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Uncoupling Protein 2 Deficiency Enhances NLRP3 Inflammasome Activation Following Hyperglycemia-Induced Exacerbation of Cerebral Ischemia and Reperfusion Damage In Vitro and In Vivo.
- Source :
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Neurochemical research [Neurochem Res] 2021 Jun; Vol. 46 (6), pp. 1359-1371. Date of Electronic Publication: 2021 Mar 18. - Publication Year :
- 2021
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Abstract
- Mitochondrial uncoupling protein 2 (UCP2) deficiency exacerbates brain damage following cerebral ischemia/reperfusion (I/R). The Nod-like receptor protein-3 (NLRP3) inflammasome also plays a vital role in cerebral I/R damage. However, the effect of UCP2 on NLRP3 inflammasome-mediated hyperglycemia and I/R damage is not clear. In the present study, UCP2-knockout (UCP2 <superscript>-/-</superscript> ) and wild-type (WT) mice were used to establish a model of middle cerebral artery occlusion (MCAO) and reperfusion under normo- and hyperglycemic conditions. HT22 cells were established as a model of oxygen-glucose deprivation and reoxygenation (OGD/R) with high glucose to mimic hyperglycemia and I/R in vitro. HT22 cells were treated with/without different concentrations of the UCP2-specific inhibitor genipin for different periods of time. The results showed that UCP2 deficiency significantly increased histopathological changes and apoptosis after cerebral I/R damage in hyperglycemic mice. Moreover, UCP2 deficiency enhanced NLRP3 inflammasome activation in neurons when cerebral I/R damage was exacerbated by hyperglycemia. Furthermore, UCP2 deficiency enhanced NLRP3 inflammasome activation and reactive oxygen species (ROS) production in HT22 cells under OGD/R and high-glucose conditions. UCP2 deficiency aggravated hyperglycemia-induced exacerbation of cerebral I/R damage. UCP2 deficiency also enhanced NLRP3 inflammasome activation and ROS production in neurons in vitro and in vivo. These findings suggest that UCP2 deficiency enhances NLRP3 inflammasome activation following hyperglycemia-induced exacerbation of cerebral I/R damage in vitro and in vivo. UCP2 may be a potential therapeutic target for hyperglycemia-induced exacerbation of cerebral I/R damage.
- Subjects :
- Animals
Apoptosis physiology
Brain pathology
Cell Line
Female
Glucose deficiency
Glucose pharmacology
Hyperglycemia pathology
Hypoxia physiopathology
Infarction, Middle Cerebral Artery pathology
Male
Mice, Inbred C57BL
Mice, Knockout
Neurons metabolism
Reactive Oxygen Species metabolism
Reperfusion Injury pathology
Mice
Hyperglycemia metabolism
Infarction, Middle Cerebral Artery metabolism
Inflammasomes metabolism
NLR Family, Pyrin Domain-Containing 3 Protein metabolism
Reperfusion Injury metabolism
Uncoupling Protein 2 deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1573-6903
- Volume :
- 46
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Neurochemical research
- Publication Type :
- Academic Journal
- Accession number :
- 33735403
- Full Text :
- https://doi.org/10.1007/s11064-021-03270-9