Intranasal administration of vitamin D attenuates blood–brain barrier disruption through endogenous upregulation of osteopontin and activation of CD44/P-gp glycosylation signaling after subarachnoid hemorrhage in rats

Budbazar Enkhjargal, Devin W. McBride, Anatol Manaenko, Cesar Reis, Yasushi Sakai, Jiping Tang, John H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

In this study, we investigated the role of vitamin D3 (VitD3) on endogenous osteopontin (OPN), a neuroprotective glycoprotein, after subarachnoid hemorrhage (SAH). The endovascular perforation SAH model in Sprague-Dawley rats was used to study the effect of intranasal VitD3 (30 ng/kg) before (Pre-SAH + VitD3) and after (Post-SAH + VitD3) subarachnoid hemorrhage. Vitamin D3 (30, 60, 120 ng/kg/day) increased more than one fold endogenous OPN expression in astrocytes and endothelial cells of rat brain. Vitamin D3 significantly decreased brain edema and Evans blue extravasation. In addition, neurobehavioral scores were significantly higher in Pre-SAH + VitD3, but partly higher in Post-SAH + VitD3, group compared with SAH group. These protective effects of vitamin D3 were completely attenuated by intracerebroventricular injection of transcription inhibitor Actinomycin D and significantly inhibited by small interfering ribonucleic acid (siRNA) for vitamin D receptor and OPN in Pre-SAH + VitD3 rats. OPN expression was significantly higher in Pre-SAH + VitD3 rats, specifically A and C, but not B, isomers were upregulated in the astrocytes, leading to CD44 splicing, and P-gp glycosylation in brain endothelial cells. The results show that intranasal vitamin D3 attenuates blood–brain barrier (BBB) disruption through endogenous upregulation of OPN and subsequent CD44 and P-gp glycosylation signals in brain endothelial cells. Furthermore, this study identifies a novel strategy for the cost-effective management of subarachnoid hemorrhage.

Original languageEnglish
Pages (from-to)2555-2566
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume37
Issue number7
DOIs
StatePublished - Jul 1 2017

ASJC Scopus Subject Areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Keywords

  • CD44 splicing
  • P-glucoprotein glycosylation
  • Subarachnoid hemorrhage
  • osteopontin
  • vitamin D
  • Neuroprotective Agents/administration & dosage
  • Osteopontin/biosynthesis
  • Up-Regulation
  • ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
  • Male
  • Glycosylation
  • Hyaluronan Receptors/metabolism
  • Vitamin D/administration & dosage
  • Administration, Intranasal
  • Rats, Sprague-Dawley
  • Dose-Response Relationship, Drug
  • Animals
  • Behavior, Animal/drug effects
  • Blood-Brain Barrier/drug effects
  • Disease Models, Animal
  • Subarachnoid Hemorrhage/drug therapy

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