NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage
Abstract Background The NLRP3 inflammasome is a critical mediator of several vascular diseases through positive regulation of proinflammatory pathways. In this study, we defined the role of NLRP3 in both the acute and delayed phases following subarachnoid hemorrhage (SAH). SAH is associated with dev...
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doaj-dc49f4eb97b14a6e89d742bf271f72992021-07-25T11:42:29ZengBMCJournal of Neuroinflammation1742-20942021-07-0118111110.1186/s12974-021-02207-xNLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhageWilliam S. Dodd0Imaray Noda1Melanie Martinez2Koji Hosaka3Brian L. Hoh4Department of Neurosurgery, College of Medicine, University of FloridaDepartment of Neurosurgery, College of Medicine, University of FloridaDepartment of Neurosurgery, College of Medicine, University of FloridaDepartment of Neurosurgery, College of Medicine, University of FloridaDepartment of Neurosurgery, College of Medicine, University of FloridaAbstract Background The NLRP3 inflammasome is a critical mediator of several vascular diseases through positive regulation of proinflammatory pathways. In this study, we defined the role of NLRP3 in both the acute and delayed phases following subarachnoid hemorrhage (SAH). SAH is associated with devastating early brain injury (EBI) in the acute phase, and those that survive remain at risk for developing delayed cerebral ischemia (DCI) due to cerebral vasospasm. Current therapies are not effective in preventing the morbidity and mortality associated with EBI and DCI. NLRP3 activation is known to drive IL-1β production and stimulate microglia reactivity, both hallmarks of SAH pathology; thus, we hypothesized that inhibition of NLRP3 could alleviate SAH-induced vascular dysfunction and functional deficits. Methods We studied NLRP3 in an anterior circulation autologous blood injection model of SAH in mice. Mice were randomized to either sham surgery + vehicle, SAH + vehicle, or SAH + MCC950 (a selective NLRP3 inhibitor). The acute phase was studied at 1 day post-SAH and delayed phase at 5 days post-SAH. Results NLRP3 inhibition improved outcomes at both 1 and 5 days post-SAH. In the acute (1 day post-SAH) phase, NLRP3 inhibition attenuated cerebral edema, tight junction disruption, microthrombosis, and microglial reactive morphology shift. Further, we observed a decrease in apoptosis of neurons in mice treated with MCC950. NLRP3 inhibition also prevented middle cerebral artery vasospasm in the delayed (5 days post-SAH) phase and blunted SAH-induced sensorimotor deficits. Conclusions We demonstrate a novel association between NLRP3-mediated neuroinflammation and cerebrovascular dysfunction in both the early and delayed phases after SAH. MCC950 and other NLRP3 inhibitors could be promising tools in the development of therapeutics for EBI and DCI.https://doi.org/10.1186/s12974-021-02207-xSubarachnoid hemorrhageMicrogliaNLRP3 inflammasomeStrokeInflammation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
William S. Dodd Imaray Noda Melanie Martinez Koji Hosaka Brian L. Hoh |
spellingShingle |
William S. Dodd Imaray Noda Melanie Martinez Koji Hosaka Brian L. Hoh NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage Journal of Neuroinflammation Subarachnoid hemorrhage Microglia NLRP3 inflammasome Stroke Inflammation |
author_facet |
William S. Dodd Imaray Noda Melanie Martinez Koji Hosaka Brian L. Hoh |
author_sort |
William S. Dodd |
title |
NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage |
title_short |
NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage |
title_full |
NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage |
title_fullStr |
NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage |
title_full_unstemmed |
NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage |
title_sort |
nlrp3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2021-07-01 |
description |
Abstract Background The NLRP3 inflammasome is a critical mediator of several vascular diseases through positive regulation of proinflammatory pathways. In this study, we defined the role of NLRP3 in both the acute and delayed phases following subarachnoid hemorrhage (SAH). SAH is associated with devastating early brain injury (EBI) in the acute phase, and those that survive remain at risk for developing delayed cerebral ischemia (DCI) due to cerebral vasospasm. Current therapies are not effective in preventing the morbidity and mortality associated with EBI and DCI. NLRP3 activation is known to drive IL-1β production and stimulate microglia reactivity, both hallmarks of SAH pathology; thus, we hypothesized that inhibition of NLRP3 could alleviate SAH-induced vascular dysfunction and functional deficits. Methods We studied NLRP3 in an anterior circulation autologous blood injection model of SAH in mice. Mice were randomized to either sham surgery + vehicle, SAH + vehicle, or SAH + MCC950 (a selective NLRP3 inhibitor). The acute phase was studied at 1 day post-SAH and delayed phase at 5 days post-SAH. Results NLRP3 inhibition improved outcomes at both 1 and 5 days post-SAH. In the acute (1 day post-SAH) phase, NLRP3 inhibition attenuated cerebral edema, tight junction disruption, microthrombosis, and microglial reactive morphology shift. Further, we observed a decrease in apoptosis of neurons in mice treated with MCC950. NLRP3 inhibition also prevented middle cerebral artery vasospasm in the delayed (5 days post-SAH) phase and blunted SAH-induced sensorimotor deficits. Conclusions We demonstrate a novel association between NLRP3-mediated neuroinflammation and cerebrovascular dysfunction in both the early and delayed phases after SAH. MCC950 and other NLRP3 inhibitors could be promising tools in the development of therapeutics for EBI and DCI. |
topic |
Subarachnoid hemorrhage Microglia NLRP3 inflammasome Stroke Inflammation |
url |
https://doi.org/10.1186/s12974-021-02207-x |
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