Dexamethasone Effects on [¹²⁵I]Albumin Distribution in Experimental RG-2 Gliomas and Adjacent Brain

Abstract

Summ ary: A total of 72 RG-2 transplanted gliomas were studied in 58 rats at three time points (1, 30, 240 min) after intravenous injection of [125Ilradioiodinated serum albumin ([125I]RISA). The animals were divided into two groups: a control group that received no treatment and a second group that was treated with five doses of 1.5 mg/kg of dexamethasone over 2.5 days. 687comparison of the tumor influx constants in control an imals and the aqueous diffusion constants of two different size molecules (RISA and amino isobutyric acid) suggests that the "pores" across RG-2 capillaries are large and may not restrict the free diffusion of RISA (estimated minimum pore diameter > 36 nm) and that the total pore area is -6.2 x 10-5 cm2 g-I in RG-2 tumor tissue. The second model, which allows for diffusion and solvent drag of RISA across tumor capillaries and through the tissue, was used to analyze the distribution profiles of RISA in peripheral tumor and adjacent brain. This anal ysis was consistent with a small bulk flow of plasma-de rived edema fluid (capillary filtration rate = 0.8 I·d g-I min -I) and a larger component of free diffusion of RISA ( K = 2 fLl g-I min-I) through pores in the tumor vessels of control animals. Dexamethasone treatment markedly reduced or eliminated the filtration of plasma-derived fluid across tumor capillaries and the movement of RISA through the extracellular space by solvent drag. These effects may be mediated by a reduction in the size of the extracellular space and/or a decrease in the pore size of tumor capillaries and could represent an important mech anism for corticosteroid control of tumor and peri tumoral brain edema.

Model Selection in Magnetic Resonance Imaging Measurements of Vascular Permeability: Gadomer in a 9L Model of Rat Cerebral Tumor

“…Because of its effective size, it should approximate radioiodinated serum albumin (RISA) when used as a measure of vascular permeability. In an examination of changes in RISA distribution in the RG-2 glioma model induced by administration of dexamethasone, Nakagawa et al (1987) determined a mean K i of 0.023670.0089 ml/ g min in untreated rats, approximately twice the value we report for Gadomer in 9L tumors. The extravascular volume in the RG-2 tumor was 0.1377 0.016 mL/g, in approximate agreement with our 9L estimate, and the plasma volume was estimated to be 0.015570.013 mL/g (Nakagawa et al, 1987).…”

“…In an examination of changes in RISA distribution in the RG-2 glioma model induced by administration of dexamethasone, Nakagawa et al (1987) determined a mean K i of 0.023670.0089 ml/ g min in untreated rats, approximately twice the value we report for Gadomer in 9L tumors. The extravascular volume in the RG-2 tumor was 0.1377 0.016 mL/g, in approximate agreement with our 9L estimate, and the plasma volume was estimated to be 0.015570.013 mL/g (Nakagawa et al, 1987). Using a large-vessel hematocrit of 0.45, our corrected estimate for vascular volume of approximately 0.01670.013 ml/ml yields a small-vessel plasma volume of approximately 0.007270.0059, which is smaller than, but not significantly different from, that of Nakagawa et al The RG-2 glioma used by Nakagawa is an aggressive, infiltrating, and nonimmunogenic tumor that is typically wellperfused.…”

Dexamethasone Prevents Hypoxic-Ischemic Brain Damage in the Neonatal Rat

“…A 3-h recovery period with the dam was followed by 3 h in 8% oxygen wit11 92% nitrogen in a plastic chamber inside a neonatal incubator with an air temperature of 37°C. This well-established model of pelinatal cerebral hypoxiaischemia reliably produces ipsilateral infarction of the striatum, thalamus, hippocampus, and overlying cortex (1 [8][9][10][11][12][13][14][15][16][17][18][19][20]. The experimental protocol was approved by the Animal Care Committee of The Hospital for Sick Children.…”

“…Treatment with veIy high doses of glucocorticoids (3-6 n~g/kg dexamethasone or 15-30 mg/kg methylprednisolone) have both reduced pathologic damage induced by experimental spinal cord trauma (5,6) and improved neurologic outcome after human spinal cord injury (7). Reductions in cerebral edema caused by tumors, infarction, pneumothorax, or convulsions with glucocorticoid therapy have also been reported (8)(9)(10)(11)(12). However, until the present study, glucocorticoid therapy did not appear to be effective in reducing brain damage due to cerebral hypoxia-ischemia.…”

“…In our study, we investigated the effect of glucocorticoid administration on the extent of brain damage produced in a perinatal model of cerebral hypoxia-ischemia in the rat (1 [8][9][10][11][12][13][14][15][16][17][18][19][20]. The results demonstrate that in the neonate, rather than exacerbating neuronal damage, glucocorticoid administration before an episode of hypoxia-ischemia actually protects the brain from injury.…”