Neuroprotection by Intrathecal Application of Liposome-entrapped Fasudil in a Rat Model of Ischemia.
- 1 January 2001
- journal article
- Published by Japan Neurosurgical Society in Neurologia medico-chirurgica
- Vol. 41 (3), 107-114
- https://doi.org/10.2176/nmc.41.107
Abstract
Pharmacological treatment for cerebral ischemia cannot attain sufficiently high concentrations of the drugs in the cerebrospinal fluid (CSF) without precipitating systemic side effects. The objective of this study is the development of a liposomal drug delivery system that maintains effective concentrations of protein kinase inhibitors fasudil in the CSF, resulting in neuroprotection against cerebral ischemia. Focal cerebral ischemia in rats was induced by middle cerebral artery occlusion using an intraluminal suture technique. Treated rats received 0.25 mg liposome-entrapped fasudil via the cisterna magna 2 hours after ischemic insult. Control rats received drug-free liposomes. Neurological condition and the infarct size were assessed at 24 and 72 hours after ischemia. The concentration of liposome-entrapped fasudil in the CSF was measured before sacrifice. Treated animals showed significantly improved neurological outcomes after the 24-hour observation period compared to the control group (p < 0.001). Treatment with 0.25 mg liposomal fasudil resulted in a reduction in the infarct area (24 hours: 29.0 ± 4.4%, 72 hours: 28.1 ± 3.9% of total brain slices) compared to controls (49.6 ± 4.6%, p < 0.001), but there was no statistical difference between 24 and 72 hours. At 24 hours post-administration, CSF concentrations of liposome-entrapped fasudil were 45.4 ± 31.5 μg/ml (20% of the injected dose). A single intrathecal injection of liposomal fasudil can maintain a therapeutic drug concentration in the CSF over a period of time, significantly decreasing infarct size in a rat model of acute ischemia.Keywords
This publication has 23 references indexed in Scilit:
- Inhibition of Neutrophil Migration by a Protein Kinase Inhibitor for the Treatment of Ischemic Brain InfarctionThe Japanese Journal of Pharmacology, 1999
- Polyethylene Glycol-Liposomal DoxorubicinDrugs, 1997
- LiposomenDrugs, 1997
- Attenuated neuropathology by nilvadipine after middle cerebral artery occlusion in rats.Stroke, 1991
- Liposome-entrapped superoxide dismutase reduces cerebral infarction in cerebral ischemia in rats.Stroke, 1990
- Reversible middle cerebral artery occlusion without craniectomy in rats.Stroke, 1989
- Determination of rat cerebrospinal fluid concentrations of adenosine, inosine, hypoxanthine, xanthine and uric acid by high performance liquid chromatographyJournal of Pharmacy and Pharmacology, 1988
- Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats.Stroke, 1986
- Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination.Stroke, 1986
- Evaluation of the efficacy of intrathecal nimodipine in canine models of chronic cerebral vasospasmJournal of Neurosurgery, 1985