methylcellulose and Hypoxia

Hypoxic-ischemic encephalopathy (HIE) in newborns is associated with high morbidity and mortality, with many babies suffering long-term neurological deficits. Currently, treatment options are limited to therapeutic hypothermia, which is not appropriate for use in all babies. Previous studies have shown protective effects of increasing the transcription factor-hypoxia-inducible factor-1 (HIF-1) in animal models, by using mild hypoxia or compounds that act as prolyl hydroxylase inhibitors (PHIs). Here, we aimed to examine the neuroprotective actions of an orally active, small molecule PHI, GSK1120360A in a neonatal rat model of hypoxia-ischemia (HI) compared to another PHI, desferrioxamine (DFX). Sprague-Dawley rats underwent HI surgery on postnatal day 7 (P7), where unilateral carotid artery occlusion was performed followed by hypoxia (8% oxygen, 3 h). Initial testing showed that GSK1120360A and erythropoietin levels were detectable in plasma at 6 h following oral exposure to GSK1120360A. For the short-term neuroprotection study, pups were assigned to receive either saline (s.c), desferrioxamine (DFX-200 mg/kg, s.c), methylcellulose (1%, oral) or GSK1120360A (30 mg/kg, oral) immediately after HI. Histological analysis showed that GSK1120360A in this setting reduced brain injury size 7 days after HI, compared to the methylcellulose vehicle control group. DFX had no significant effect on injury size compared to saline group at the same 7 day timepoint. In the long-term neuroprotection study, pups were randomly assigned to be administered methylcellulose (1%, oral) or GSK1120360A (30 mg/kg, oral) immediately after HI. On P42, rats underwent behavioural testing using the forelimb grip strength, grid walking and novel object recognition tasks, and brains were collected for histological analysis. Long-term behavioural deficits were observed in grid walking, grip strength and novel object recognition tests after HI which were not improved in the GSK1120360A treatment group compared to the methylcellulose group. Similarly, there was no improvement in injury size on P42 in the GSK1120360A study group compared to the methylcellulose group. Here, we have shown that GSK1120360A can reduce brain injury at 7 days but that this neuroprotective benefit is not maintained when examined at 5 weeks after HI.

Topics: Animals; Animals, Newborn; Brain; Brain Injuries; Deferoxamine; Hypoxia; Hypoxia-Ischemia, Brain; Methylcellulose; Neuroprotective Agents; Prolyl-Hydroxylase Inhibitors; Rats; Rats, Sprague-Dawley

The macromolecular polymer, methyl cellulose (MC), is a known hepatosplenomegalic agent which promotes a state of experimental hypersplenism in rats. This is characterized by massive splenomegaly, pancytopenia of the blood elements, medullary hypoplasia, and marked gross and histologic alteration of the liver, kidney, adrenals, and lungs. Massive splenomegaly results from storage of this inert material by splenic macrophages. In the present study, chronic MC administration in rats augmented the hepatic Ep response to hypoxia but did not appreciably affect renal production of Ep. Splenectomy resulted in a decrease in the extrarenal Ep response to hypoxia indicating a possible role of the massively enlarged spleen of these MC-treated rats in extrarenal Ep production. The augmentation of extrarenal Ep elaboration may be attributed to a stimulatory effect of MC on the hepatic and splenic macrophages.

Topics: Animals; Erythropoietin; Female; Hematocrit; Hypoxia; Kidney; Liver; Methylcellulose; Rats; Spleen

Splenomegaly accompanied by anaemia, increased reticulocyte and decreased thrombocyte counts, was induced in Wistar rats by a long-term intraperitoneal administration of methylcellulose. Compared to controls, hypersplenic rats showed significantly enhanced utilization of 59-Fe by red cells and increased titre of erythropoietin. After the exposure of rats to hypoxic hypoxia corresponding to an altitude of 7,000 m for 6 h, no difference in the erythropoietin titre was found in either group. The results suggest that experimental hypersplenism alone does not affect the production of erythropoietin and does not stimulate the formation of an inhibitor of erythropoietin or erythropoiesis. The increased titre of erythropoietin and enhanced utilization of radioiron by red cells in rats with hypersplenism were found to be due to haemolytic anaemia leading to the stimulation of erythropoiesis.

Topics: Anemia, Hemolytic; Animals; Erythrocytes; Erythropoiesis; Erythropoietin; Hypersplenism; Hypoxia; Iron; Male; Methylcellulose; Rats