PMID- 30818045
OWN - NLM
STAT- MEDLINE
DCOM- 20200213
LR  - 20240228
IS  - 1096-1186 (Electronic)
IS  - 1043-6618 (Print)
IS  - 1043-6618 (Linking)
VI  - 142
DP  - 2019 Apr
TI  - NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive 
      impairment and vasoneuronal remodeling after ischemia.
PG  - 237-250
LID - S1043-6618(18)31044-2 [pii]
LID - 10.1016/j.phrs.2019.01.035 [doi]
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.
CI  - Copyright (c) 2019. Published by Elsevier Ltd.
FAU - Ward, Rebecca
AU  - Ward R
AD  - Departments of Neuroscience and Regenerative Medicine, Augusta University, 
      Augusta, GA, United States.
FAU - Li, Weiguo
AU  - Li W
AD  - Pathology & Laboratory Medicine, Medical University of South Carolina, 
      Charleston, SC, United States; Ralph H. Johnson Veterans Administration Medical 
      Center, Charleston, SC, United States.
FAU - Abdul, Yasir
AU  - Abdul Y
AD  - Pathology & Laboratory Medicine, Medical University of South Carolina, 
      Charleston, SC, United States; Ralph H. Johnson Veterans Administration Medical 
      Center, Charleston, SC, United States.
FAU - Jackson, LaDonya
AU  - Jackson L
AD  - Center for Pharmacy and Experimental Therapeutics, University of Georgia College 
      of Pharmacy, Augusta, GA, United States.
FAU - Dong, Guangkuo
AU  - Dong G
AD  - Physiology, Augusta University, Augusta, GA, United States.
FAU - Jamil, Sarah
AU  - Jamil S
AD  - Pathology & Laboratory Medicine, Medical University of South Carolina, 
      Charleston, SC, United States.
FAU - Filosa, Jessica
AU  - Filosa J
AD  - Physiology, Augusta University, Augusta, GA, United States.
FAU - Fagan, Susan C
AU  - Fagan SC
AD  - Center for Pharmacy and Experimental Therapeutics, University of Georgia College 
      of Pharmacy, Augusta, GA, United States.
FAU - Ergul, Adviye
AU  - Ergul A
AD  - Physiology, Augusta University, Augusta, GA, United States; Pathology & 
      Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United 
      States. Electronic address: ergul@musc.edu.
LA  - eng
GR  - R01 NS063965/NS/NINDS NIH HHS/United States
GR  - I01 BX000891/BX/BLRD VA/United States
GR  - R01 NS083559/NS/NINDS NIH HHS/United States
GR  - R01 HL089067/HL/NHLBI NIH HHS/United States
GR  - R01 NS104573/NS/NINDS NIH HHS/United States
GR  - R01 NS097818/NS/NINDS NIH HHS/United States
GR  - UL1 TR002378/TR/NCATS NIH HHS/United States
GR  - I01 BX000347/BX/BLRD VA/United States
GR  - RF1 NS083559/NS/NINDS NIH HHS/United States
GR  - TL1 TR002382/TR/NCATS NIH HHS/United States
GR  - P01 HL134604/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20190225
PL  - Netherlands
TA  - Pharmacol Res
JT  - Pharmacological research
JID - 8907422
RN  - 0 (Furans)
RN  - 0 (Heterocyclic Compounds, 4 or More Rings)
RN  - 0 (Indenes)
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Sulfonamides)
RN  - 0 (Sulfones)
RN  - 6RS86E2BWQ 
      (N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cognitive Dysfunction/drug therapy/etiology/*immunology
MH  - Diabetes Mellitus, Experimental/complications/drug therapy/*immunology
MH  - Furans/*pharmacology/therapeutic use
MH  - Heterocyclic Compounds, 4 or More Rings
MH  - Hippocampus/drug effects/immunology/pathology
MH  - Indenes
MH  - Infarction, Middle Cerebral Artery/drug therapy/*immunology
MH  - Inflammasomes/*immunology
MH  - Male
MH  - Mice
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/*immunology
MH  - Neurons/drug effects/pathology
MH  - Neuroprotective Agents/*pharmacology/therapeutic use
MH  - Rats, Wistar
MH  - Sulfonamides/*pharmacology/therapeutic use
MH  - Sulfones
PMC - PMC6486792
MID - NIHMS1024884
OTO - NOTNLM
OT  - Diabetes
OT  - Hippocampus
OT  - NLRP3 inflammasome
OT  - Neurovascular unit
OT  - Stroke
OT  - Vascular cognitive impairment and dementia (VCID)
COIS- Conflicts of interest R Ward declares she has no conflict of interest. W Li 
      declares he has no conflict of interest. Y Abdul declares he has no conflict of 
      interest. L Jackson declares she has no conflict of interest. G Dong declares he 
      has no conflict of interest. S Jamil declares she has no conflict of interest. J 
      Filosa declares she has no conflict of interest.SC Fagan declares she has no 
      conflict of interest. A Ergul declares she has no conflict of interest.
EDAT- 2019/03/01 06:00
MHDA- 2020/02/14 06:00
PMCR- 2020/04/01
CRDT- 2019/03/01 06:00
PHST- 2018/07/19 00:00 [received]
PHST- 2019/01/07 00:00 [revised]
PHST- 2019/01/17 00:00 [accepted]
PHST- 2019/03/01 06:00 [pubmed]
PHST- 2020/02/14 06:00 [medline]
PHST- 2019/03/01 06:00 [entrez]
PHST- 2020/04/01 00:00 [pmc-release]
AID - S1043-6618(18)31044-2 [pii]
AID - 10.1016/j.phrs.2019.01.035 [doi]
PST - ppublish
SO  - Pharmacol Res. 2019 Apr;142:237-250. doi: 10.1016/j.phrs.2019.01.035. Epub 2019 
      Feb 25.