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

OBJECT Tenascin-C (TNC), a matricellular protein, is induced in the brain following subarachnoid hemorrhage (SAH). The authors investigated if TNC causes brain edema and blood-brain barrier (BBB) disruption following experimental SAH. METHODS C57BL/6 wild-type (WT) or TNC knockout (TNKO) mice were subjected to SAH by endovascular puncture. Ninety-seven mice were randomly allocated to WT sham-operated (n = 16), TNKO sham-operated (n = 16), WT SAH (n = 34), and TNKO SAH (n = 31) groups. Mice were examined by means of neuroscore and brain water content 24–48 hours post-SAH; and Evans blue dye extravasation and Western blotting of TNC, matrix metalloproteinase (MMP)-9, and zona occludens (ZO)-1 at 24 hours post-SAH. As a separate study, 16 mice were randomized to WT sham-operated, TNKO sham-operated, WT SAH, and TNKO SAH groups (n = 4 in each group), and activation of mitogen-activated protein kinases (MAPKs) was immunohistochemically evaluated at 24 hours post-SAH. Moreover, 40 TNKO mice randomly received an intracerebroventricular injection of TNC or phosphate-buffered saline, and effects of exogenous TNC on brain edema and BBB disruption following SAH were studied. RESULTS Deficiency of endogenous TNC prevented neurological impairments, brain edema formation, and BBB disruption following SAH; it was also associated with the inhibition of both MMP-9 induction and ZO-1 degradation. Endogenous TNC deficiency also inhibited post-SAH MAPK activation in brain capillary endothelial cells. Exogenous TNC treatment abolished the neuroprotective effects shown in TNKO mice with SAH. CONCLUSIONS Tenascin-C may be an important mediator in the development of brain edema and BBB disruption following SAH, mechanisms for which may involve MAPK-mediated MMP-9 induction and ZO-1 degradation. TNC could be a molecular target against which to develop new therapies for SAH-induced brain injuries.

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Effect of controlled cortical impact on the passage of pituitary adenylate cyclase activating polypeptide (PACAP) across the blood-brain barrier

Peptides ◽

10.1016/j.peptides.2017.10.013 ◽

2018 ◽

Vol 99 ◽

pp. 8-13 ◽

Cited By ~ 2

Author(s):

Elizabeth M. Rhea ◽

Kristin M. Bullock ◽

William A. Banks

Keyword(s):

Adenylate Cyclase ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Controlled Cortical Impact ◽

Blood Brain ◽

Pituitary Adenylate Cyclase ◽

Cortical Impact

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SPARC Aggravates Blood-Brain Barrier Disruption via Integrin αVβ3/MAPKs/MMP-9 Signaling Pathway after Subarachnoid Hemorrhage

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9739977 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Takeshi Okada ◽

Hidenori Suzuki ◽

Zachary D. Travis ◽

Orhan Altay ◽

Jiping Tang ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Signaling Pathway ◽

Brain Edema ◽

Blood Brain Barrier ◽

Integrin Αvβ3 ◽

Brain Barrier ◽

Sham Operation ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Brain Barrier Disruption

Blood-brain barrier (BBB) disruption is a common and critical pathology following subarachnoid hemorrhage (SAH). We investigated the BBB disruption property of secreted protein acidic and rich in cysteine (SPARC) after SAH. A total of 197 rats underwent endovascular perforation to induce SAH or sham operation. Small interfering ribonucleic acid (siRNA) for SPARC or scrambled siRNA was administered intracerebroventricularly to rats 48 h before SAH. Anti-SPARC monoclonal antibody (mAb) 236 for functional blocking or normal mouse immunoglobulin G (IgG) was administered intracerebroventricularly 1 h after SAH. Selective integrin αVβ3 inhibitor cyclo(-RGDfK) or phosphate-buffered saline was administered intranasally 1 h before SAH, along with recombinant SPARC treatment. Neurobehavior, SAH severity, brain edema, immunohistochemical staining, and Western blot were evaluated. The expression of SPARC and integrin αVβ3 was upregulated after SAH in the endothelial cells. SPARC siRNA and anti-SPARC mAb 236 prevented neuroimpairments and brain edema through protection of BBB as measured by IgG extravasation 24 and 72 h after SAH. Recombinant SPARC aggravated neuroimpairments and cyclo(-RGDfK) suppressed the harmful neurological effects via inhibition of activated c-Jun N-terminal kinase, p38, and matrix metalloproteinase-9 followed by retention of endothelial junction proteins. SPARC may induce post-SAH BBB disruption via integrin αVβ3 signaling pathway.

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Postulated Role of Vasoactive Neuropeptide-Related Immunopathology of the Blood Brain Barrier and Virchow-Robin Spaces in the Aetiology of Neurological-Related Conditions

Mediators of Inflammation ◽

10.1155/2008/792428 ◽

2008 ◽

Vol 2008 ◽

pp. 1-5 ◽

Cited By ~ 8

Author(s):

D. R. Staines ◽

E. W. Brenu ◽

S. Marshall-Gradisnik

Keyword(s):

Adenylate Cyclase ◽

Blood Brain Barrier ◽

Phosphodiesterase Inhibitors ◽

Brain Barrier ◽

Immune Functions ◽

Small Vessels ◽

Blood Brain ◽

Pituitary Adenylate Cyclase ◽

The Central Nervous System ◽

Immunological Homeostasis

Vasoactive neuropeptides (VNs) such as pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have critical roles as neurotransmitters, vasodilators including perfusion and hypoxia regulators, as well as immune and nociception modulators. They have key roles in blood vessels in the central nervous system (CNS) including maintaining functional integrity of the blood brain barrier (BBB) and blood spinal barrier (BSB). VNs are potent activators of adenylate cyclase and thus also have a key role in cyclic AMP production affecting regulatory T cell and other immune functions. Virchow-Robin spaces (VRSs) are perivascular compartments surrounding small vessels within the CNS and contain VNs. Autoimmunity of VNs or VN receptors may affect BBB and VRS function and, therefore, may contribute to the aetiology of neurological-related conditions including multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. VN autoimmunity will likely affect CNS and immunological homeostasis. Various pharmacological and immunological treatments including phosphodiesterase inhibitors and plasmapheresis may be indicated.

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Transport of Pituitary Adenylate Cyclase-Activating Polypeptide Across the Blood-Brain Barrier and the Prevention of Ischemia-Induced Death of Hippocampal Neurons

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1996.tb17489.x ◽

2006 ◽

Vol 805 (1) ◽

pp. 270-277 ◽

Cited By ~ 56

Author(s):

WILLIAM A. BANKS ◽

DAIGAKU UCHIDA ◽

AKIRA ARIMURA ◽

ANIKO SOMOGYVÁRI-VIGH ◽

SEIJI SHIODA

Keyword(s):

Adenylate Cyclase ◽

Blood Brain Barrier ◽

Hippocampal Neurons ◽

Brain Barrier ◽

Blood Brain ◽

Pituitary Adenylate Cyclase

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Hyperbaric Oxygen Intervention Modulates Early Brain Injury after Experimental Subarachnoid Hemorrhage in Rats: Possible Involvement of TLR4/NF-κ B-Mediated Signaling Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000445586 ◽

2016 ◽

Vol 38 (6) ◽

pp. 2323-2336 ◽

Cited By ~ 4

Author(s):

Hao Liu ◽

Ming Yang ◽

Li Pan ◽

Peng Liu ◽

Lianting Ma

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Signaling Pathway ◽

Brain Edema ◽

Blood Brain Barrier ◽

Hyperbaric Oxygen ◽

Early Brain Injury ◽

Brain Barrier ◽

Enzyme Linked Immunosorbent Assay ◽

Blood Brain

Background/Aims: Previous studies have proved that the activation of TLR4/NF-κ B signaling pathway is involved in inflammatory processes in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Hyperbaric oxygen (HBO) intervention has successfully been used to treat several animal models of tissue injury via its anti-inflammation property. This study was undertaken to investigate the influence of HBO administration on the TLR4/NF-κ B signaling pathway in rats at the early stage of SAH. Methods: Male Sprague-Dawley rats (n = 150) were randomly divided into 5 groups: the sham, the sham + 2.8 atmospheres absolute (ATA) HBO group, the SAH group, the SAH + 2.0ATA HBO group, the SAH + 2.8ATA HBO group. Each group (n = 30) was randomly subdivided into three subgroups that were examined at the following time points: 24 h, 48 h and 72 h post-injury. HBO (100% O2, 2.0ATA or 2.8ATA for 90mins) was initiated 12 h after injury. Neurological deficit, brain edema and blood-brain barrier (BBB) permeability were assessed to evaluate the development of EBI. The expressions of TLR4, NF-κ B and pro-inflammatory cytokines in the cortical were determined by real time polymerase chain reaction (RT-PCR), western blot, immunohistochemistry, or enzyme-linked immunosorbent assay (ELISA). Results: Our study showed that treatment with HBO significantly decreased the expressions of TLR4, NF-κ B and the downstream inflammatory agents, such as TNF-α, IL-6, IL-1β and ICAM-1, and also improved brain edema, blood-brain barrier permeability and neurologic function. Conclusions: These findings indicate that HBO treatment may result in abatement of the development of EBI after SAH, possibly through suppression of TLR4/NF-κ B signaling pathway.

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