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.
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.
1 Departments of Anesthesiology and Physiology, Loma Linda University, Loma Linda, CA, USA.|2 Departments of Neurology and Psychiatry, National Medical University, Mongolia.
Budbazar
B
Enkhjargal
1 Departments of Anesthesiology and Physiology, Loma Linda University, Loma Linda, CA, USA.
Devin W
DW
McBride
1 Departments of Anesthesiology and Physiology, Loma Linda University, Loma Linda, CA, USA.
Anatol
A
Manaenko
1 Departments of Anesthesiology and Physiology, Loma Linda University, Loma Linda, CA, USA.
Cesar
C
Reis
3 Laboratory of Physiology and Pharmacology, Faculty of Health Science Technology, Bunkyo Gakuin University, Saitama, Japan.
Yasushi
Y
Sakai
1 Departments of Anesthesiology and Physiology, Loma Linda University, Loma Linda, CA, USA.
Jiping
J
Tang
1 Departments of Anesthesiology and Physiology, Loma Linda University, Loma Linda, CA, USA.
John H
JH
Zhang
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000281:Administration, Intranasal; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006031:Glycosylation; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D053495:Osteopontin / Q000096:biosynthesis*; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D014807:Vitamin D / Q000008:administration & dosage / Q000627:therapeutic use*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018960:Hyaluronan Receptors; D018696:Neuroprotective Agents; C506897:Spp1 protein, rat; D053495:Osteopontin; D014807:Vitamin D
CD44 splicing; P-glucoprotein glycosylation; Subarachnoid hemorrhage; osteopontin; vitamin D
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