Dissociation between vasospasm and functional improvement in a murine model of subarachnoid hemorrhage.
OBJECTIVE
The efficacy of nimodipine was examined in a murine model of subarachnoid hemorrhage (SAH). End points included the diameter of the lumen of the middle cerebral artery (MCA) and behavioral outcome. An apolipoprotein E (apoE)-mimetic peptide, acetyl-AS-Aib-LRKL-Aib-KRLL-amide, previously shown to have promise in this model was tested both alone and in combination with nimodipine. The effects of carboxyamidotriazole (CAI), a non-voltage-gated calcium channel blocker, were explored using the same animal paradigm.


METHODS
Experimental SAH was induced in male C57B1/6J mice. For 3 days postoperatively, behavioral analyses were performed. In the first experiment, the mice were treated with vehicle or with low- or high-dose CAI for 3 days. In the second experiment, the mice were treated with vehicle, high- and low-dose nimodipine, and/or the apoE-mimetic peptide. On postoperative Day 3 each mouse was killed and perfused. Following this, the right MCA was removed and its lumen measured. Mice that received nimodipine demonstrated significant behavioral improvements when compared with vehicle-treated mice, but there was no clear dose-dependent effect on MCA diameter. Administration of the apoE-mimetic peptide was associated with improved functional performance and a significant reduction in vasospasm. Mice that received high-dose CAI performed worse on functional tests, despite a significant increase in the diameters of their MCA lumina.


CONCLUSIONS
These results demonstrate a dissociation between vasospasm and neurological outcomes that is consistent with findings of previous clinical trials.
Mesis
Rachel G
RG
Multidisciplinary Neuroprotection Laboratories and the Department of Medicine (Neurology), Duke University Medical Center and Duke University School of Medicine, Durham, North Carolina, USA.
Wang
Haichen
H
Lombard
Frederick W
FW
Yates
Robert
R
Vitek
Michael P
MP
Borel
Cecil O
CO
Warner
David S
DS
Laskowitz
Daniel T
DT
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000737:chemistry; D001522:Behavior, Animal; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000473:pathology; D009460:Neurologic Examination; D009553:Nimodipine / Q000627:therapeutic use; D010455:Peptides / Q000627:therapeutic use; D011930:Reaction Time / Q000187:drug effects; D045442:Rotarod Performance Test / Q000379:methods; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*
D000959:Antihypertensive Agents; D001057:Apolipoproteins E; D002121:Calcium Channel Blockers; D010455:Peptides; D014230:Triazoles; D009553:Nimodipine; C062058:carboxyamido-triazole