Skip to main content
SpringerLink
Log in

Development of calcitonin gene-related peptide slow-release tablet implanted in CSF space for prevention of cerebral vasospasm after experimental subarachnoid haemorrhage

  • Published:
Acta Neurochirurgica Aims and scope Submit manuscript

Summary

The calcitonin gene-related peptide (CGRP), a known potent intrinsic cerebral vasodilator, is contained in the sensory nerves from trigeminal ganglia that inervate the cerebral arteries. We previously reported that human α CGRP (hCGRP) dilates spastic cerebral arteries after experimental subarachnoid haemorrhage (SAH) in rabbits. In the present study, we investigated the prophylactic potential of a sustained higher cerebrospinal fluid level ofhCGRP against experimental cerebral vasospasm. AnhCGRP slow-release tablet (hCGRP s-r tablet) was developed for cisternal implantation. Experimental SAH was induced by percutaneous cisternal injection of autologous arterial blood. Angiography was initiated on day 1 (before SAH) and performed everyday. ThehCGRP s-r tablet was implanted into the cisterna magna on day 2 in the treated groups. The spastic response of the basilar artery was maximized on day 4 in the non-treated (80.7% of day 1) and the placebo-treated (79.3%) groups. In contrast, the arterial diameters on day 4 were 96.1% and 90.5% of day 1 in the groups implanted withhCGRP 24 μg and 153 μg s-r tablets, respectively. We also measured the concentration ofhCGRP in the cerebrospinal fluid (CSF) following implantation of thehCGRP 24 μg s-r tablet in the cisterna magna. The hCGRP concentration before implantation was below the dectable level. Following implantation, thehCGRP level in the CSF was 23.12 nmol/L on the second day and remained at elevated levels until the fifth day. These experiments suggest that the intrathecal single implantation of thehCGRP s-r tablet could produce an elevated concentration ofhCGRP in the CSF over five days and have prevented the cerebral vasospasm after SAH in the rabbit. ThehCGRP s-r tablet may be clinically applicable in the treatment of patients with SAH against cerebral vasospasm.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Arbab MRA, Wikland L, Svendgaard NA (1986) Origin and distribution of cerebral vascular innervation from superior cervical, trigeminal and spinal ganglia investigated with retrograde and anterograde WGA-HRP tracing in the rat. Neuroscience 19: 695–708

    PubMed  Google Scholar 

  2. Arienta C, Balbi S, Caroli M, Fumagalli G (1991) Depletion of calcitonin gene-related peptide in perivascular nerves during acute phase of posthemorrhagic vasospasm in the rabbit. Brain Res Bull 27: 605–609

    PubMed  Google Scholar 

  3. Asano T, Matsui T, Takuwa Y (1991) Lipid peroxidation, protein kinase C, and cerebral vasospasm. Crit Rev Neurosurg 1: 361–379

    Google Scholar 

  4. Baker KF, Zervas NT, Pile-Spellman J, Vacanti FX, Miller D (1987) Angiographic evidence of basilar artery constriction in the rabbit: a new model of vasospasm. Surg Neurol 27: 107–112

    PubMed  Google Scholar 

  5. Brain SD, Williums TJ, Tippins JR, Morris HR, MacIntyre I (1985) Calcitonin gene-related peptide is a potent vasodilator. Nature 313: 54–56

    PubMed  Google Scholar 

  6. Edvinsson L, Alafaci C, Delgado T, Ekman R, Jansen I, Svendgaard NA, Uddman R (1991) Neuropeptide Y and vasoactive intestinal peptide in experimental subarachnoid haemorrhage: immunocytochemistry, radioimmunoassay and pharmacology. Acta Neurol Scand 83: 103–109

    PubMed  Google Scholar 

  7. Edvinsson L, Delgado T, Ekman R, Jansen I, Svendgaard NA, Uddman R (1990) Involvement of perivascular sensory fibers in the pathophysiology of cerebral vasospasm following subarachnoid hemorrhage. J Cereb Blood Flow Metab 10: 602–607

    PubMed  Google Scholar 

  8. Edvinsson L, Ekman R, Jansen I, Ottosson A, Uddman R (1987) Peptide-containing nerve fibers in human cerebral arteries: immunocytochemistry, radioimmunoassay, and in vitro pharmacology. Ann Neurol 21: 431–437

    PubMed  Google Scholar 

  9. Edvinsson L, Hara H, Uddman R (1989) Retrograde tracing of nerve fibers to the rat middle cerebral artery with true blue: colocalization with different peptides. J Cereb Blood Flow Metab 9: 212–218

    PubMed  Google Scholar 

  10. European CGRP in Subarachnoid Haemorrhage Study Group (1992) Effect of calcitonin-gene-related peptide in patients with delayed postoperative cerebral ischaemia after aneurysmal subarachnoid haemorrhage. Lancet 339: 831–834

    Google Scholar 

  11. Hongo K, Ogawa H, Kassell NF, Nakagomi T, Sasaki T, Tsukahara T, Lehman R (1988) Comparison of intraluminal and extraluminal inhibitory effects of hemoglobin on endothelium-dependent relaxation of rabbit basilar artery. Stroke 19: 1550–1555

    PubMed  Google Scholar 

  12. Hongo K, Tsukahara T, Kassell NF, Ogawa H (1989) Effect of subarachnoid hemorrhage on calcitonin gene-related peptide-induced relaxation in rabbit basilar artery. Stroke 20: 100–104

    PubMed  Google Scholar 

  13. Ichiki Y, Kitamura K, Kangawa K, Kawamoto M, Matsuo H, Eto T (1992) Organ distribution and characterization of porcine peptides (VIP, CGRP and PHI) that increase cAMP in rats platelets. Biochem Biophys Res Commun 187: 1587–1593

    PubMed  Google Scholar 

  14. Johnston EG, Bell BA, Robertson IJA, Miller JD, Haliburn C, O'Shaughnessy D, Riddell AJ, O'Laoire SA (1990) Effect of calcitonin-gene-related peptide on postoperative neurological deficits after subarachnoid haemorrhage. Lancet 335: 869–872

    PubMed  Google Scholar 

  15. Kageyama M, Yanagisawa T, Taira N (1993) Calcitonin gene-related peptide relaxes porcine coronary arteries via cyclic AMP-dependent mechanisms, but not activation of ATP-sensitive potassium channels. J Pharmacol Exp Ther 265: 490–497

    PubMed  Google Scholar 

  16. Kaminuma T, Ehama R, Ochiai N, Banba T, Watabe K, Tajima M, Imaizumi S, Shimizu H, Ahmad I, Yoshimoto T (1994) Controlled release of calcitonin gene-related peptide. Drug Delivery System 9: 275

    Google Scholar 

  17. Kassell NF, Torner JC, Haley EC, Jane JA, Adams HP, Kongable GL (1990) The international cooperative study on the timing of aneurysm surgery. Part 1: overall management results. J Neurosurg 73: 18–36

    PubMed  Google Scholar 

  18. Kassell NF, Torner JC, Jane JA, Haley EC, Adams HP (1990) The international cooperative study on the timing of aneurysm surgery. Part 2: surgical results. J Neurosurg 73: 37–47

    PubMed  Google Scholar 

  19. Kobayashi H, Ide H, Handa Y, Aradachi H, Arai Y, Kubota T (1992) Effect of leukotriene antagonist on experimental delayed cerebral vasospasm. Neurosurgery 31: 550–556

    PubMed  Google Scholar 

  20. Kubota T, Handa Y, Tsuchida A, Kaneko M, Kobayashi H, Kubota T (1993) The kinetics of lymphocyte subsets and macrophages in subarachnoid hemorrhage in rats. Stroke 24: 1993–2000

    PubMed  Google Scholar 

  21. Marshall I (1992) Mechanism of vascular relaxation by the calcitonin gene-related peptide. Ann N Y Acad Sei 657: 204–215

    Google Scholar 

  22. Matsui T, Kaizu H, Itoh S, Asano T (1994) The role of active smooth-muscle contraction in the occurrence of chronic vasospasm in the canine two-hemorrhage model. J Neurosurg 80: 276–282

    PubMed  Google Scholar 

  23. McCulloch J, Kingman T, Uddman R, Edvinsson L (1987) The vasomotor significance of the trigemino-cerebrovascular innervation. J Cereb Blood Flow Metab 7: S225

    Google Scholar 

  24. Minami N, Tani E, Maeda Y, Yamaura I, Fukami M (1992) Effects of inhibitors of protein kinase C and calpain in experimental delayed cerebral vasospasm. J Neurosurg 76: 111–118

    PubMed  Google Scholar 

  25. Minami N, Tani E, Maeda Y, Yamaura I, Nakano A (1993) Immunoblotting of contractile and cytoskeletal proteins of canine basilar artery in vasospasm. Neurosurgery 33: 698–706

    PubMed  Google Scholar 

  26. Nakagomi T, Kassell NF, Hongo K, Sasaki T (1990) Pharmacological reversibility of experimental cerebral vasospasm. Neurosurgery 27: 582–586

    PubMed  Google Scholar 

  27. Nakagomi T, Kassell NF, Sasaki T, Fujiwara S, Lehman RM, Torner JC (1987) Impairment of endothelium-dependent vasodilation induced by acetylcholine and adenosine triphosphate following experimental subarachnoid hemorrhage. Stroke 18: 482–489

    PubMed  Google Scholar 

  28. Naylor AR, Robertson IJA, Edwards CRW, Merrick MV, Sellar RJ, O'Shaughnessy D, Miller JD (1991) Cerebral vasospasm following subarachnoid hemorrhage: effect of calcitonin gene-related peptide on middle cerebral artery velocities using trans-cranial doppler sonography. Surg Neurol 36: 278–280

    PubMed  Google Scholar 

  29. Nishizawa S, Peterson JW, Shimoyama I, Uemura K (1992) Relation between protein kinase C and calmodulin systems in cerebrovascular contraction: investigation of the pathogenesis of vasospasm after subarachnoid hemorrhage. Neurosurgery 31: 711–716

    PubMed  Google Scholar 

  30. Nozaki K, Kikuchi H, Mizuno N (1989) Changes of calcitonin gene-related peptide-like immunoreactivity in cerebrovascular nerve fibers in the dog after experimentally produced subarachnoid hemorrhage. Neurosci Lett 102: 27–32

    PubMed  Google Scholar 

  31. Nozaki K, Okamoto S, Uemura Y, Kikuchi H, Mizuno N (1990) Vascular relaxation properties of calcitonin gene-related peptide and vasoactive intestinal polypeptide in subarachnoid hemorrhage. J Neurosurg 72: 792–797

    PubMed  Google Scholar 

  32. Nozaki K, Uemura Y, Okamoto S, Kikuchi H, Mizuno N (1989) Relaxant effect of calcitonin gene-related peptide on cerebral arterial spasm induced by experimental subarachnoid hemorrhage in dogs. J Neurosurg 71: 558–564

    PubMed  Google Scholar 

  33. Paoletti P, Gaetani P, Grignani B, Pacchiarini L, Silvani V, Rodriguez Y, Baena R (1988) CSF leukotriene C4 following subarachnoid hemorrhage. J Neurosurg 69: 488–93

    PubMed  Google Scholar 

  34. Pasqualin A, Tsukahara T, Kongo K, Van Beek O, Kassell NF, Tomer JC (1992) Cerebrovascular effects of substance P after experimental subarachnoid haemorrhage. Acta Neurochir (Wien) 119: 139–145

    Google Scholar 

  35. Peterson JW, Kwun B, Teramura A, Hackett JD, Morgan JA, Nishizawa S, Bun T, Zervas NT (1989) Immunological reaction against the aging human subarachnoid erythrocyte. J Neurosurg 71: 718–726

    PubMed  Google Scholar 

  36. Pluta RM, Zauner A, Morgan JK, Muraszko KM, Oldfield EH (1992) Is vasospasm related to proliferative arteriopathy? J Neurosurg 77: 740–748

    PubMed  Google Scholar 

  37. Pollay M, Davson H (1963) The passage of certain substances out of the cerebrospinal fluid. Brain 86: 137–150

    PubMed  Google Scholar 

  38. Rasmussen H, Takuwa Y, Park S (1987) Protein kinase C in the regulation of smooth muscle contraction. FASEB J 1: 177–185

    PubMed  Google Scholar 

  39. Saito A, Masaki T, Uchiyama T, Lee T, Goto K (1989) Calcitonin gene-related peptide and vasodilator nerves in large cerebral arteries of cat. J Pharmacol Exp Ther, 248: 455–462

    PubMed  Google Scholar 

  40. Shimizu H, Imaizumi S, Ahmad I, Kaminuma T, Tajima M, Yoshimoto T (1994) Effect of calcitonin gene-related peptide and vasoactive intestinal polypeptide on delayed cerebral vasospasm studied after experimental subarachnoid hemorrhage in rabbits. No Shinkei Geka 22: 131–139

    PubMed  Google Scholar 

  41. Shishido T, Suzuki R, Qian L, Hirakawa K (1994) The role of Superoxide anions in the pathogenesis of cerebral vasospasm. Stroke 25: 864–868

    PubMed  Google Scholar 

  42. Spallone A, Pastore FS (1989) Cerebral vasospasm in a double-injection model in rabbit. Surg Neurol 32: 408–417

    PubMed  Google Scholar 

  43. Takuwa Y, Matsui T, Abe Y, Nagafuji T, Yamashita K, Asano T (1993) Alteration in protein kinase C activity and membrane lipid metabolism in cerebral vasospasm after subarachnoid hemorrhage. J Cereb Blood Flow Metab 13: 409–415

    PubMed  Google Scholar 

  44. Toshima M, Kassell NF, Tanaka Y, Dougherty DA (1992) Effect of intracisternal and intravenous calcitonin gene-related peptide on experimental cerebral vasospasm in rabbits. Acta Neurochir (Wien) 119: 134–138

    Google Scholar 

  45. Tran Dinh YR, Debdi M, Couraud J, Creminon C, Seylaz J, Sercombe R (1994) Time course of variation in rabbit cerebrospinal fluid levels of calcitonin gene-related peptide- and substance P-like immunoreactivity in experimental subarachnoid hemorrhage. Stroke 25: 160–164

    PubMed  Google Scholar 

  46. Tsuji T, Weir BKA, Cook DA (1989) Time-dependent effects of extraluminally-applied oxyhemoglobin and endothelial removal on vasodilator responses in isolated, perfused canine basilar arteries. Pharmacology 38: 101–112

    PubMed  Google Scholar 

  47. Uddman R, Edvinsson L, Ekman R, Kingman T, McCulloch J (1985) Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett 62: 131–136

    PubMed  Google Scholar 

  48. Vollmer DG, Hongo K, Ogawa H, Tsukahara T, Kassell NF (1991) A study of effectiveness of the iron-chelating agent deferoxamine as vasospasm prophylaxis in a rabbit model of subarachnoid hemorrhage. Neurosurgery 28: 27–32

    PubMed  Google Scholar 

  49. Welch K (1963) Secretion of cerebrospinal fluid by choroid plexus of the rabbit. Am J Physiol 205: 617–624

    PubMed  Google Scholar 

  50. Yamaura I, Tani E, Saido TC, Suzuki K, Minami N, Maeda Y (1993) Calpain-calpastatin system of canine basilar artery in vasospasm. J Neurosurg 79: 537–543

    PubMed  Google Scholar 

  51. Yanamoto H, Kikuchi H, Okamoto S, Nozaki K (1992) Preventive effect of synthetic serine protease inhibitor, FUT-175, on cerebral vasospasm in rabbits. Neurosurgery 30: 351–357

    PubMed  Google Scholar 

  52. Zang Q, Hara H, Kobayashi S (1993) Distribution patterns of sensory innervation from the trigeminal ganglion to cerebral arteries in rabbits studied by wheat germ agglutinin-conjugated horseradish peroxidase anterograde tracing. Neurosurgery 32: 993–999

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Tohoku University School of Medicine, Sendai

    I. Ahmad, H. Shimizu & T. Yoshimoto

  2. Department of Neurosurgery, Iwate Prefectoral Isawa Hospital, Iwate

    S. Imaizumi

  3. Shiseido Research Centre, Yokohama, Japan

    T. Kaminuma, N. Ochiai & M. Tajima

Authors
  1. I. Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Imaizumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. Kaminuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N. Ochiai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Tajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T. Yoshimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ahmad, I., Imaizumi, S., Shimizu, H. et al. Development of calcitonin gene-related peptide slow-release tablet implanted in CSF space for prevention of cerebral vasospasm after experimental subarachnoid haemorrhage. Acta neurochir 138, 1230–1240 (1996). https://doi.org/10.1007/BF01809753

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01809753

Keywords

Search

Navigation