The neuroprotective effects of intrathecal administration of the selective N-type calcium channel blocker ziconotide in a rat model of spinal ischemia.
OBJECTIVE
Spinal cord ischemia and resulting paraplegia represent a major complication associated with surgical repair of the thoracoabdominal aorta. Although the mechanism of spinal neuronal degeneration during ischemia is unclear, it may involve excessive calcium influx via N-type voltage-sensitive calcium channels (VSCCs). The neuroprotective capacity of intrathecal (IT) administration of the selective N-type VSCC blocker ziconotide, previously shown to be potently analgesic, was studied.


METHODS
In a rat aortic occlusion model, spinal cord ischemia was induced for 8, 9, or 10 minutes by occluding the descending thoracic aorta. Ziconotide was administered IT as (1) a continuous infusion of 300 or 600 ng/kg/h initiated 24 hours before ischemia and continuing an additional 24 hours or (2) a 0.3 microgram bolus injected 45 minutes before the induction of ischemia. Animals were allowed to live for 24 hours, and recovery of motor function was evaluated during this period. Spinal cords were processed using a silver impregnation technique and microtubule-associated protein type II (MAP2) immunohistochemistry.


RESULTS
Continuous IT infusion of ziconotide provided significant protection against 8- and 9-minute occlusions, but not 10-minute occlusions, as indicated by recovery of motor function, degree of spinal neuronal degeneration, and loss of MAP2 immunoreactivity. Acute IT pretreatment with ziconotide provided transient protection during the initial 4 hours of reperfusion; however, this protective effect was no longer present at 24 hours.


CONCLUSIONS
These data implicate N-type VSCC activation in spinal neuronal degeneration caused by transient spinal ischemia, because selective blockade of this channel by continuous IT infusion of ziconotide was protective against injurious intervals of spinal ischemia. Based on these findings, ziconotide may provide both neuroprotection and preemptive analgesia for aortic aneurysm surgery.
Burns
L H
LH
Elan Pharmaceuticals, 3760 Haven Avenue, Menlo Park, CA 94025, USA.
Jin
Z
Z
Bowersox
S S
SS
D000704:Analysis of Variance; D000818:Animals; D001013:Aorta, Thoracic; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D007263:Infusions, Parenteral; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D013116:Spinal Cord / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D020960:omega-Conotoxins
D002121:Calcium Channel Blockers; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D010455:Peptides; D020960:omega-Conotoxins; C078452:ziconotide