doi:10.1093/brain/awu166
Brain 2014: 137; 1–2
| e304
BRAIN A JOURNAL OF NEUROLOGY
LETTER TO THE EDITOR PACAP-induced migraine: a possible CNS effect? Peer Carsten Tfelt-Hansen Department of Neurology, University of Copenhagen, North Zealand Hospital, Hillerød, Denmark Correspondence to: Peer Carsten Tfelt-Hansen E-mail: [email protected]
‘PACAP38 and VIP receptors are present in cerebral and extracranial arteries (Knutsson and Edvinsson, 2002; Chan et al., 2011), but neither exogenously administered PACAP38 nor VIP caused dilatation of cerebral arteries, suggesting no passage of the peptides across the blood– brain barrier during the experiment. Previous in vitro studies of rat and human cerebral arteries showed that abluminal, but not luminal application of PACAP38 and VIP caused relaxation of smooth muscle
cells of the rat middle cerebral artery (Gra¨nde et al., 2012).Collectively, these data suggest that central effects of PACAP38 and VIP after systemic administration are unlikely in the human being’ (Amin et al., 2014).
Also in a previous study with healthy volunteers, the middle meningeal artery but not the middle cerebral artery, was dilated after PACAP38 infusion (Amin et al., 2012). The presence of receptors for both polypeptides in both extracerebral arteries (middle meningeal artery) and cerebral arteries (middle cerebral artery) combined with an effect on only middle meningeal artery in vivo suggests a barrier between the blood and the muscle cells of the tunica media of the middle cerebral artery. The authors suppose that this presumed barrier, observed with both these polypeptides in man (no effect on middle cerebral artery) (Amin et al., 2012, 2014) and rat (no effect on middle cerebral artery with luminal administration of PACAP38) (Gra¨nde et al., 2012) has the same attributes as the blood–brain barrier, and therefore state that central effects of PACAP38 and vasoactive intestinal polypeptide are unlikely (Amin et al., 2014). Lack of effect of a substance with possible vascular effect on middle cerebral artery (indicating a barrier), however, needs not predict no transport of the substance across the blood–brain barrier. Thus luminal application of PACAP38 in rat middle cerebral artery in vitro did not dilate the artery (Gra¨nde et al., 2012). In contrast, PACAP38 crosses the blood–brain barrier in rat by a specific, saturable mechanism (Banks et al., 1996). PACAP is transported across the blood–brain barrier as an intact peptide to enter the parenchymal space of the brain (Banks et al., 1996). The amount entering the whole brain is only moderate: the per cent intravenous (iv) dose taken up per gram of brain (%iv/g) is only 0.118%, but this is six times more than the %iv/g (0.02%) for morphine (Banks et al., 1996). The amount of PACAP38 entering the brain is sufficient to exert neuroprotection in vivo in animal studies (Brenneman, 2007). Vasoactive intestinal polypeptide
Advance Access publication July 14, 2014 ß The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://brain.oxfordjournals.org/ by guest on September 12, 2015
Sir, The two peptides pituitary adenyl cyclase-activating polypeptide-38 (PACAP) and vasoactive intestinal polypeptide (VIP), given intravenously in humans, both dilate extracerebral cranial arteries, but only PACAP38 (Schytz et al., 2009)—not vasoactive intestinal polypeptide (Rahmannn et al., 2008)—induces migraine-like attacks in patients with migraine. Possible mechanisms for the difference in migraine induction were investigated in a recent crossover study in which 16 of 24 patients with migraine developed migraine after intravenous PACAP infusion, and vasoactive intestinal polypeptide infusion induced migraine in 4 of 24 patients (Amin et al., 2014). Magnetic resonance angiography showed dilatation of the superficial temporal artery and the extracranial part of the middle meningeal artery after both polypeptides whereas there was no effect on the middle cerebral artery with neither polypeptide (Amin et al., 2014). The vasodilatation of the superficial temporal artery and middle meningeal artery was the same for both polypeptides after 20 min but only persisted after 2 h for PACAP38. The migraine-like attacks were treated effectively with subcutaneous sumatriptan (n = 6) and this was associated with a constriction of superficial temporal artery and middle meningeal artery but not middle cerebral artery (Amin et al., 2014). The authors discuss several possible explanations for the difference in migraine induction, including prolonged dilatation of extracerebral arteries combined with sensitization of trigeminal perivascular afferents (Amin et al., 2014). The authors note that:
e304
| Brain 2014: 137; 1–2
References Amin FM, Hougaard A, Schytz HW, Asghar MS, Lundholm E, Parvaiz AI, et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide38. Brain 2014; 137: 779–94. Banks WA, Uchida D, Arimura A, Somogyva´ri-Vigh A, Shioda S. Transport of pituitary adenylate cyclase-activating polypeptide across the blood-brain barrier and the prevention of ischemia-induced death of hippocampal neurons. Ann N Y Acad Sci 1996; 805: 270–7. Brenneman DE. Neuroprotection: a comparative view of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Peptides 2007; 28: 1720–6. Chan KY, Baun M, de Vries R, van den Bogaerdt AJ, Dirven CM, Danser AH, et al. Pharmacological characterization of VIP and PACAP receptors in the human meningeal and coronary artery. Cephalalgia 2011; 31: 181–9. Dogrukol-Ak D, Banks WA, Tuncel N, Tuncel M. Passage of vasoactive intestinal peptide across the blood-brain barrier. Peptides 2003; 24: 437–44. Gra¨nde G, Nilsson E, Edvinsson L. Comparison of responses to vasoactive drugs in human and rat cerebral arteries using myograph and pressurized cerebral artery method. Cephalalgia 2012; 33: 152–9. Knutsson M, Edvinsson L. Distribution of mRNA for VIP and PACAP receptors in human cerebral arteries and cranial ganglia. Neuroreport 2002; 13: 507–9. Maniyar FH, Sprenger T, Monteith T, Schankin C, Goadsby PJ. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain 2014; 137 (Pt 1): 232–41. Rahmann A, Wienecke T, Hansen JM, Fahrenkrug J, Olesen J, Ashina M. Vasoactive intestinal peptide causes marked cephalic vasodilatation, but does not induce migraine. Cephalalgia 2008; 28: 226–36. Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 2009; 132: 16–25.
Downloaded from http://brain.oxfordjournals.org/ by guest on September 12, 2015
crosses the blood–brain barrier in mice by transmembrane diffusion (Dogrukol-Ak et al., 2003) and is also a neuroprotector, but it is generally 100–1000 times less potent than PACAP38 in producing neuroprotection in the brain (Brenneman, 2007). A possible passage of PACAP and vasoactive intestinal polypeptide across the human blood–brain barrier has not been investigated, but animal studies suggest that such an effect could be present (Banks et al., 1996; Dogrukol-Ak et al., 2003); and the lack of an effect of the two polypeptides on the middle cerebral artery in patients with migraine (Amin et al., 2014) most likely does not exclude such an effect, confer the results in rats (Banks et al., 1996; Gra¨nde et al., 2012). In animal studies PACAP and vasoactive intestinal polypeptide have different neuroprotection potency (Brenneman, 2007), and could be different for other brain effects. This could theoretically explain the observation (Amin et al., 2014) that the two vasodilators dilate the extracerebral arteries to the same extent (but with different duration) but only one of these (PACAP) induces migraine-like attacks. I suggest that the possibility of a central effect of migraine-inducing drugs and substances should be investigated further. For nitroglycerin-induced migraine-like attacks in a subset of patients with premonitory symptoms after nitroglycerin, it was recently shown in a PET study that there is brain activation in several regions including the hypothalamus in the premonitory phase (Maniyar et al., 2014). The problem of the exact site of action of PACAP in this human migraine model should be fully elucidated before considering development of e.g. a specific PAC1 receptor antagonist for human use with the perspective of possible later therapeutic use in migraine.
Letter to the Editor
Brain 2014: 137; 1–2
| e304
BRAIN A JOURNAL OF NEUROLOGY
LETTER TO THE EDITOR PACAP-induced migraine: a possible CNS effect? Peer Carsten Tfelt-Hansen Department of Neurology, University of Copenhagen, North Zealand Hospital, Hillerød, Denmark Correspondence to: Peer Carsten Tfelt-Hansen E-mail: [email protected]
‘PACAP38 and VIP receptors are present in cerebral and extracranial arteries (Knutsson and Edvinsson, 2002; Chan et al., 2011), but neither exogenously administered PACAP38 nor VIP caused dilatation of cerebral arteries, suggesting no passage of the peptides across the blood– brain barrier during the experiment. Previous in vitro studies of rat and human cerebral arteries showed that abluminal, but not luminal application of PACAP38 and VIP caused relaxation of smooth muscle
cells of the rat middle cerebral artery (Gra¨nde et al., 2012).Collectively, these data suggest that central effects of PACAP38 and VIP after systemic administration are unlikely in the human being’ (Amin et al., 2014).
Also in a previous study with healthy volunteers, the middle meningeal artery but not the middle cerebral artery, was dilated after PACAP38 infusion (Amin et al., 2012). The presence of receptors for both polypeptides in both extracerebral arteries (middle meningeal artery) and cerebral arteries (middle cerebral artery) combined with an effect on only middle meningeal artery in vivo suggests a barrier between the blood and the muscle cells of the tunica media of the middle cerebral artery. The authors suppose that this presumed barrier, observed with both these polypeptides in man (no effect on middle cerebral artery) (Amin et al., 2012, 2014) and rat (no effect on middle cerebral artery with luminal administration of PACAP38) (Gra¨nde et al., 2012) has the same attributes as the blood–brain barrier, and therefore state that central effects of PACAP38 and vasoactive intestinal polypeptide are unlikely (Amin et al., 2014). Lack of effect of a substance with possible vascular effect on middle cerebral artery (indicating a barrier), however, needs not predict no transport of the substance across the blood–brain barrier. Thus luminal application of PACAP38 in rat middle cerebral artery in vitro did not dilate the artery (Gra¨nde et al., 2012). In contrast, PACAP38 crosses the blood–brain barrier in rat by a specific, saturable mechanism (Banks et al., 1996). PACAP is transported across the blood–brain barrier as an intact peptide to enter the parenchymal space of the brain (Banks et al., 1996). The amount entering the whole brain is only moderate: the per cent intravenous (iv) dose taken up per gram of brain (%iv/g) is only 0.118%, but this is six times more than the %iv/g (0.02%) for morphine (Banks et al., 1996). The amount of PACAP38 entering the brain is sufficient to exert neuroprotection in vivo in animal studies (Brenneman, 2007). Vasoactive intestinal polypeptide
Advance Access publication July 14, 2014 ß The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://brain.oxfordjournals.org/ by guest on September 12, 2015
Sir, The two peptides pituitary adenyl cyclase-activating polypeptide-38 (PACAP) and vasoactive intestinal polypeptide (VIP), given intravenously in humans, both dilate extracerebral cranial arteries, but only PACAP38 (Schytz et al., 2009)—not vasoactive intestinal polypeptide (Rahmannn et al., 2008)—induces migraine-like attacks in patients with migraine. Possible mechanisms for the difference in migraine induction were investigated in a recent crossover study in which 16 of 24 patients with migraine developed migraine after intravenous PACAP infusion, and vasoactive intestinal polypeptide infusion induced migraine in 4 of 24 patients (Amin et al., 2014). Magnetic resonance angiography showed dilatation of the superficial temporal artery and the extracranial part of the middle meningeal artery after both polypeptides whereas there was no effect on the middle cerebral artery with neither polypeptide (Amin et al., 2014). The vasodilatation of the superficial temporal artery and middle meningeal artery was the same for both polypeptides after 20 min but only persisted after 2 h for PACAP38. The migraine-like attacks were treated effectively with subcutaneous sumatriptan (n = 6) and this was associated with a constriction of superficial temporal artery and middle meningeal artery but not middle cerebral artery (Amin et al., 2014). The authors discuss several possible explanations for the difference in migraine induction, including prolonged dilatation of extracerebral arteries combined with sensitization of trigeminal perivascular afferents (Amin et al., 2014). The authors note that:
e304
| Brain 2014: 137; 1–2
References Amin FM, Hougaard A, Schytz HW, Asghar MS, Lundholm E, Parvaiz AI, et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide38. Brain 2014; 137: 779–94. Banks WA, Uchida D, Arimura A, Somogyva´ri-Vigh A, Shioda S. Transport of pituitary adenylate cyclase-activating polypeptide across the blood-brain barrier and the prevention of ischemia-induced death of hippocampal neurons. Ann N Y Acad Sci 1996; 805: 270–7. Brenneman DE. Neuroprotection: a comparative view of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Peptides 2007; 28: 1720–6. Chan KY, Baun M, de Vries R, van den Bogaerdt AJ, Dirven CM, Danser AH, et al. Pharmacological characterization of VIP and PACAP receptors in the human meningeal and coronary artery. Cephalalgia 2011; 31: 181–9. Dogrukol-Ak D, Banks WA, Tuncel N, Tuncel M. Passage of vasoactive intestinal peptide across the blood-brain barrier. Peptides 2003; 24: 437–44. Gra¨nde G, Nilsson E, Edvinsson L. Comparison of responses to vasoactive drugs in human and rat cerebral arteries using myograph and pressurized cerebral artery method. Cephalalgia 2012; 33: 152–9. Knutsson M, Edvinsson L. Distribution of mRNA for VIP and PACAP receptors in human cerebral arteries and cranial ganglia. Neuroreport 2002; 13: 507–9. Maniyar FH, Sprenger T, Monteith T, Schankin C, Goadsby PJ. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain 2014; 137 (Pt 1): 232–41. Rahmann A, Wienecke T, Hansen JM, Fahrenkrug J, Olesen J, Ashina M. Vasoactive intestinal peptide causes marked cephalic vasodilatation, but does not induce migraine. Cephalalgia 2008; 28: 226–36. Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 2009; 132: 16–25.
Downloaded from http://brain.oxfordjournals.org/ by guest on September 12, 2015
crosses the blood–brain barrier in mice by transmembrane diffusion (Dogrukol-Ak et al., 2003) and is also a neuroprotector, but it is generally 100–1000 times less potent than PACAP38 in producing neuroprotection in the brain (Brenneman, 2007). A possible passage of PACAP and vasoactive intestinal polypeptide across the human blood–brain barrier has not been investigated, but animal studies suggest that such an effect could be present (Banks et al., 1996; Dogrukol-Ak et al., 2003); and the lack of an effect of the two polypeptides on the middle cerebral artery in patients with migraine (Amin et al., 2014) most likely does not exclude such an effect, confer the results in rats (Banks et al., 1996; Gra¨nde et al., 2012). In animal studies PACAP and vasoactive intestinal polypeptide have different neuroprotection potency (Brenneman, 2007), and could be different for other brain effects. This could theoretically explain the observation (Amin et al., 2014) that the two vasodilators dilate the extracerebral arteries to the same extent (but with different duration) but only one of these (PACAP) induces migraine-like attacks. I suggest that the possibility of a central effect of migraine-inducing drugs and substances should be investigated further. For nitroglycerin-induced migraine-like attacks in a subset of patients with premonitory symptoms after nitroglycerin, it was recently shown in a PET study that there is brain activation in several regions including the hypothalamus in the premonitory phase (Maniyar et al., 2014). The problem of the exact site of action of PACAP in this human migraine model should be fully elucidated before considering development of e.g. a specific PAC1 receptor antagonist for human use with the perspective of possible later therapeutic use in migraine.
Letter to the Editor
