Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm

Matthew J. McGirt, Gustavo Pradilla, Federico G. Legnani, Quoc Anh Thai, Pablo F. Recinos, Rafael J. Tamargo, Richard E. Clatterbuck

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE: Experimental evidence suggests that intercellular adhesion molecule-1 mediated leukocyte extravasation contributes to the pathogenesis of cerebral vasospasm. Simvastatin, an HMG-CoA reductase inhibitor, decreases intercellular adhesion molecule-1 expression and competitively inhibits leukocyte intercellular adhesion molecule-1 binding. We hypothesized that administration of simvastatin after the onset of subarachnoid hemorrhage (SAH) would attenuate perivascular granulocyte migration and ameliorate cerebral vasospasm in a rabbit model of SAH. METHODS: New Zealand white rabbits (n = 15) underwent injection of autologous blood into the cisterna magna or sham surgery followed by subcutaneous injection of simvastatin (40 mg/kg) or vehicle 30 minutes, 24 hours, and 48 hours after SAH or sham surgery. Seventy-two hours later, basilar artery lumen diameter was measured by in situ perfusion/fixation and image analysis. CD-18 monoclonal antibody stained perivascular granulocytes and macrophages were counted under light microscopy. RESULTS: In vehicle treated rabbits, mean ± standard deviation basilar artery diameter was reduced 3 days after SAH (n = 5) versus sham (n = 5) rabbits (0.49 ± 0.08 mm versus 0.75 ± 0.03 mm, P <0.01). After SAH, mean ± standard deviation basilar artery diameter was greater in simvastatin (n = 5) treated rabbits versus vehicle (n = 5) (0.63 ± 0.04 mm versus 0.49 ± 0.08 mm, P <0.01). In vehicle treated rabbits, SAH resulted in an increase in the mean ± standard deviation perivascular CD18 cell count (sham-vehicle, 2.8 ± 2; SAH-vehicle 90 ± 27; P <0.01). Subcutaneous administration of simvastatin attenuated this increase in perivascular CD18-positive cells after SAH (SAH statin, 41.6 ± 13; SAH vehicle, 90 ± 27; P <0.001). CONCLUSION: Subcutaneous administration of simvastatin after the onset of SAH attenuates perivascular granulocyte migration and ameliorates basilar artery vasospasm after experimental SAH in rabbits. 5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, may potentially serve as agents in the prevention of cerebral vasospasm after SAH.

Original languageEnglish
Pages (from-to)945-949
Number of pages5
JournalNeurosurgery
Volume58
Issue number5
DOIs
Publication statusPublished - May 2006

Fingerprint

Intracranial Vasospasm
Simvastatin
Subarachnoid Hemorrhage
Basilar Artery
Rabbits
Intercellular Adhesion Molecule-1
Granulocytes
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Cisterna Magna
Cell Adhesion Molecules
Subcutaneous Injections
Coenzyme A
Microscopy

Keywords

  • Cerebral vasospasm
  • Intercellular adhesion molecule-1
  • Simvastatin
  • Subarachnoid hemorrhage

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

Cite this

Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm. / McGirt, Matthew J.; Pradilla, Gustavo; Legnani, Federico G.; Thai, Quoc Anh; Recinos, Pablo F.; Tamargo, Rafael J.; Clatterbuck, Richard E.

In: Neurosurgery, Vol. 58, No. 5, 05.2006, p. 945-949.

Research output: Contribution to journalArticle

McGirt, Matthew J. ; Pradilla, Gustavo ; Legnani, Federico G. ; Thai, Quoc Anh ; Recinos, Pablo F. ; Tamargo, Rafael J. ; Clatterbuck, Richard E. / Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm. In: Neurosurgery. 2006 ; Vol. 58, No. 5. pp. 945-949.
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abstract = "OBJECTIVE: Experimental evidence suggests that intercellular adhesion molecule-1 mediated leukocyte extravasation contributes to the pathogenesis of cerebral vasospasm. Simvastatin, an HMG-CoA reductase inhibitor, decreases intercellular adhesion molecule-1 expression and competitively inhibits leukocyte intercellular adhesion molecule-1 binding. We hypothesized that administration of simvastatin after the onset of subarachnoid hemorrhage (SAH) would attenuate perivascular granulocyte migration and ameliorate cerebral vasospasm in a rabbit model of SAH. METHODS: New Zealand white rabbits (n = 15) underwent injection of autologous blood into the cisterna magna or sham surgery followed by subcutaneous injection of simvastatin (40 mg/kg) or vehicle 30 minutes, 24 hours, and 48 hours after SAH or sham surgery. Seventy-two hours later, basilar artery lumen diameter was measured by in situ perfusion/fixation and image analysis. CD-18 monoclonal antibody stained perivascular granulocytes and macrophages were counted under light microscopy. RESULTS: In vehicle treated rabbits, mean ± standard deviation basilar artery diameter was reduced 3 days after SAH (n = 5) versus sham (n = 5) rabbits (0.49 ± 0.08 mm versus 0.75 ± 0.03 mm, P <0.01). After SAH, mean ± standard deviation basilar artery diameter was greater in simvastatin (n = 5) treated rabbits versus vehicle (n = 5) (0.63 ± 0.04 mm versus 0.49 ± 0.08 mm, P <0.01). In vehicle treated rabbits, SAH resulted in an increase in the mean ± standard deviation perivascular CD18 cell count (sham-vehicle, 2.8 ± 2; SAH-vehicle 90 ± 27; P <0.01). Subcutaneous administration of simvastatin attenuated this increase in perivascular CD18-positive cells after SAH (SAH statin, 41.6 ± 13; SAH vehicle, 90 ± 27; P <0.001). CONCLUSION: Subcutaneous administration of simvastatin after the onset of SAH attenuates perivascular granulocyte migration and ameliorates basilar artery vasospasm after experimental SAH in rabbits. 5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, may potentially serve as agents in the prevention of cerebral vasospasm after SAH.",
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T1 - Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm

AU - McGirt, Matthew J.

AU - Pradilla, Gustavo

AU - Legnani, Federico G.

AU - Thai, Quoc Anh

AU - Recinos, Pablo F.

AU - Tamargo, Rafael J.

AU - Clatterbuck, Richard E.

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N2 - OBJECTIVE: Experimental evidence suggests that intercellular adhesion molecule-1 mediated leukocyte extravasation contributes to the pathogenesis of cerebral vasospasm. Simvastatin, an HMG-CoA reductase inhibitor, decreases intercellular adhesion molecule-1 expression and competitively inhibits leukocyte intercellular adhesion molecule-1 binding. We hypothesized that administration of simvastatin after the onset of subarachnoid hemorrhage (SAH) would attenuate perivascular granulocyte migration and ameliorate cerebral vasospasm in a rabbit model of SAH. METHODS: New Zealand white rabbits (n = 15) underwent injection of autologous blood into the cisterna magna or sham surgery followed by subcutaneous injection of simvastatin (40 mg/kg) or vehicle 30 minutes, 24 hours, and 48 hours after SAH or sham surgery. Seventy-two hours later, basilar artery lumen diameter was measured by in situ perfusion/fixation and image analysis. CD-18 monoclonal antibody stained perivascular granulocytes and macrophages were counted under light microscopy. RESULTS: In vehicle treated rabbits, mean ± standard deviation basilar artery diameter was reduced 3 days after SAH (n = 5) versus sham (n = 5) rabbits (0.49 ± 0.08 mm versus 0.75 ± 0.03 mm, P <0.01). After SAH, mean ± standard deviation basilar artery diameter was greater in simvastatin (n = 5) treated rabbits versus vehicle (n = 5) (0.63 ± 0.04 mm versus 0.49 ± 0.08 mm, P <0.01). In vehicle treated rabbits, SAH resulted in an increase in the mean ± standard deviation perivascular CD18 cell count (sham-vehicle, 2.8 ± 2; SAH-vehicle 90 ± 27; P <0.01). Subcutaneous administration of simvastatin attenuated this increase in perivascular CD18-positive cells after SAH (SAH statin, 41.6 ± 13; SAH vehicle, 90 ± 27; P <0.001). CONCLUSION: Subcutaneous administration of simvastatin after the onset of SAH attenuates perivascular granulocyte migration and ameliorates basilar artery vasospasm after experimental SAH in rabbits. 5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, may potentially serve as agents in the prevention of cerebral vasospasm after SAH.

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KW - Cerebral vasospasm

KW - Intercellular adhesion molecule-1

KW - Simvastatin

KW - Subarachnoid hemorrhage

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