Abstract
Smoking is a preventable risk factor for stroke and smoking-derived nicotine exacerbates post-ischemic damage via inhibition of estrogen receptor beta (ER-β) signaling in the brain of female rats. ER-β regulates inflammasome activation in the brain. Therefore, we hypothesized that chronic nicotine exposure activates the inflammasome in the brain, thus exacerbating ischemic brain damage in female rats. To test this hypothesis, adult female Sprague-Dawley rats (6–7 months old) were exposed to nicotine (4.5 mg/kg/day) or saline for 16 days. Subsequently, brain tissue was collected for immunoblot analysis. In addition, another set of rats underwent transient middle cerebral artery occlusion (tMCAO; 90 min) with or without nicotine exposure. One month after tMCAO, histopathological analysis revealed a significant increase in infarct volume in the nicotine-treated group (64.24 ± 7.3 mm3; mean ± SEM; n = 6) compared to the saline-treated group (37.12 ± 7.37 mm3; n = 7, p < 0.05). Immunoblot analysis indicated that nicotine increased cortical protein levels of caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC) and pro-inflammatory cytokines interleukin (IL)-1β by 88% (p < 0.05), 48% (p < 0.05) and 149% (p < 0.05), respectively, when compared to the saline-treated group. Next, using an in vitro model of ischemia in organotypic slice cultures, we tested the hypothesis that inhibition of nicotine-induced inflammasome activation improves post-ischemic neuronal survival. Accordingly, slices were exposed to nicotine (100 ng/mL; 14–16 days) or saline, followed by treatment with the inflammasome inhibitor isoliquiritigenin (ILG; 24 h) prior to oxygen-glucose deprivation (OGD; 45 min). Quantification of neuronal death demonstrated that inflammasome inhibition significantly decreased nicotine-induced ischemic neuronal death. Overall, this study shows that chronic nicotine exposure exacerbates ischemic brain damage via activation of the inflammasome in the brain of female rats.
Highlights
Cigarette smoking is a preventable risk factor for stroke, and smoking-ingested nicotine exacerbates post-stroke brain damage [1,2]
What is more striking is that even among women there are studies that clearly link more damaging effects of stroke in women who combine oral contraceptive (OC)/hormone replacement therapy (HRT) and cigarette smoking. This points to the facts that: (1) OC/HRT and cigarette smoking/tobacco use have synergistic deleterious effects on a woman’s brain and (2) a gender non-specific risk factor of cigarette smoking has unique effects on the female brain that need to be identified and targeted to reduce consequences of stroke in women
Because our previous results demonstrated that nicotine reduced the level of membrane-bound and mitochondrial ER-β in the hippocampus, in this study, we investigated protein expression of ER-β in the cortex, the main brain area vulnerable after transient middle cerebral artery occlusion
Summary
Cigarette smoking is a preventable risk factor for stroke, and smoking-ingested nicotine exacerbates post-stroke brain damage [1,2]. What is more striking is that even among women there are studies that clearly link more damaging effects of stroke in women who combine OC/HRT and cigarette smoking This points to the facts that: (1) OC/HRT and cigarette smoking/tobacco use have synergistic deleterious effects on a woman’s brain and (2) a gender non-specific risk factor of cigarette smoking has unique effects on the female brain that need to be identified and targeted to reduce consequences of stroke in women. In laboratory studies on female rats, we confirmed the aforementioned epidemiological findings that chronic nicotine exposure reduced endogenous 17β-estradiol (E2; a potent estrogen) levels [9]. In the current study, we hypothesized that chronic nicotine exposure activates the inflammasome in the brain, exacerbating ischemic brain damage in female rats
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