Delayed neurocognitive recovery (dNCR) is a major complication after anesthesia and surgery in older adults. Alpha‐synuclein (α‐syn; encoded by the gene, SNCA) has recently been shown to play an important role in hippocampus‐dependent working memory. Aggregated forms of α‐syn are associated with multiple neurotoxic mechanisms, such as mitochondrial dysfunction and cell death. In this study, we found that blocking α‐syn improved both mitochondrial function and mitochondria‐dependent neuronal apoptosis in a mouse model of dNCR. Various forms of α‐syn (including total α‐syn, phosphorylated‐Ser129‐α‐syn, and oligomers) were upregulated in hippocampal tissue and extracted mitochondria after surgical challenge. Clenbuterol is a novel transcription modulator of Scna. Clenbuterol significantly attenuated surgery‐induced progressive accumulation of various toxic α‐syn forms in the hippocampus, as well as mitochondrial damage and memory deficits in aged mice following surgery. We also observed excessive mitochondrial α‐syn accumulation and increased mitochondria‐mediated apoptosis in vitro using nerve growth factor‐differentiated PC12 cells and primary hippocampal neurons exposed to lipopolysaccharide. To further validate the neuroprotective effect of α‐syn inhibition, we used a lentiviral Snca‐shRNA (Lv‐shSnca) to knockdown Snca. Of note, Lv‐shSnca transfection significantly inhibited neuronal apoptosis mediated by the mitochondrial apoptosis pathway in neurons exposed to lipopolysaccharide. This α‐syn inhibition improved the disruption to mitochondrial morphology and function, as well as decreased levels of apoptosis. Our results suggest that targeting pathological α‐syn may achieve neuroprotection through regulation of mitochondrial homeostasis and suppression of apoptosis in the aged hippocampus, further strengthening the therapeutic potential of targeting α‐syn for dNCR.

Postoperative neurocognitive impairment is an urgent problem with global aging accelerating. The prevention and treatment of postoperative neurocognitive impairment have been widely investigated but lack effective strategies. Low-intensity pulsed ultrasound (LIPUS), a non-invasive tool, has shown an effect on neuroprotection, but whether it could attenuate the postoperative neurocognitive impairment and the underlying mechanisms remains unknown. An experimental setup for LIPUS stimulation of the hippocampus was well established. A laparotomy model in aged mice was applied, and a Morris water maze was used to assess cognitive function. RT-qPCR and western blotting were used to detect levels of Piezo1, synapse-associated proteins in the hippocampus, respectively. Immunofluorescent staining was also used to determine the neural activation and Piezo1 expression. The results showed that LIPUS increased synapse-related proteins of the hippocampus and attenuated cognitive impairment in aged mice. Meanwhile, LIPUS suppressed the overexpression of Piezo1 in the hippocampus. We further found that LIPUS promoted Calpain1 activity and increased extracellular regulated protein kinases (Erk) phosphorylation. Our results suggested that LIPUS could improve cognitive impairment and increase hippocampal synaptogenesis through the Piezo1-mediated Calpain1/ Erk pathway. LIPUS could be used as an effective physical intervention to alleviate postoperative cognitive dysfunction in the aged population.

Postoperative cognitive impairment is more likely to occur in elderly patients and in those with neurodegenerative diseases. The mechanisms underlying this impairment include neuroinflammation and oxidative stress. The increase in reactive oxygen species during oxidative stress causes cellular and molecular injury to neurons, including DNA damage, which aggravate brain dysfunction. Vitamin C has antioxidant effects and improves cognitive function in patients with Alzheimer's disease. However, it is unclear whether it can ameliorate surgery-induced cognitive impairment by inhibiting oxidative stress. In this study, 6-month-old mice overexpressing mutant amyloid precursor protein and presenilin-1 (APP/PS1) were subjected to laparotomy. The open field and fear conditioning tests were used to assess cognitive function. Mice that underwent surgery showed cognitive impairment without changes in spontaneous locomotor activity. Oxidative stress, DNA damage and inflammatory mediators were increased in the hippocampus after surgery. The expression levels of non-homologous end-joining DNA repair-associated proteins, including Ku heterodimer, DNA-dependent protein kinase catalytic subunit, X-ray repair cross complementing 4 (XRCC4) and XRCC4-like factor, were increased after surgery. Vitamin C pretreatment effectively attenuated cognitive dysfunction induced by surgery and reduced oxidative stress and DNA damage. Our findings suggest that DNA damage plays an important role in surgery-induced cognitive dysfunction, and that vitamin C pretreatment may have therapeutic potential as a preventative approach for the cognitive impairment.

The effects of the intravenous anesthetics propofol and etomidate on circulation are significantly different; however, their differing effects on miRNA expression in the cardiovascular system are not clearly understood. The purpose of this study is to investigate the effects of these two anesthetics on miRNA expression profiles in the heart and blood vessels. Rats were randomly divided into a propofol group and an etomidate group. Spontaneous breathing was maintained throughout the anesthesia process and the rats’ oxygen supply was ensured. Heart and thoracic aorta tissue was harvested 3 h after induction. The expression profiles of cardiovascular miRNAs were detected by microarray 4.0 analysis. Twelve representative miRNAs were selected for qRT-PCR validation, and their target genes were predicted using bioinformatics methods. Microarray analysis showed 16 differentially expressed miRNAs in heart tissue from the propofol group compared with the etomidate group (10 up-regulated and 6 down-regulated), while in the blood vessels there were 25 altered miRNAs (10 up-regulated, 15 down-regulated). After verifying 12 representative miRNAs via qRT-PCR, the results showed no significant difference in the expression of miRNAs in the heart tissue, but a significant difference in the expression of 5 miRNAs in vessel tissue between the two groups. Bioinformatics analysis predicts that the target genes of the 5 differentially expressed miRNAs are associated with chemical synapse signaling pathways. Propofol and etomidate have different effects on the expression of cardiovascular miRNAs, and further research is needed to elucidate the functional consequences of these differentially expressed miRNAs.

Delayed neurocognitive recovery (dNCR) is a common complication that occurs post-surgery, especially in elderly individuals. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex plays an essential role in various membrane fusion events, such as synaptic vesicle exocytosis and autophagosome–lysosome fusion. Although SNARE complex dysfunction has been observed in several neurodegenerative disorders, the causal link between SNARE-mediated membrane fusion and dNCR remains unclear. We previously demonstrated that surgical stimuli caused cognitive impairment in aged rats by inducing α-synuclein accumulation, inhibiting autophagy, and disrupting neurotransmitter release in hippocampal synaptosomes. Here, we evaluated the effects of propofol anesthesia plus surgery on learning and memory and investigated levels of SNARE proteins and chaperones in hippocampal synaptosomes. Aged rats that received propofol anesthesia and surgery exhibited learning and memory impairments in a Morris water maze test and decreased levels of synaptosome-associated protein 25, synaptobrevin/vesicle-associated membrane protein 2, and syntaxin 1. Levels of SNARE chaperones, including mammalian uncoordinated-18, complexins 1 and 2, cysteine string protein-α, and N-ethylmaleimide-sensitive factor, were all significantly decreased following anesthesia with surgical stress. However, the synaptic vesicle marker synaptophysin was unaffected. The autophagy-enhancer rapamycin attenuated structural and functional disturbances of the SNARE complex and ameliorated disrupted neurotransmitter release. Our results indicate that perturbations of SNARE proteins in hippocampal synaptosomes may underlie the occurrence of dNCR. Moreover, the protective effect of rapamycin may partially occur through recovery of SNARE structural and functional abnormalities. Our findings provide insight into the molecular mechanisms underlying dNCR.