TY - JOUR
T1 - Pituitary Adenylate Cyclase-Activating Polypeptide Attenuates Brain Edema by Protecting Blood–Brain Barrier and Glymphatic System After Subarachnoid Hemorrhage in Rats
AU - Fang, Yuanjian
AU - Shi, Hui
AU - Ren, Reng
AU - Huang, Lei
AU - Okada, Takeshi
AU - Lenahan, Cameron
AU - Gamdzyk, Marcin
AU - Travis, Zachary D.
AU - Lu, Qin
AU - Tang, Lihui
AU - Huang, Yi
AU - Zhou, Keren
AU - Tang, Jiping
AU - Zhang, Jianmin
AU - Zhang, John H.
N1 - Publisher Copyright:
© 2020, The American Society for Experimental NeuroTherapeutics, Inc.
PY - 2020/10
Y1 - 2020/10
N2 - Brain edema is a vital contributor to early brain injury after subarachnoid hemorrhage (SAH), which is responsible for prolonged hospitalization and poor outcomes. Pharmacological therapeutic targets on edema formation have been the focus of research for decades. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to participate in neural development and brain injury. Here, we used PACAP knockout CRISPR to demonstrate that endogenous PACAP plays an endogenous neuroprotective role against brain edema formation after SAH in rats. The exogenous PACAP treatment provided both short- and long-term neurological benefits by preserving the function of the blood–brain barrier and glymphatic system after SAH. Pretreatment of inhibitors of PACAP receptors showed that the PACAP-involved anti-edema effect and neuroprotection after SAH was facilitated by the selective PACAP receptor (PAC1). Further administration of adenylyl cyclase (AC) inhibitor and sulfonylurea receptor 1 (SUR1) CRISPR activator suggested that the AC–cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) axis participated in PACAP signaling after SAH, which inhibited the expression of edema-related proteins, SUR1 and aquaporin-4 (AQP4), through SUR1 phosphorylation. Thus, PACAP may serve as a potential clinical treatment to alleviate brain edema in patients with SAH.
AB - Brain edema is a vital contributor to early brain injury after subarachnoid hemorrhage (SAH), which is responsible for prolonged hospitalization and poor outcomes. Pharmacological therapeutic targets on edema formation have been the focus of research for decades. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to participate in neural development and brain injury. Here, we used PACAP knockout CRISPR to demonstrate that endogenous PACAP plays an endogenous neuroprotective role against brain edema formation after SAH in rats. The exogenous PACAP treatment provided both short- and long-term neurological benefits by preserving the function of the blood–brain barrier and glymphatic system after SAH. Pretreatment of inhibitors of PACAP receptors showed that the PACAP-involved anti-edema effect and neuroprotection after SAH was facilitated by the selective PACAP receptor (PAC1). Further administration of adenylyl cyclase (AC) inhibitor and sulfonylurea receptor 1 (SUR1) CRISPR activator suggested that the AC–cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) axis participated in PACAP signaling after SAH, which inhibited the expression of edema-related proteins, SUR1 and aquaporin-4 (AQP4), through SUR1 phosphorylation. Thus, PACAP may serve as a potential clinical treatment to alleviate brain edema in patients with SAH.
KW - Subarachnoid hemorrhage
KW - blood–brain barrier
KW - brain edema
KW - glymphatic system
KW - pituitary adenylate cyclase-activating polypeptide
KW - Rats
KW - Male
KW - Brain Edema/drug therapy
KW - Pituitary Adenylate Cyclase-Activating Polypeptide/administration & dosage
KW - Rats, Sprague-Dawley
KW - Animals
KW - Blood-Brain Barrier/drug effects
KW - Glymphatic System/drug effects
KW - Subarachnoid Hemorrhage/drug therapy
UR - http://www.scopus.com/inward/record.url?scp=85090776304&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85090776304&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/99d8324e-49e6-3937-9090-acfe5b9cf3da/
U2 - 10.1007/s13311-020-00925-3
DO - 10.1007/s13311-020-00925-3
M3 - Article
C2 - 32918234
SN - 1933-7213
VL - 17
SP - 1954
EP - 1972
JO - Neurotherapeutics
JF - Neurotherapeutics
IS - 4
ER -