Oxidative stress and inflammation damage play pivotal roles in vascular dementia (VaD). Trimethylamine N-oxide (TMAO), an intestinal microbiota-stemming metabolite, was reported to promote inflammation and oxidative stress, involved in the etiology of several diseases. Still, these effects have not been investigated in VaD. Here, we tested whether pre-existing, circulating, high levels of TMAO could affect VaD-induced cognitive decline. TMAO (120 mg/kg) was given to rats for a total of 8 weeks, and these rats underwent a sham operation or bilateral common carotid artery (2VO) surgery after 4 weeks of treatment. Four weeks after surgery, the 2VO rats exhibited hippocampal-dependent cognitive function declines and synaptic plasticity dysfunction, accompanied by an increase in oxidative stress, neuroinflammation, and apoptosis. TMAO administration, which increased plasma and hippocampal TMAO at 4 weeks postoperatively, further aggravated these effects, resulting in exaggerated cognitive and synaptic plasticity impairment, though not within the Sham group. Moreover, TMAO treatment activated the NLRP3 inflammasome and decreased SIRT1 protein expression within the hippocampus. However, these effects of TMAO were significantly attenuated by the overexpression of SIRT1. Our findings suggest that TMAO increases oxidative stress-induced neuroinflammation and apoptosis by inhibiting the SIRT1 pathway, thereby exacerbating cognitive dysfunction and neuropathological changes in VaD rats.

Background: After ischemic stroke (IS), microglia and astrocytes undergo polarization, transforming into a pro-inflammatory phenotype (M1 or A1). According to previous studies, exosomes might play an important role in the interplay between M1 microglia and A1 astrocytes after IS. Methods: We used the microglial oxygen-glucose deprivation/reperfusion (OGD/R) model and ultracentrifugation to extract M1 microglial exosomes (M1-exos). Subsequently, we identified circSTRN3 enriched in exosomes through RNA sequencing and detected the role of circSTRN3 in astrocyte activation based on bioinformatics analysis, immunofluorescence, Western blotting, and polymerase chain reaction analysis. We validated these findings in the middle cerebral artery occlusion/reperfusion (MCAO/R) model of adult male C57BL/6J mice. Finally, we confirmed the correlation among circSTRN3, miR-331-5p, and stroke severity score in exosomes isolated from peripheral blood of IS patients. Results: Our findings revealed that M1-exos promoted A1 astrocyte activation. CircSTRN3 was abundant in M1-exos, which could sponge miR-331-5p to affect mitochondrial antiviral signaling protein (MAVS), activate NF-κB pathway, and participate in A1 astrocyte activation. In addition, overexpressed circSTRN3 augmented the infarct size and neurological dysfunction in MCAO/R models, while miR-331-5p mimics reversed the effect. Furthermore, circSTRN3 in IS patients was positively correlated with stroke severity score (R² = 0.83, P < 0.001), while miR-331-5p demonstrated a negative correlation with the same score (R² = 0.81, P < 0.001). Conclusion: Taken together, our research indicated that circSTRN3 from M1-exos could promote A1 astrocyte activation and exacerbate ischemic brain injury via miR331-5p/MAVS/NF-κB axis.

Background: Stress hyperglycemia may deteriorate stroke outcomes, but its impact on the prognosis following mechanical thrombectomy remains unclear. This study aimed to evaluate the effects of stress hyperglycemia on in-hospital and 3-month outcomes in stroke patients with anterior circulation occlusion undergoing mechanical thrombectomy. Methods: A total of 415 patients who had mechanical thrombectomy in the anterior circulation were enrolled. The stress hyperglycemia ratio (SHR) was calculated as the fasting glucose to glycated hemoglobin ratio and was categorized into tertiles (i.e., SHR1–3). In-hospital and 3-month outcomes were compared using multivariable regression models. The impact of SHR stratified by diabetes status was evaluated and the predictive accuracy of the Totaled Health Risks in Vascular Events (THRIVE)-c risk score was explored with the inclusion of SHR. Results: Compared to the SHR1–2 groups, the SHR3 group exhibited significantly higher rates of 24 h symptomatic intracranial hemorrhage (adjusted odds ratio [aOR], 4.088; 95% confidence interval [CI], 1.551–10.772; p = 0.004) and 72 h early neurological deterioration (aOR, 3.505; 95% CI, 1.984–6.192; p < 0.001), while the incidence of post-stroke pneumonia did not differ significantly between the groups (aOR, 1.379; 95% CI, 0.838–2.268; p = 0.206). At three months, the SHR3 group had a worse distribution of modified Rankin scale (aOR, 2.261; 95% CI, 1.495–3.421; p < 0.001) and faced a higher risk of functional dependence (adjusted hazard ratio [aHR], 1.629; 95% CI, 1.230–2.158; p = 0.001) as well as all-cause mortality (aHR, 1.986; 95% CI, 1.235–3.194; p = 0.005). The adverse effects of an elevated SHR were more pronounced in non-diabetic patients, and incorporating SHR significantly enhanced the predictive accuracy of the THRIVE-c score for poor stroke outcomes. Conclusions: Stress hyperglycemia could be related to the risks of in-hospital complications and 3-month poor outcomes following mechanical thrombectomy in the anterior circulation.