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Pituitary Adenylate Cyclase-Activating Polypeptide Attenuates Brain Edema by Protecting Blood-Brain Barrier and Glymphatic System After Subarachnoid Hemorrhage in Rats
- Source :
- Neurotherapeutics
- Publication Year :
- 2020
-
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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00925-3) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Adenosine monophosphate
Male
endocrine system
Subarachnoid hemorrhage
Adenylate kinase
Brain Edema
Pharmacology
Blood–brain barrier
Neuroprotection
Adenylyl cyclase
Rats, Sprague-Dawley
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
medicine
Animals
Pharmacology (medical)
cardiovascular diseases
Receptor
business.industry
Subarachnoid Hemorrhage
medicine.disease
nervous system diseases
Rats
030104 developmental biology
medicine.anatomical_structure
chemistry
Blood-Brain Barrier
Pituitary Adenylate Cyclase-Activating Polypeptide
Glymphatic system
Original Article
Neurology (clinical)
business
Glymphatic System
030217 neurology & neurosurgery
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 18787479
- Volume :
- 17
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
- Accession number :
- edsair.doi.dedup.....60a1328f86d10c15d0ca14a1a00e54b6