Posttreatment with adenovirus-mediated gene transfer of calcitonin gene—related peptide to reverse cerebral vasospasm in dogs

Motoyoshi SatohDepartments of Neurosurgery and Physiology, University of Mississippi Medical Center, Jackson, Mississippi; and Departments of Internal Medicine and Pharmacology, and Cardiovascular Center, University of Iowa College of Medicine; and Veterans Affairs Medical Center, Iowa City, Iowa

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Eddie PerkinsDepartments of Neurosurgery and Physiology, University of Mississippi Medical Center, Jackson, Mississippi; and Departments of Internal Medicine and Pharmacology, and Cardiovascular Center, University of Iowa College of Medicine; and Veterans Affairs Medical Center, Iowa City, Iowa

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Hitoshi KimuraDepartments of Neurosurgery and Physiology, University of Mississippi Medical Center, Jackson, Mississippi; and Departments of Internal Medicine and Pharmacology, and Cardiovascular Center, University of Iowa College of Medicine; and Veterans Affairs Medical Center, Iowa City, Iowa

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Jiping TangDepartments of Neurosurgery and Physiology, University of Mississippi Medical Center, Jackson, Mississippi; and Departments of Internal Medicine and Pharmacology, and Cardiovascular Center, University of Iowa College of Medicine; and Veterans Affairs Medical Center, Iowa City, Iowa

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Yi ChunDepartments of Neurosurgery and Physiology, University of Mississippi Medical Center, Jackson, Mississippi; and Departments of Internal Medicine and Pharmacology, and Cardiovascular Center, University of Iowa College of Medicine; and Veterans Affairs Medical Center, Iowa City, Iowa

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Donald D. HeistadDepartments of Neurosurgery and Physiology, University of Mississippi Medical Center, Jackson, Mississippi; and Departments of Internal Medicine and Pharmacology, and Cardiovascular Center, University of Iowa College of Medicine; and Veterans Affairs Medical Center, Iowa City, Iowa

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John H. ZhangDepartments of Neurosurgery and Physiology, University of Mississippi Medical Center, Jackson, Mississippi; and Departments of Internal Medicine and Pharmacology, and Cardiovascular Center, University of Iowa College of Medicine; and Veterans Affairs Medical Center, Iowa City, Iowa

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Object. Gene transfer to cerebral vessels is a promising new therapeutic approach for cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was undertaken to explore whether a delayed treatment with adenovirus encoding the prepro-calcitonin gene—related peptide (CGRP), 2 days after initial blood injection, reduces cerebral vasospasm in a double-hemorrhage model of severe vasospasm in dogs.

Methods. In 20 dogs, arterial blood was injected into the cisterna magna on Days 0 and 2. Thirty minutes after the second blood injection, the animals received either adenovirus encoding the prepro-CGRP gene (AdCMVCGRP—treated group, eight dogs) or adenovirus encoding the β-galactosidase gene (AdCMVβgal—treated group, six dogs) under the cytomegalovirus (CMV) promoter. One group of dogs did not receive treatment and served as controls (control SAH group, six dogs). Angiography was performed on Days 0 and 7 to assess cerebral vasospasm. On Day 7 following angiography, the animals were killed and their brains were stained with X-gal to detect the distribution of gene expression. Cerebrospinal fluid (CSF) was also tested for CGRP immunoreactivity.

Severe vasospasm was observed in control SAH dogs on Day 7, and the mean basilar artery (BA) diameter was 53.4 ± 5.5% of the value measured on Day 0. Treatment with AdCMVβgal did not alter vasospasm (the BA diameter was 55 ± 3.9% of that measured on Day 0). The leptomeninges and adventitia of the BAs of dogs treated using AdCMVβgal demonstrated positive staining with X-gal. High levels of CGRP were measured in CSF from dogs that received AdCMVCGRP. In the group treated with AdCMVCGRP, vasospasm was significantly reduced (the BA diameter was 78.2 ± 5.3% of that measured on Day 0, p < 0.05 compared with the control SAH group and the AdCMVβgal group).

Conclusions. In a model of severe vasospasm in dogs, gene transfer of CGRP after injection of blood attenuated cerebral vasospasm after SAH.

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