Trimethylamine N-oxide Aggravates Neuro-inflammation via lncRNA Fendrr/miR-145-5p/PXN axis in Vascular Dementia Rats
Vascular dementia (2VO) is the second-most cause of dementia, and our previous investigation showed that Trimethylamine-N-oxide (TMAO) exacerbates cognitive dysfunction and neuropathological changes in 2VO rats. Therefore, this study is aimed to evaluate the mechanism of TMAO in 2VO. Bilateral common carotid artery (2VO) model was established in rats and TMAO (120 mg/kg) was administered for 8 consecutive weeks, 4 weeks preoperatively and 4 weeks postoperatively. High-throughput sequencing was performed to find out the effects of TMAO treatment on lncRNA expression in rat hippocampus and bioinformatics analysis was conducted to identify potential downstream targets. Learning and spatial memory capacities were measured, as well as inflammatory factors. Nissl staining was used to observe neuronal injury in the CA1 area of the hippocampus. TMAO administration upregulated lncRNA Fendrr expression in the rat hippocampus, while the damaging effects of TMAO were counteracted after knockdown of Fendrr. Fendrr was highly expressed in 2VO rats and sponged miR-145-5p, which targets PXN. Silencing of Fendrr or PXN, or promotion of miR-145-5p improved neurological function injury, reduced neuronal damage, as well as repressed inflammation response. Inhibition of miR-145-5p abrogated up Fendrr knockdown mediated influence on 2VO rats. Taken together, our results showed that TMAO inhibits the miR-145-5p/PXN axis by increasing the Fendrr expression, thus exacerbating the development of 2VO. Overall design: The hippocampal tissues of lncRNA profiles in 2VO rats  and 2VO rats were continuously administered TMAO