽  
Fine Print

✓ The authors have previously reported that intracarotid infusion of 5 µg leukotriene C4 (LTC4) selectively increases blood-tumor barrier permeability in rat RG-2 tumors. In this study, rats harboring RG-2 tumors were given 15-minute intracarotid infusions of LTC4 at concentrations ranging from 0.5 µg to 50.0 µg (seven rats in each dose group). Blood-tumor and blood-brain barrier permeability were determined by quantitative autoradiography using 14C aminoisobutyric acid. The transfer constant for permeability (Ki) within the tumors was increased twofold by LTC4 doses of 2.5, 5.0, and 50.0 µg compared to vehicle alone (90.00 ±21.14, 92.68 ± 15.04, and 80.17 ± 16.15 vs. 39.37 ± 6.45 µl/gm/min, respectively; mean ± standard deviation; p < 0.01). No significant change in Ki within the tumors was observed at the 0.5-µg LTC4 dose. Blood-brain barrier permeability was selectively increased within the tumors. At no dose in this study did leukotrienes increase permeability within normal brain. To determine the duration of increased opening of the blood-tumor barrier by LTC4 administration, Ki was measured at 15, 30, and 60 minutes after termination of a 15-minute LTC4 infusion (seven rats at each time point). The mean Ki value was still high at 15 minutes (92.68 ± 15.04 µl/gm/min), but declined at 30 minutes (56.58 ± 12.50 µl/gm/min) and 60 minutes (55.40 ± 8.10 µl/gm/min) after the end of LTC4 infusion. Sulfidopeptide leukotrienes LTC4, LTD4, LTE4 and LTF4 were infused to compare their potency in opening the blood-tumor barrier. The mean leukotriene E4 was the most potent, increasing the permeability value 37½ fold compared with vehicle alone (139.86 ± 23.95 vs. 39.37 ± 6.45 µl/gm/min).

Tumor-associated neurological dysfunction prevented by lazaroids in rats

1991 ◽  
Vol 74 (1) ◽  
pp. 112-115 ◽  
Author(s):  
Wesley A. King ◽  
Keith L. Black ◽  
Kiyonobu Ikezaki ◽  
Scott Conklin ◽  
Donald P. Becker
Keyword(s):  
Vascular Permeability ◽  
Tumor Model ◽  
Neurological Dysfunction ◽  
Control Group ◽  
Content Type ◽  
Brain Tumor Model ◽  
Walker 256 ◽  
Walker 256 Tumors ◽  
Fine Print ◽  
Better Than

✓ The efficacy of U-74006F and U-78517F in the treatment of blood-tumor barrier permeability and tumor-associated neurological dysfunction was evaluated in a brain-tumor model in rats. U-74006F is a 21-aminosteroid and U-78517F is a 2-methylamino chroman. Rats with stereotactically implanted Walker 256 tumors were treated with methylprednisolone, U-74006F, U-78517F, or vehicle (0.05 N HCl) on Days 6 through 10 following implantation. Neurological function and vascular permeability were assessed on Day 10. Methylprednisolone and U-74006F were equally effective at preventing neurological dysfunction compared to the control group (p < 0.01); U-78517F was slightly less effective than U-74006F and methylprednisolone but was significantly better than vehicle in preventing neurological dysfunction. Delivery of methylprednisolone resulted in a significant decrease in tumor vascular permeability (p < 0.006) while U-74006F and U-78517F had no effect on permeability. This suggests that U-74006F and U-78517F prevented tumor-associated neurological dysfunction by a mechanism other than decreasing permeability in tumor capillaries, and that U-74006F or U-78517F could prove useful in the treatment of brain tumors.

The effect of interleukin-2 on the blood-brain barrier in the 9L gliosarcoma rat model

1989 ◽  
Vol 70 (1) ◽  
pp. 92-96 ◽  
Author(s):  
Joseph T. Alexander ◽  
Stephen C. Saris ◽  
Edward H. Oldfield
Keyword(s):  
Blood Brain Barrier ◽  
Interleukin 2 ◽  
Brain Barrier ◽  
High Dose ◽  
Normal Brain ◽  
Content Type ◽  
Tumor Bearing ◽  
Blood Brain ◽  
Significant Difference ◽  
Fine Print

✓ Carbon-14-labeled aminoisobutyric acid was used to determine local blood-to-tissue transfer constants in 22 Fischer rats with intracerebral 9L gliosarcomas that received either high-dose parenteral interleukin-2 (IL-2) or a control injection. In tumor and peritumoral tissue, the transfer constants in the IL-2-treated animals (89.6 ± 14.6 and 35.8 ± 6.0, respectively, mean ± standard error of the mean) were larger (p < 0.05) than in control animals (61.4 ± 6.4 and 14.6 ± 2.2, respectively). In contrast, in normal frontal and occipital tissue contralateral to the tumor-bearing hemisphere, there was no significant difference between the transfer constants in IL-2-treated and control animals. Furthermore, treatment of animals with IL-2 excipient caused no change in permeability as compared to animals treated with Hanks' balanced salt solution. Parenteral injection of IL-2 increases blood-brain barrier disruption in tumor-bearing rat brain but does not increase the vascular permeability of normal brain. Methods to prevent this increased tumor vessel permeability are required before parenteral IL-2 can be used safely for the treatment of primary or metastatic brain tumors.

Decadron in the treatment of cerebral abscess

1976 ◽  
Vol 45 (3) ◽  
pp. 301-310 ◽  
Author(s):  
Gilbert R. C. Quartey ◽  
Jane Anne Johnston ◽  
Bohdan Rozdilsky
Keyword(s):  
Staphylococcus Aureus ◽  
Inflammatory Response ◽  
Streptococcus Pyogenes ◽  
Granulation Tissue ◽  
Medical Literature ◽  
Control Group ◽  
Normal Brain ◽  
Content Type ◽  
Antibiotic Group ◽  
Fine Print

✓ Forty rabbits were inoculated with Streptococcus pyogenes or Staphylococcus aureus to produce cerebral abscesses. One-third of the rabbits received no treatment and served as controls. One-third received dexamethasone (Decadron) plus an appropriate antibiotic. One-third received only the appropriate antibiotic in the same dosage. The animals were sacrificed 10 days after inoculation and the brains examined. In the control group, an abscess at the stage of granulation tissue encapsulation containing the inoculated organisms was found. The surrounding brain showed a marked inflammatory response. In the Decadron plus antibiotic group, necrotic lesions were found containing the inoculated organisms and surrounded by relatively normal brain. In the group treated with antibiotic alone, healed glial scars were found in relatively normal brain. Our findings are discussed with reference to the medical literature regarding the influence of glucocorticoids on the inflammatory response and the efficacy of antibiotics when this response is suppressed.

Sign in / Sign up

Export Citation Format

Share Document