Prevention of cerebral vasospasm by local delivery of cromakalim with a biodegradable controlled-release system in a rat model of subarachnoid hemorrhage.

Abstract

OBJECT:

One mechanism that contributes to cerebral vasospasm is the impairment of potassium channels in vascular smooth muscles. Adenosine triphosphate-sensitive potassium channel openers (PCOs) appear to be particularly effective for dilating cerebral arteries in experimental models of subarachnoid hemorrhage (SAH). A mode of safe administration that provides timed release of PCO drugs is still a subject of investigation. The authors tested the efficacy of locally delivered intrathecal cromakalim, a PCO, incorporated into a controlled-release system to prevent cerebral vasospasm in a rat model of SAH.

METHODS:

Cromakalim was coupled to a viscous carrier, hyaluronan, 15% by weight. In vitro release kinetics studies showed a steady release of cromakalim over days. Fifty adult male Sprague-Dawley rats weighing 350-400 g each were divided into 10 groups and treated with various doses of cromakalim or cromakalim/hyaluronan in a rat double SAH model. Treatment was started 30 minutes after the second SAH induction. Animals were killed 3 days after treatment, and the basilar arteries were processed for morphometric measurements and histological analysis.

RESULTS:

Controlled release of cromakalim from the cromakalim/hyaluronan implant at a dose of 0.055 mg/kg significantly increased lumen patency in a dose-dependent manner up to 94 +/- 8% (mean +/- standard error of the mean) of the basilar arteries of the sham group compared with the empty polymer group (p = 0.006). Results in the empty polymer group were not different from those in the SAH-only group, with a lumen patency of 65 +/- 12%. Lumen patencies of the cromakalim-only groups did not differ in statistical significance at low (64 +/- 9%) or high (66 +/- 7%) doses compared to the SAH-only group.

CONCLUSIONS:

Treatment of SAH with a controlled-release cromakalim/hyaluronan implant prevented experimental cerebral vasospasm in this rat double hemorrhage model; this inhibition was dose-dependent. The authors' results confirm that sustained delivery of cromakalim perivascularly to cerebral vessels could be an effective therapeutic strategy in the treatment of cerebral vasospasm after SAH.

• Authors: Ibrahim Omeis, Weiliam Chen, Meena Jhanwar-Uniyal, Renato Rozental, Raj Murali, John M Abrahams
• Journal: Journal of neurosurgery (J Neurosurg) Vol. 110 Issue 5 Pg. 1015-20 (May 2009) ISSN: 0022-3085 [Print] United States
• PMID: 19119878 (Publication Type: Journal Article)

Chemical References

• Potassium Channels
• Vasodilator Agents
• Cromakalim
• Hyaluronic Acid

Topics

• Absorbable Implants
• Animals
• Cromakalim (administration & dosage)
• Drug Delivery Systems
• Hyaluronic Acid
• Male
• Potassium Channels (drug effects)
• Rats
• Rats, Sprague-Dawley
• Subarachnoid Hemorrhage (complications)
• Vasodilator Agents (administration & dosage)
• Vasospasm, Intracranial (prevention & control)