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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1954-1972
Number of pages19
JournalNeurotherapeutics
Volume17
Issue number4
DOIs
StatePublished - Oct 2020

ASJC Scopus Subject Areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

Keywords

  • Subarachnoid hemorrhage
  • blood–brain barrier
  • brain edema
  • glymphatic system
  • pituitary adenylate cyclase-activating polypeptide
  • Rats
  • Male
  • Brain Edema/drug therapy
  • Pituitary Adenylate Cyclase-Activating Polypeptide/administration & dosage
  • Rats, Sprague-Dawley
  • Animals
  • Blood-Brain Barrier/drug effects
  • Glymphatic System/drug effects
  • Subarachnoid Hemorrhage/drug therapy

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