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Adropin preserves the blood-brain barrier through a Notch1/Hes1 pathway after intracerebral hemorrhage in mice.

ABSTRACT: Adropin is expressed in the CNS and plays a crucial role in the development of stroke. However, little is currently known about the effects of adropin on the blood-brain barrier (BBB) function after intracerebral hemorrhage (ICH). In this study, the role of adropin in collagenase-induced ICH was investigated in mice. At 1-h post-ICH, mice were administered with recombinant human adropin by intranasal. Brain water +content, BBB permeability, and neurological function were measured at different time intervals. Proteins were quantified using western blot analysis, and the localizations of adropin and Notch1 were visualized via immunofluorescence staining. It is shown that adropin reduced brain water content and improved neurological functions. Adropin preserved the functionality of BBB by increasing N-cadherin expression and reducing extravasation of albumin. Moreover, in vivo knockdown of Notch1 and Hes1 both abolished the protective effects of adropin. Taken together, our data demonstrate that adropin constitutes a potential treatment value for ICH by preserving BBB and improving functional outcomes through the Notch1 signaling pathway.

SUBMITTER: Yu L

PROVIDER: S-EPMC5729103 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Adropin preserves the blood-brain barrier through a Notch1/Hes1 pathway after intracerebral hemorrhage in mice.

Yu Lingyan L Lu Zhengyang Z Burchell Sherrefa S Nowrangi Derek D Manaenko Anatol A Li Xue X Xu Yang Y Xu Ningbo N Tang Jiping J Dai Haibin H Zhang John H JH

Journal of neurochemistry 20171117 6

Adropin is expressed in the CNS and plays a crucial role in the development of stroke. However, little is currently known about the effects of adropin on the blood-brain barrier (BBB) function after intracerebral hemorrhage (ICH). In this study, the role of adropin in collagenase-induced ICH was investigated in mice. At 1-h post-ICH, mice were administered with recombinant human adropin by intranasal. Brain water +content, BBB permeability, and neurological function were measured at different ti ...[more]

PMID: 29030969

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Project description:Blood-brain barrier (BBB) disruption and subsequent brain edema play important roles in the secondary neuronal death and neurological dysfunction that are observed following intracerebral hemorrhage (ICH). In previous studies, transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable mechanosensitive channel, was shown to induce cytotoxicity in many types of cells and to play a role in orchestrating barrier functions. In the present study, we explored the role of TRPV4 in ICH-induced brain injury, specifically investigating its effect on BBB disruption. Autologous arterial blood was injected into the basal ganglia of rats to mimic ICH. Adult male Sprague Dawley rats were randomly assigned to sham and experimental groups for studies on the time course of TRPV4 expression after ICH. The selective TRPV4 antagonist HC-067047 and TRPV4 siRNA were administered to evaluate the effects of TRPV4 inhibition. GSK1016790A, a TRPV4 agonist, was administered to naive rats to verify the involvement of TRPV4-induced BBB disruption. A PKC inhibitor, dihydrochloride (H7), and a selective RhoA inhibitor, C3 transferase, were administered to clarify the involvement of the PKCα/RhoA/MLC2 pathway following ICH. Post-ICH assessments including functional tests, brain edema measurements, Evans blue extravasation, western blotting and immunohistochemical assays were performed. TRPV4 inhibition remarkably ameliorated neurological symptoms, brain edema, and neuronal death, as well as BBB disruption, 24-72 h following ICH. Meanwhile, TRPV4 blockade preserved the expression of adherens and tight junction proteins, as well as BBB integrity, by inhibiting stress fiber formation, which might be correlated with the regulation of components of the PKCα/RhoA/MLC2 pathway. Furthermore, adherens and tight junction protein degradation induced by GSK1016790A treatment in naive rats was also related to PKCα/RhoA/MLC2-pathway-mediated stress fiber formation. Based on these findings, therapeutic interventions targeting TRPV4 may represent a novel approach to ameliorate secondary brain injury following ICH.

Dataset Information

Adropin preserves the blood-brain barrier through a Notch1/Hes1 pathway after intracerebral hemorrhage in mice.

Publications

Adropin preserves the blood-brain barrier through a Notch1/Hes1 pathway after intracerebral hemorrhage in mice.

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