A quinine-squaramide catalyzed enantioselective vinylogous Mannich reaction between benzothiazolimines and γ-butenolides for efficient preparation of chiral N-benzothiazole butyrolactones.

A highly effective and enantioselective vinylogous Mannich reaction between benzothiazolimines and γ-butenolides catalyzed by a quinine based squaramide has been disclosed. A series of chiral benzothiazole amines containing a γ,γ-disubstituted butanolide scaffold bearing an adjacent chiral stereocenter have been successfully obtained in good to excellent yields (up to 91%) with excellent enantioselectivities (up to >99% ee) and diastereoselectivities (>20 : 1 dr) with broad substrate generality under mild conditions. The new scaffold integrated with both chiral benzothiazolimine and γ-butenolide moieties may provide a possibility for the development of new pharmaceutical entities.

Multiple exposures to sevoflurane across postnatal development may cause cognitive deficits in older age.

BACKGROUND: The aim of the study was to determine the effects of repeated anesthesia exposure across postnatal development. METHODS: Seventy-two newborn Sprague-Dawley rats were randomly divided into Sev group and Con-aged group. Sev groups were exposed to 2.6% sevoflurane for 2 h on postnatal day (P) 7, P14, and P21; the Con groups only received carrier gas for 2 h. Learning and memory were evaluated using the MWM test at P31 (juvenile), P91 (adult), and 18 months postnatally (aged). The relative expression of APP and Mapt mRNA was detected by RT-PCR, while Aß, tau, and P-tau protein levels were analyzed by immunohistochemistry. RESULTS: After repeated inhalation of sevoflurane, MWM test performance was significantly decreased in the Sev-aged group compared to the Con-aged group (P > 0.05). The relative expression of APP and Mapt mRNA was not significantly different between groups in each growth period (P > 0.05). The tau expression in the juvenile hippocampal CA1, CA3, and dentate gyrus regions increased markedly in the Sev group, while P-tau only increased in the hippocampal CA3 region in the Sev-adult group. The expression of tau, P-tau, and Aß in the hippocampal regions was upregulated in the Sev-aged group. CONCLUSIONS: Multiple exposures to sevoflurane across postnatal development can induce or aggravate cognitive impairment in old age. IMPACT: Whether multiple sevoflurane exposures across postnatal development cause cognitive impairment in childhood, adulthood, or old age, as well as the relationship between sevoflurane and the hippocampal Aß, tau, and P-tau proteins, remains unknown. This study's results demonstrate that multiple exposures to sevoflurane across postnatal development do not appear to affect cognitive function in childhood and adulthood; however, multiple exposures may lead to a cognitive function deficit in old age. The underlying mechanism may involve overexpression of the tau, P-tau, and Aß proteins in the hippocampus.

Gastrodin improves neuroinflammation-induced cognitive dysfunction in rats by regulating NLRP3 inflammasome.

Neuroinflammation is the main pathological mechanism of cognitive dysfunction caused by neurodegenerative diseases, and effective preventive and therapeutic measures are not available. We predicted the key targets of gastrodin's effects upon neuroinflammation through Network Pharmacology and molecular docking. Then the predicted targets were used to study how gastrodin affected cognitive dysfunction triggered by lipopolysaccharide-induced neuroinflammation in rats and its mechanisms. Three-month-old male rats were intraperitoneally injected with lipopolysaccharide for 3 days (d), 7 d and 14 d respectively. Gastrodin improved learning and memory ability of rats with neuroinflammation. Lipopolysaccharide enhanced the levels of pro-inflammatory cytokines, such as TNF-α, IL-1ß and IL-6, in rat hippocampus, which could be reversed by gastrodin. Gastrodin also inhibited the activation of microglia. Our findings suggested that gastrodin exerted neuroprotective effects in rats with neuroinflammation by impacting the TLR4-NF-kB-NLRP3 pathway. Therefore, gastrodin may be a potential therapeutic agent for neuroinflammation-induced cognitive dysfunction.

The role of TREM1 in regulating microglial polarization in sevoflurane-induced perioperative neurocognitive disorders.

Microglia-mediated neuroinflammatory responses play a key role in perioperative neurocognitive disorders (PND). Triggering receptor expressed on myeloid cells-1 (TREM1) has been shown to be a key regulator of inflammation. However, its role in PND remains largely unknown. This study aimed to evaluate the role of TREM1 in sevoflurane-induced PND. We applied AAV knockdown TREM1 in hippocampal microglia in aging mice. The mice were then subjected to neurobehavioral and biochemical testing after the intervention of sevoflurane. We found that sevoflurane inhalation can cause PND in mice, increase hippocampal TREM1 expression, polarize microglia to M1 type, upregulate TNF-α and IL-1ß expression (pro-inflammatory), and inhibit TGF-ß and IL-10 expression (anti-inflammatory). Knocking down TREM1 can improve sevoflurane-induced cognitive dysfunction, reduce M1 type marker iNOS, and increase M2 type marker ARG, improving the neuroinflammation. TREM1 is a target for sevoflurane-induced PND prevention.

Effect of multiple neonatal sevoflurane exposures on hippocampal apolipoprotein E levels and learning and memory abilities.

BACKGROUND: Sevoflurane anesthesia is widely used in pediatric patients. In this study, we investigated whether early multiple exposures to sevoflurane induced cognitive dysfunction by altering the hippocampal expression of ApoE later in development. METHODS: Sprague-Dawley rats were exposed to 2.6% sevoflurane at postnatal day 7 (P7), P14, and P21 for 2 h. The ability of learning and memory was assessed using the Morris water maze at P37 and P97. The hippocampal volume was measured by magnetic resonance imaging (MRI) at P37 and P97. The hippocampal expression of ApoE was assessed by immunohistochemical analyses and real-time polymerase chain reaction (PCR). RESULTS: Behavioral testing revealed that the ability of learning and memory in the sevoflurane-exposed rats was decreased compared with the control animals; however, there was no significant difference (P > 0.05). The MRI results showed a significant decrease in the left hippocampal volume, left maximum hippocampal length, and right maximum hippocampal length in the sevoflurane young group compared with the control young group (P < 0.05). The brain volume, left maximum hippocampal length, right hippocampal volume, and maximum brain length were significantly lower in the sevoflurane adult group than in the control adult group (P < 0.05). In young animals, the ApoE expression in the hippocampal CA1 and CA3 regions and the ApoE mRNA level were significantly higher compared with the control group (P < 0.05), but not in the dentate gyrus region (P > 0.05). Among the adult animals, there was no significant difference between the groups in any parameter tested (P > 0.05). CONCLUSION: Multiple exposures to sevoflurane during the neonatal period decreased the volume of the hippocampus and increased the hippocampal expression of ApoE. The differential expression level of ApoE in different hippocampal subdivisions suggested that the expression of ApoE was regionally specific and reversible.

Effect of repeated neonatal sevoflurane exposure on the learning, memory and synaptic plasticity at juvenile and adult age.

Currently sevoflurane is the volatile anesthetic most wildly used in pediatric surgery. Whether neonatal exposure to sevoflurane brings about a long-lasting adverse impact even at juvenile and adult age, attracts extensive concerns. However, to date the consensus has not been reached and how exposure to sevoflurane in early life affects long-term ability of learning and memory is not fully elucidated. To obtain further insight into this issue, 32 neonatal SD rats were assigned into control group (group C, n=16) and sevoflurane group (group SEV, n=16). At postnatal day 7 (P7), 14 (P14) and 21 (P21) rats pups in group SEV received repeated exposure to 2.6% sevoflurane for 2 h. At juvenile and adult age, Morris water maze (MWM) was used to determine the spatial memory performance. Subsequently long-term and short-term synaptic plasticity in hippocampal CA1 region were investigated by in vivo electrophysiological method. Our behavioral data revealed that repeated exposure to 2.6% sevoflurane in early life did not result in marked behavioral abnormalities. However, in electrophysiological experiment, long-term potentiation (LTP) in hippocampal neurons of animals neonatally exposed to sevoflurane was significantly inhibited as compared to animals in group C at both juvenile and adult age. Pair-pulse facilitation (PPF) ratio in group SEV at juvenile and adult age was augmented to varying extent. These effects were most noticeable at juvenile stage with tendency of alleviation during adulthood. The present study provides an alternative explanation for the mechanism underlying developmental neurotoxicity of sevoflurane, which may ameliorate future preventive and therapeutic strategies.