Journal Article

Pituitary Adenylate Cyclase-Activating Polypeptide Attenuates Brain Edema by Protecting Blood–Brain Barrier and Glymphatic System After Subarachnoid Hemorrhage in Rats

Travis, Zachary D., Huang, Lei, Fang, Yuanjian, Lu, Qin, Shi, Hui, Zhang, Jianmin, Tang, Lihui, Zhou, Keren, Huang, Yi, Okada, Takeshi, Lenahan, Cameron, Tang, Jiping, Ren, Reng, Gamdzyk, Marcin, Zhang, John H.

2020

Overview

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.

• Publisher: Elsevier Inc,Springer International Publishing,Springer Nature B.V
• Subject: Adenosine kinase / Animals / Aquaporin 4 / Biomedical and Life Sciences / Biomedicine / Blood-brain barrier / Blood-Brain Barrier - drug effects / Blood-Brain Barrier - metabolism / Blood-Brain Barrier - pathology / brain edema / Brain Edema - drug therapy / Brain Edema - metabolism / Brain Edema - pathology / Brain injury / CRISPR / Cyclic AMP / Edema / glymphatic system / Glymphatic System - drug effects / Glymphatic System - metabolism / Glymphatic System - pathology / Kinases / Male / Neurobiology / Neurology / Neuroprotection / Neurosciences / Neurosurgery / Original / Original Article / PAC1 protein / Phosphorylation / Pituitary adenylate cyclase-activating polypeptide / Pituitary Adenylate Cyclase-Activating Polypeptide - administration & dosage / Pituitary adenylate cyclase-activating polypeptide receptors / Polypeptides / Protein kinase A / Rats / Rats, Sprague-Dawley / Stroke / Subarachnoid hemorrhage / Subarachnoid Hemorrhage - drug therapy / Subarachnoid Hemorrhage - metabolism / Subarachnoid Hemorrhage - pathology / Sulfonylurea / Therapeutic targets / Traumatic brain injury