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−/−) 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.
Highlights
Ischemic stroke is identified as one of the major causes of disability and mortality worldwide
The neuroprotective effects of uncoupling protein 2 (UCP2) are likely related to the regulation of reactive oxygen species (ROS) and neuroinflammation
Our study showed that UCP2 deficiency significantly increased histopathological changes and apoptosis after cerebral I/R in normoglycemic and hyperglycemic mice
Summary
Ischemic stroke is identified as one of the major causes of disability and mortality worldwide. Hyperglycemia is an important independent risk factor for ischemic stroke and induces the occurrence and development of cerebral I/R damage [1, 2]. Previous studies have shown that the exacerbation of ROS production, promotion of neuroinflammation, and extensive programmed cell death are possible mechanisms associated with hyperglycemia-exacerbated cerebral I/R damage. Recent evidence suggests that inflammation is a major factor in cerebral I/R damage due to the inflammatory response and the accumulation of inflammatory cells [3, 4]. The molecular mechanism by which hyperglycemia exacerbates ischemic brain injury is still unclear. No effective drugs have been found to treat hyperglycemia-exacerbated ischemic brain injury. Research on neuroprotection and targeted inflammation is very important in preventing and treating hyperglycemia-exacerbated cerebral I/R damage
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