methylcellulose and Brain-Injuries

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

Intranasal drug delivery provided an alternative and effective approach for the intervention of an intracerebral hemorrhage (ICH). However, the short retention time at the absorption site and slow drug transport in intranasal gel influence the drug bioavailability and outcome of ICH. Herein, we fabricated a novel intranasal gel with oriented drug migration utilizing a charge-driven strategy to attenuate brain injury after ICH. Nicardipine hydrochloride (NCD) was entrapped in chitosan nanoparticles (CS NPs) and dispersed in an HAMC gel. Subsequently, one side of the gel was coated with a positively charged film. The oriented migration of CS NPs in the HAMC gel was determined, and the drug bioavailability was also enhanced. Furthermore, a blood-induced ICH rat model was established to evaluate the therapeutic effect of CS NPs + HAMC composites. Intranasal administration of the CS NPs + HAMC (+) composite showed a stronger neuroprotective effect in terms of brain edema reduction and neural apoptosis inhibition compared to the CS NPs + HAMC composite. These results suggested that the oriented and rapid drug transport from nose to brain can be achieved using the charge-driven strategy, and this intranasal drug delivery system has the potential to provide a new therapeutic strategy for the treatment of ICH.

Topics: Administration, Intranasal; Animals; Brain Injuries; Cerebral Hemorrhage; Chitosan; Drug Carriers; Drug Liberation; Gels; Hyaluronic Acid; Male; Methylcellulose; Nanoparticles; Neuroprotective Agents; Nicardipine; Rats, Sprague-Dawley

Tissue engineering in the post-injury brain represents a promising option for cellular replacement and rescue, providing a cell scaffold for either transplanted or resident cells. We have characterized the use of methylcellulose (MC) as a scaffolding material, whose concentration and solvent were varied to manipulate its physical properties. MC solutions were produced to exhibit low viscosity at 23 degrees C and form a soft gel at 37 degrees C, thereby making MC attractive for minimally invasive procedures in vivo. Degradation and swelling studies in vitro demonstrated a small amount of initial polymer erosion followed by relative polymer stability over the 2-week period tested as well as increased hydrogel mass due to solvent uptake. Concentrations up to 8% did not elicit cell death in primary rat astrocytes or neurons at 1 or 7 days. Acellular 2% MC (30 microl) was microinjected into the brains of rats 1 week after cortical impact injury (velocity = 3 m/s, depth = 2 mm) and examined at 2 days (n = 8; n = 3, vehicle injected) and 2 weeks (n = 5; n = 3, vehicle injected). The presence of MC did not alter the size of the injury cavity or change the patterns of gliosis as compared to injured, vehicle-injected rats (detected using antibodies against GFAP and ED1). Collectively, these data indicate that MC is well suited as a biocompatible injectable scaffold for the repair of defects in the brain.

Topics: Animals; Biocompatible Materials; Brain Injuries; Cells, Cultured; Gels; Glial Fibrillary Acidic Protein; Materials Testing; Methylcellulose; Microscopy, Electron, Scanning; Rats