Transport of the pituitary adenylate cyclase-activating polypeptide across the blood-brain barrier: implications for migraine

TY - JOUR

T1 - Transport of the pituitary adenylate cyclase-activating polypeptide across the blood-brain barrier

T2 - implications for migraine

AU - Amin, Faisal Mohammad

AU - Schytz, Henrik Winther

PY - 2018/12/1

Y1 - 2018/12/1

N2 - BACKGROUND: Pituitary adenylate cyclase-activating polypeptide (PACAP) is widely distributed in the nervous system and is involved in migraine pathophysiology. Understanding the function of the blood-brain barrier (BBB) in relation to PACAP is important to the understand the mechanisms behind PACAP-induced migraine attacks, but also to develop antimigraine drugs targeting the PACAP receptors Here, we aim to review the transport ability of PACAP across the BBB.METHODS: We performed a systematic literature search on PubMed to identify studies reporting original data on PACAP and BBB. The search was finalized in July 2017.RESULTS: The literature search identified 96 papers of which 11 contained relevant data. In addition, two papers were known to be relevant and were included. A total of 13 papers studies were included in the final analysis. Preclinical studies (n = 10) suggest the existence of specific PACAP transport systems across the BBB, while human PACAP studies failed to show vasodilator effect of PACAP on the cerebral arteries from the lumen (n = 3).CONCLUSION: PACAP38 is transported over the BBB actively, while PACAP27 cross the BBB by diffusion over the membrane, but after crossing the endothelial membrane both isoforms are either rapidly degraded or efflux back from brain to blood. Thus, a direct central action of the PACAPs is unlikely. This is supported by studies showing selective PACAP effect on extra-cerebral arteries.

AB - BACKGROUND: Pituitary adenylate cyclase-activating polypeptide (PACAP) is widely distributed in the nervous system and is involved in migraine pathophysiology. Understanding the function of the blood-brain barrier (BBB) in relation to PACAP is important to the understand the mechanisms behind PACAP-induced migraine attacks, but also to develop antimigraine drugs targeting the PACAP receptors Here, we aim to review the transport ability of PACAP across the BBB.METHODS: We performed a systematic literature search on PubMed to identify studies reporting original data on PACAP and BBB. The search was finalized in July 2017.RESULTS: The literature search identified 96 papers of which 11 contained relevant data. In addition, two papers were known to be relevant and were included. A total of 13 papers studies were included in the final analysis. Preclinical studies (n = 10) suggest the existence of specific PACAP transport systems across the BBB, while human PACAP studies failed to show vasodilator effect of PACAP on the cerebral arteries from the lumen (n = 3).CONCLUSION: PACAP38 is transported over the BBB actively, while PACAP27 cross the BBB by diffusion over the membrane, but after crossing the endothelial membrane both isoforms are either rapidly degraded or efflux back from brain to blood. Thus, a direct central action of the PACAPs is unlikely. This is supported by studies showing selective PACAP effect on extra-cerebral arteries.

KW - Animals

KW - Blood-Brain Barrier/metabolism

KW - Brain/metabolism

KW - Cerebral Arteries/metabolism

KW - Humans

KW - Migraine Disorders/metabolism

KW - Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism

KW - Protein Transport/physiology

KW - Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism

U2 - 10.1186/s10194-018-0861-3

DO - 10.1186/s10194-018-0861-3

M3 - Review

C2 - 29785578

SN - 1129-2369

VL - 19

SP - 1

EP - 6

JO - Journal of Headache and Pain

JF - Journal of Headache and Pain

IS - 1

M1 - 35

ER -