NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia

Rebecca Ward, Weiguo Li, Yasir Abdul, La Donya Jackson, Guangkuo Dong, Sarah Jamil, Jessica Andrea Filosa, Susan C. Fagan, Adviye Ergul

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Diabetes increases the risk and worsens the progression of cognitive impairment via the greater occurrence of small vessel disease and stroke. Yet, the underlying mechanisms are not fully understood. It is now accepted that cardiovascular health is critical for brain health and any neurorestorative approaches to prevent/delay cognitive deficits should target the conceptual neurovascular unit (NVU) rather than neurons alone. We have recently shown that there is augmented hippocampal NVU remodeling after a remote ischemic injury in diabetes. NLRP3 inflammasome signaling has been implicated in the development of diabetes and neurodegenerative diseases, but little is known about the impact of NLRP3 activation on functional and structural interaction within the NVU of hippocampus, a critical part of the brain that is involved in forming, organizing, and storing memories. Endothelial cells are at the center of the NVU and produce trophic factors such as brain derived neurotrophic factor (BDNF) contributing to neuronal survival, known as vasotrophic coupling. Therefore, the aims of this study focused on two hypotheses: 1) diabetes negatively impacts hippocampal NVU remodeling and worsens cognitive outcome after stroke, and 2) NLRP3 inhibition with MCC950 will improve NVU remodeling and cognitive outcome following stroke via vasotrophic (un)coupling between endothelial cells and hippocampal neurons. Stroke was induced through a 90-min transient middle cerebral artery occlusion (MCAO) in control and high-fat diet/streptozotocin-induced (HFD/STZ) diabetic male Wistar rats. Saline or MCC950 (3 mg/kg), an inhibitor of NLRP3, was injected at 1 and 3 h after reperfusion. Cognition was assessed over time and neuronal density, blood-brain barrier (BBB) permeability as well as NVU remodeling (aquaporin-4 [AQP4] polarity) was measured on day 14 after stroke. BDNF was measured in endothelial and hippocampal neuronal cultures under hypoxic and diabetes-mimicking condition with and without NLRP3 inhibition. Diabetes increased neuronal degeneration and BBB permeability, disrupted AQP4 polarity, impaired cognitive function and amplified NLRP3 activation after ischemia. Inhibition with MCC950 improved cognitive function and vascular integrity after stroke in diabetic animals and prevented hypoxia-mediated decrease in BDNF secretion. These results are the first to provide essential data showing MCC950 has the potential to become a therapeutic to prevent neurovascular remodeling and worsened cognitive decline in diabetic patients following stroke.

Original languageEnglish (US)
Pages (from-to)237-250
Number of pages14
JournalPharmacological Research
Volume142
DOIs
StatePublished - Apr 1 2019

Fingerprint

Inflammasomes
Ischemia
Stroke
Brain-Derived Neurotrophic Factor
Aquaporin 4
Cognition
Blood-Brain Barrier
Permeability
Endothelial Cells
Neurons
Middle Cerebral Artery Infarction
Health
Brain
High Fat Diet
Streptozocin
Cognitive Dysfunction
Inhibition (Psychology)
Neurodegenerative Diseases
Reperfusion
Blood Vessels

Keywords

  • Diabetes
  • Hippocampus
  • NLRP3 inflammasome
  • Neurovascular unit
  • Stroke
  • Vascular cognitive impairment and dementia (VCID)

ASJC Scopus subject areas

  • Pharmacology

Cite this

NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia. / Ward, Rebecca; Li, Weiguo; Abdul, Yasir; Jackson, La Donya; Dong, Guangkuo; Jamil, Sarah; Filosa, Jessica Andrea; Fagan, Susan C.; Ergul, Adviye.

In: Pharmacological Research, Vol. 142, 01.04.2019, p. 237-250.

Research output: Contribution to journalArticle

Ward, Rebecca ; Li, Weiguo ; Abdul, Yasir ; Jackson, La Donya ; Dong, Guangkuo ; Jamil, Sarah ; Filosa, Jessica Andrea ; Fagan, Susan C. ; Ergul, Adviye. / NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia. In: Pharmacological Research. 2019 ; Vol. 142. pp. 237-250.
@article{20578d6726d6479a95441d83a8e1f9a4,
title = "NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia",
abstract = "Diabetes increases the risk and worsens the progression of cognitive impairment via the greater occurrence of small vessel disease and stroke. Yet, the underlying mechanisms are not fully understood. It is now accepted that cardiovascular health is critical for brain health and any neurorestorative approaches to prevent/delay cognitive deficits should target the conceptual neurovascular unit (NVU) rather than neurons alone. We have recently shown that there is augmented hippocampal NVU remodeling after a remote ischemic injury in diabetes. NLRP3 inflammasome signaling has been implicated in the development of diabetes and neurodegenerative diseases, but little is known about the impact of NLRP3 activation on functional and structural interaction within the NVU of hippocampus, a critical part of the brain that is involved in forming, organizing, and storing memories. Endothelial cells are at the center of the NVU and produce trophic factors such as brain derived neurotrophic factor (BDNF) contributing to neuronal survival, known as vasotrophic coupling. Therefore, the aims of this study focused on two hypotheses: 1) diabetes negatively impacts hippocampal NVU remodeling and worsens cognitive outcome after stroke, and 2) NLRP3 inhibition with MCC950 will improve NVU remodeling and cognitive outcome following stroke via vasotrophic (un)coupling between endothelial cells and hippocampal neurons. Stroke was induced through a 90-min transient middle cerebral artery occlusion (MCAO) in control and high-fat diet/streptozotocin-induced (HFD/STZ) diabetic male Wistar rats. Saline or MCC950 (3 mg/kg), an inhibitor of NLRP3, was injected at 1 and 3 h after reperfusion. Cognition was assessed over time and neuronal density, blood-brain barrier (BBB) permeability as well as NVU remodeling (aquaporin-4 [AQP4] polarity) was measured on day 14 after stroke. BDNF was measured in endothelial and hippocampal neuronal cultures under hypoxic and diabetes-mimicking condition with and without NLRP3 inhibition. Diabetes increased neuronal degeneration and BBB permeability, disrupted AQP4 polarity, impaired cognitive function and amplified NLRP3 activation after ischemia. Inhibition with MCC950 improved cognitive function and vascular integrity after stroke in diabetic animals and prevented hypoxia-mediated decrease in BDNF secretion. These results are the first to provide essential data showing MCC950 has the potential to become a therapeutic to prevent neurovascular remodeling and worsened cognitive decline in diabetic patients following stroke.",
keywords = "Diabetes, Hippocampus, NLRP3 inflammasome, Neurovascular unit, Stroke, Vascular cognitive impairment and dementia (VCID)",
author = "Rebecca Ward and Weiguo Li and Yasir Abdul and Jackson, {La Donya} and Guangkuo Dong and Sarah Jamil and Filosa, {Jessica Andrea} and Fagan, {Susan C.} and Adviye Ergul",
year = "2019",
month = "4",
day = "1",
doi = "10.1016/j.phrs.2019.01.035",
language = "English (US)",
volume = "142",
pages = "237--250",
journal = "Pharmacological Research",
issn = "1043-6618",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia

AU - Ward, Rebecca

AU - Li, Weiguo

AU - Abdul, Yasir

AU - Jackson, La Donya

AU - Dong, Guangkuo

AU - Jamil, Sarah

AU - Filosa, Jessica Andrea

AU - Fagan, Susan C.

AU - Ergul, Adviye

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Diabetes increases the risk and worsens the progression of cognitive impairment via the greater occurrence of small vessel disease and stroke. Yet, the underlying mechanisms are not fully understood. It is now accepted that cardiovascular health is critical for brain health and any neurorestorative approaches to prevent/delay cognitive deficits should target the conceptual neurovascular unit (NVU) rather than neurons alone. We have recently shown that there is augmented hippocampal NVU remodeling after a remote ischemic injury in diabetes. NLRP3 inflammasome signaling has been implicated in the development of diabetes and neurodegenerative diseases, but little is known about the impact of NLRP3 activation on functional and structural interaction within the NVU of hippocampus, a critical part of the brain that is involved in forming, organizing, and storing memories. Endothelial cells are at the center of the NVU and produce trophic factors such as brain derived neurotrophic factor (BDNF) contributing to neuronal survival, known as vasotrophic coupling. Therefore, the aims of this study focused on two hypotheses: 1) diabetes negatively impacts hippocampal NVU remodeling and worsens cognitive outcome after stroke, and 2) NLRP3 inhibition with MCC950 will improve NVU remodeling and cognitive outcome following stroke via vasotrophic (un)coupling between endothelial cells and hippocampal neurons. Stroke was induced through a 90-min transient middle cerebral artery occlusion (MCAO) in control and high-fat diet/streptozotocin-induced (HFD/STZ) diabetic male Wistar rats. Saline or MCC950 (3 mg/kg), an inhibitor of NLRP3, was injected at 1 and 3 h after reperfusion. Cognition was assessed over time and neuronal density, blood-brain barrier (BBB) permeability as well as NVU remodeling (aquaporin-4 [AQP4] polarity) was measured on day 14 after stroke. BDNF was measured in endothelial and hippocampal neuronal cultures under hypoxic and diabetes-mimicking condition with and without NLRP3 inhibition. Diabetes increased neuronal degeneration and BBB permeability, disrupted AQP4 polarity, impaired cognitive function and amplified NLRP3 activation after ischemia. Inhibition with MCC950 improved cognitive function and vascular integrity after stroke in diabetic animals and prevented hypoxia-mediated decrease in BDNF secretion. These results are the first to provide essential data showing MCC950 has the potential to become a therapeutic to prevent neurovascular remodeling and worsened cognitive decline in diabetic patients following stroke.

AB - Diabetes increases the risk and worsens the progression of cognitive impairment via the greater occurrence of small vessel disease and stroke. Yet, the underlying mechanisms are not fully understood. It is now accepted that cardiovascular health is critical for brain health and any neurorestorative approaches to prevent/delay cognitive deficits should target the conceptual neurovascular unit (NVU) rather than neurons alone. We have recently shown that there is augmented hippocampal NVU remodeling after a remote ischemic injury in diabetes. NLRP3 inflammasome signaling has been implicated in the development of diabetes and neurodegenerative diseases, but little is known about the impact of NLRP3 activation on functional and structural interaction within the NVU of hippocampus, a critical part of the brain that is involved in forming, organizing, and storing memories. Endothelial cells are at the center of the NVU and produce trophic factors such as brain derived neurotrophic factor (BDNF) contributing to neuronal survival, known as vasotrophic coupling. Therefore, the aims of this study focused on two hypotheses: 1) diabetes negatively impacts hippocampal NVU remodeling and worsens cognitive outcome after stroke, and 2) NLRP3 inhibition with MCC950 will improve NVU remodeling and cognitive outcome following stroke via vasotrophic (un)coupling between endothelial cells and hippocampal neurons. Stroke was induced through a 90-min transient middle cerebral artery occlusion (MCAO) in control and high-fat diet/streptozotocin-induced (HFD/STZ) diabetic male Wistar rats. Saline or MCC950 (3 mg/kg), an inhibitor of NLRP3, was injected at 1 and 3 h after reperfusion. Cognition was assessed over time and neuronal density, blood-brain barrier (BBB) permeability as well as NVU remodeling (aquaporin-4 [AQP4] polarity) was measured on day 14 after stroke. BDNF was measured in endothelial and hippocampal neuronal cultures under hypoxic and diabetes-mimicking condition with and without NLRP3 inhibition. Diabetes increased neuronal degeneration and BBB permeability, disrupted AQP4 polarity, impaired cognitive function and amplified NLRP3 activation after ischemia. Inhibition with MCC950 improved cognitive function and vascular integrity after stroke in diabetic animals and prevented hypoxia-mediated decrease in BDNF secretion. These results are the first to provide essential data showing MCC950 has the potential to become a therapeutic to prevent neurovascular remodeling and worsened cognitive decline in diabetic patients following stroke.

KW - Diabetes

KW - Hippocampus

KW - NLRP3 inflammasome

KW - Neurovascular unit

KW - Stroke

KW - Vascular cognitive impairment and dementia (VCID)

UR - http://www.scopus.com/inward/record.url?scp=85062403801&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062403801&partnerID=8YFLogxK

U2 - 10.1016/j.phrs.2019.01.035

DO - 10.1016/j.phrs.2019.01.035

M3 - Article

VL - 142

SP - 237

EP - 250

JO - Pharmacological Research

JF - Pharmacological Research

SN - 1043-6618

ER -