[Frontiers in Bioscience E2, 1502-1513, June 1, 2010]

Intranasal delivery of calcitonin gene-related peptide reduces cerebral vasospasm in rats

Bao-liang Sun1, Fa-ping Shen1,2, Qing-jian Wu1,3, Shu-mei Chi1,4, Ming-feng Yang1, Hui Yuan1, Fang-min Xie1,5, Yan-bo Zhang1, Jun Chen6, Feng Zhang6

1Key Laboratory of Cerebral Microcirculation at the Universities of Shandong, Department of Neurology, Affiliated Hospital of Taishan Medical College, Taian, Shandong 271000, China, 2Longnan Hospital, Daqing Oil Field General Hospital Group, Daqing, Heilongjiang 163001, China, 3Department of Neurology, Central Hospital of Jining, Jining, Shandong 272000, China, 4Department of Neurology, Central Hospital of Binzhou, Binzhou, Shandong 251700, China, 5Department of Neurosurgery, Affiliated Hospital of Taishan Medical College, Taian, Shandong 271000, China, 6Department of Neurology and Center for Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
Materials and Methods
3.1. Animals and physiologic parameter monitoring
3.2. Intranasal administration of CGRP
3.3. Measurement of CGRP distribution in CSF, blood and brain tissues
3.4. Rat model of SAH
3.5. Measurement of basilar artery diameter
3.6. Measurement of regional cerebral blood flow
3.7. Cell death assay
3.8. Measurement of circulating endothelial cells
3.9. Immunohistochemistry
3.10. Western blot
3.11. VEGF mRNA measurement
3.12. Statistical analysis
Results
4.1. Intranasal administration of CGRP was more efficient than IV injection in its delivery to CSF and brain
4.2. CGRP attenuated vasospasm in SAH
4.3. CGRP reduced cortical cell death after SAH
4.4. CGRP decreased endothelial death in vasospasm and SAH
4.5. CGRP upregulated VEGF transcription and expression
Discussion
Acknowledgements
References

1. ABSTRACT

Cerebral vasospasm is the primary cause of sequelae and poor clinical conditions of subarachnoid hemorrhage (SAH); therefore, it is imperative to relieve vasospasm and improve cerebral blood supply. Calcitonin gene-related peptide (CGRP) is a potent vasodilator that is normally released by trigeminal sensory fibers but depleted following SAH. We propose that intranasal application may be an effective way to deliver CGRP to the brain and ameliorate vasospasm after SAH. In this study, we intranasally applied CGRP to rats and induced SAH by double-injection of autologous blood into the cisterna magna. Compared to intravenous injection, intranasal delivery led to a 10-fold higher level of CGRP in the brain. Intranasal CGRP significantly ameliorated vasospasm, improved cerebral blood flow, and reduced cortical and endothelial cell death. Moreover, CGRP increased the levels of vascular endothelial growth factor and stimulated angiogenesis. Altogether, our data demonstrate that intranasal CGRP delivery is a promising method for moderating vasospasm and reducing the associated ischemic brain injury after SAH in rats, and suggest that it may be a potential approach in clinic.