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.
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References
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
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
Asano T, Matsui T, Takuwa Y (1991) Lipid peroxidation, protein kinase C, and cerebral vasospasm. Crit Rev Neurosurg 1: 361–379
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
Brain SD, Williums TJ, Tippins JR, Morris HR, MacIntyre I (1985) Calcitonin gene-related peptide is a potent vasodilator. Nature 313: 54–56
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Marshall I (1992) Mechanism of vascular relaxation by the calcitonin gene-related peptide. Ann N Y Acad Sei 657: 204–215
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
McCulloch J, Kingman T, Uddman R, Edvinsson L (1987) The vasomotor significance of the trigemino-cerebrovascular innervation. J Cereb Blood Flow Metab 7: S225
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
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
Nakagomi T, Kassell NF, Hongo K, Sasaki T (1990) Pharmacological reversibility of experimental cerebral vasospasm. Neurosurgery 27: 582–586
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
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
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
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
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
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
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
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
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
Pluta RM, Zauner A, Morgan JK, Muraszko KM, Oldfield EH (1992) Is vasospasm related to proliferative arteriopathy? J Neurosurg 77: 740–748
Pollay M, Davson H (1963) The passage of certain substances out of the cerebrospinal fluid. Brain 86: 137–150
Rasmussen H, Takuwa Y, Park S (1987) Protein kinase C in the regulation of smooth muscle contraction. FASEB J 1: 177–185
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
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
Shishido T, Suzuki R, Qian L, Hirakawa K (1994) The role of Superoxide anions in the pathogenesis of cerebral vasospasm. Stroke 25: 864–868
Spallone A, Pastore FS (1989) Cerebral vasospasm in a double-injection model in rabbit. Surg Neurol 32: 408–417
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
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
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
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
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
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
Welch K (1963) Secretion of cerebrospinal fluid by choroid plexus of the rabbit. Am J Physiol 205: 617–624
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
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
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
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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
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DOI: https://doi.org/10.1007/BF01809753