Effect of osmotic blood-brain barrier disruption on gentamicin penetration into the cerebrospinal fluid and brains of normal rabbits

Abstract

Rapid infusion of hyperosmolar solutions into the internal carotid artery transiently disrupts the blood-brain barrier, permitting entry of substances that are ordinarily excluded from the nervous system. This study compared gentamicin concentrations in the cerebrospinal fluid (CSF) and brain tissue of rabbits receiving intracarotid infusions of 2 molal mannitol with those in three groups of control animals. After catheter placement and intravenous gentamicin administration (20 mg/kg), rabbits received either 2 molal mannitol in the internal carotid artery, 2 molal mannitol intravenously, 0.9%o saline in the internal carotid artery, or 0.9%o saline intravenously. Mannitol and saline were administered in 8-ml bolus injections over 40 s. After 2 h, serum, CSF, and brain specimens were obtained for antibiotic assay, Gentamicin concentrations in serum were comparable in all groups (mean concentrations ranged from 14.6 to 17.9 ,ug/ml at 60 min and from 5.7 to 7.4 g/ml at 135 min), but gentamicin concentrations in CSF and brains were significantly higher in animals in the group receiving mannitol in the internal carotid artery. In this group the mean gentamicin concentration in CSF, 5.3 ,ug/ml, was twofold greater than those in the other three groups (range, 1.7 to 2.6 ,ug/ml). Similarly, the mean gentamicin concentration in the brains of animals in the group receiving mannitol in the internal carotid artery, 2.3 ,ug/g was significantly higher than those in the other groups (mean of measurable values, 1.4 pug/g, in all three control groups). Osmotic disruption of the blood-brain barrier enhanced the penetration of gentamicin into CSF and brain tissue.

The designer aminoglycoside NB84 significantly reduces glycosaminoglycan accumulation associated with MPS I-H in the Idua-W392X mouse

“…Megalin is expressed in epithelial cells, including the choroid plexus modified ependymal cells that line the cerebral ventricles, which directs a portion of circulating aminoglycosides to the cerebrospinal fluid (CSF) [52]. In healthy animal models, aminoglycosides accumulate in the CSF at levels that are approximately 20% of serum aminoglycoside levels [53, 54]. Based on those results, we expected at least a portion of the aminoglycosides that we tested to cross the blood-brain barrier.…”

Characterization of an MPS I-H knock-in mouse that carries a nonsense mutation analogous to the human IDUA-W402X mutation

“…However, stem cell transplantation is currently the only therapy shown to prevent neurological deterioration in MPS I-H patients, since exogenously supplied α-L-iduronidase cannot cross the blood-brain barrier [45, 46]. Because some of the compounds previously shown to suppress premature stop mutations can cross the blood-brain barrier to some extent [47-52], this therapeutic approach might be a way to alleviate the neurological phenotype in MPS I-H patients that carry nonsense mutations. Since the Idua-W392X mouse has several quantifiable phenotypes that could be conveniently monitored, this mouse model may provide a useful tool to evaluate the effectiveness of suppression therapy for MPS I-H, either alone or in conjunction with other therapeutic approaches.…”

α-l-Iduronidase Premature Stop Codons and Potential Read-Through in Mucopolysaccharidosis Type I Patients

“…This strategy has the potential to generate a residual level of normal a-L-iduronidase protein and activity in affected MPS I patients. Gentamicin can cross the blood brain barrier (albeit with low permeability), 42 but the new compound PTC124 has been reported to be more easily absorbed with fewer side-effects †. This therapy has the potential to address brain pathology that is not accessible by intravenous administration of enzyme replacement therapy.…”