Dysregulation of the Gut Microbiota Contributes to Sevoflurane-Induced Cognitive Dysfunction in Aged Mice by Activating the NLRP3 Inflammasome.

Postoperative cognitive dysfunction (POCD), a common complication in elderly patients after surgery, seriously affects patients' quality of life. Long-term or repeated inhalation of sevoflurane can cause neuroinflammation, which is a risk factor for POCD. However, the underlying mechanism needs to be further explored. Recent research had revealed a correlation between neurological disorders and changes in the gut microbiota. Dysfunction of the gut microbiota is involved in the occurrence and development of central nervous system diseases. Here, we found that cognitive dysfunction in aged mice induced by sevoflurane exposure (3%, 2 hours daily, for 3 days) was related to gut microbiota dysbiosis, while probiotics improved cognitive function by alleviating dysbiosis. Sevoflurane caused a significant decrease in the abundance of Akkermansia (P<0.05), while probiotics restored the abundance of Akkermansia. Compared to those in the control group, sevoflurane significantly increased the expression of NLRP3 inflammasome-associated proteins in the gut and brain in the sevoflurane-exposed group, thus causing neuroinflammation and synaptic damage, which probiotics can mitigate (con vs. sev, P < 0.01; p+sev vs. sev, P < 0.05). In conclusion, for the first time, our study revealed that dysbiosis of the gut microbiota caused by sevoflurane anesthesia contributes to the NLRP3 inflammasome-mediated neuroinflammation and cognitive dysfunction from the perspective of the gut-brain axis. Perhaps postoperative cognitive impairment in elderly patients can be alleviated or even prevented by regulating the gut microbiota. This study provides new insights and methods for the prevention and treatment of cognitive impairment induced by sevoflurane.

Minocycline Attenuates Sevoflurane-Induced Postoperative Cognitive Dysfunction in Aged Mice by Suppressing Hippocampal Apoptosis and the Notch Signaling Pathway-Mediated Neuroinflammation.

Postoperative cognitive dysfunction (POCD), an important postoperative neurological complication, is very common and has an elevated incidence in elderly patients. Sevoflurane, an inhaled anesthetic, has been demonstrated to be associated with POCD in both clinical and animal studies. However, how to prevent POCD remains unclear. Minocycline, a commonly used antibiotic can cross the blood-brain barrier and exert an inhibitory effect on inflammation in the central nervous system. The present work aimed to examine the protective effect and mechanism of minocycline on sevoflurane-induced POCD in aged mice. We found that 3% sevoflurane administered 2 h a day for 3 consecutive days led to cognitive impairment in aged animals. Further investigation revealed that sevoflurane impaired synapse plasticity by causing apoptosis and neuroinflammation and thus induced cognitive dysfunction. However, minocycline pretreatment (50 mg/kg, i.p, 1 h prior to sevoflurane exposure) significantly attenuated learning and memory impairments associated with sevoflurane in aged animals by suppressing apoptosis and neuroinflammation. Moreover, a mechanistic analysis showed that minocycline suppressed sevoflurane-triggered neuroinflammation by inhibiting Notch signaling. Similar results were also obtained in vitro. Collectively, these findings suggested minocycline may be an effective drug for the prevention of sevoflurane-induced POCD in elderly patients.

Sevoflurane inhibits histone acetylation and contributes to cognitive dysfunction by enhancing the expression of ANP32A in aging mice.

Postoperative cognitive dysfunction (POCD) is a major clinical complication after surgery under general anesthesia, particularly in elderly patients, but the mechanisms remain unclear. We recently found that the anaesthetization of aging C57BL/6 J mice (14-16 months) with sevoflurane (3%, two hours each day for three consecutive days) can induce cognitive dysfunction and synaptic plasticity deficits. Further studies demonstrated that sevoflurane induced ANP32A (acidic leucine-rich nuclear phosphoprotein-32A) overexpression by stimulating C/EBPß (CCAAT/enhancer binding protein-ß), which could suppress histone acetylation at H3K18, H3K14, H4K5, and H4K12 and decrease the binding of H3K18 and H3K14 to the promoters of GluN2B and GluN2A, respectively. These results suggest that sevoflurane can inhibit histone acetylation and contribute to cognitive dysfunction by enhancing the expression of ANP32A in aging mice. Our study provides new insights into aging-associated POCD and potential molecular markers for protection.

Low genetic diversity and strong immunogenicity within the apical membrane antigen-1 of plasmodium ovale spp. imported from africa to china.

Malaria is still an important challenge for global public health because of its extensive mortality and morbidity. Plasmodium ovale is mainly distributed in tropical regions of Africa and Asia. it includes two distinct ovale malaria species, which are P. ovale curtisi and P. ovale wallikeri. Apical membrane antigen-1 (AMA-1) is an asexual blood-stage protein which is essential for Plasmodium. Thus far, no study on gene polymorphism and immunogenicity of P. ovale AMA-1 (PoAMA-1) has been conducted. Amplified poama1 gene products from 14 P ovale curtisi samples and 12 P ovale wallikeri samples imported from Africa to Jiangsu Province, China were sequenced and their polymorphisms were analyzed. We expressed recombinant PoAMA-1 (rPoAMA-1, 53 kDa) proteins in an E. coli expression system and evaluated immune responses against the rPoAMA-1 in BALB/c mice. We identified a synonymous mutation in nucleotide position 333 of the pocama-1 gene and powama-1 did not reveal any variation. The humoral and cellular immune responses to rPoAMA-1 were evaluated using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. rPoAMA-1-immunized mice produced specific antibodies as verified by immunoblotting. The rPoAMA-1 induced high antibody titers (1: 640,000), and had high avidity indexes (an average of 78.63% and 83.40%). The antibodies also recognized the native proteins, namely, crude antigen from blood stages. Cross-reactivity between rPocAMA-1 and rPowAMA-1 was observed. Moreover, rPoAMA-1 s induced interferon (IFN)-gamma-secreting cells in mice and increased lymphocyte proliferation response. Low genetic diversity was observed in poama-1 from the Jiangsu Province imported malaria cases, and further studies conclusively showed its strong immunogenicity. Significant cross-reactivity was found between rPocAMA-1 and rPowAMA-1, suggesting that a single PoAMA-1 antigen could be used to diagnose P. ovale curtisi or P. ovale wallikeri patient simultaneously. However, further evaluation needs to be carried out to validate the potential and limitations of PoAMA-1 as a candidate vaccine.

Suberoylanilide hydroxamic acid reversed cognitive and synaptic plasticity impairments induced by sevoflurane exposure in adult mice.

Although it has been shown that sevoflurane exposure could impair the cognitive function, there are few effective treatments to prevent this disorder. Suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylase, plays an important role in hippocampal memory formation, which has been proven to enhance memory. As such, we explored whether SAHA could improve the memory impairment induced by sevoflurane in adult mice. In the present study, adult male C57BL/6 mice were exposed to 3% sevoflurane for 6 h, and then the cognitive impairment in Morris water maze was found at 24 h after anesthesia. Moreover, an impairment in long-term potentiation was also detected in the isolated hippocampal slices. SAHA administrated intraperitoneally 2 h before anesthesia improved cognitive and synaptic plasticity impairments. SAHA also significantly reversed the decreases in Ac-H3, brain-derived neurotrophic factor, tropomyosin-related kinase B, and p-cAMP response element-binding expressions induced by sevoflurane exposure, and reduced the level of apoptosis-related protein cleaved caspase-3. We concluded that cognitive and synaptic plasticity impairments induced by sevoflurane exposure could be reversed by normalizing the histone acetylation state. The effect is related to inhibiting cell apoptosis and activating the brain-derived neurotrophic factor/tropomyosin-related kinase B/cAMP response element-binding signaling pathway in the hippocampus.

Local injection to sciatic nerve of dexmedetomidine reduces pain behaviors, SGCs activation, NGF expression and sympathetic sprouting in CCI rats.

Neuropathic pain has become an intractable health threat, with its profound effect on quality of life. Dorsal root ganglia (DRG) is evidenced to play a crucial role in neuropathic pain. The peripheral nociceptive afferents seem to be essential not only to initiate the process of neuropathic pain, but also to maintain and modulate it. Dexmedetomidine (DEX), a highly selective agonist of α2-adrenergic receptor (α2-AR), has provided significant analgesia in neuropathic pain. In the present study, we found that local injection to sciatic nerve of DEX alleviated heat hypersensitivity induced by chronic constriction injury (CCI). Western blotting revealed that DEX inhibited the over-expression of nerve growth factor (NGF) significantly. Immunohistofluorescence results showed that DEX inhibited glia cells activation and sympathetic sprouting simultaneously in DRG. Our study suggests that DEX attenuates neuropathic pain in CCI rats by down-regulation of satellite glial cells (SGCs) activation, NGF expression and sympathetic sprouting.

The effect of sevoflurane on the cognitive function of rats and its association with the inhibition of synaptic transmission.

To observe the effects of different concentrations of sevoflurane on synaptotagmin 1 (Syt1) expression, synaptic long term depression (LTD), and paired pulse depression (PPD) in the rat hippocampus as well as to investigate the association between these effects and the cognitive function of rats. A total of 24 male Sprague-Dawley (SD) rats were selected and randomly divided into 3 groups: the control group (group A), which inhaled air; group B, which inhaled 0.65 minimum alveolar concentration (MAC) sevoflurane for 2 h; and group C, which inhaled 1.30 MAC sevoflurane for 2 h. The subsequent experiments were performed after one day. (1) Y maze tests were performed, and the expression of Syt1 in hippocampal tissues was detected using western blot. (2) The changes in LTD and PPD in rat hippocampal slices were examined using electrophysiological techniques. Compared to the control group, the cognitive function was decreased and Syt1 expression in the hippocampus was significantly decreased in rats in the 1.30 MAC sevoflurane inhalation group. After 60 min of low frequency stimulation, the amplitudes of population spike (PS) potentials in rat hippocampal slices were significantly decreased. After induction of PPD, the P2/P1 ratio was significantly increased. No indicators in the 0.65 MAC sevoflurane inhalation group showed any significant changes. Inhalation of high concentrations of sevoflurane significantly reduced Syt1 protein levels in the rat hippocampus, significantly inhibited the release of presynaptic neurotransmitters, and reduced the efficiency of synaptic transmission, thus causing memory impairment.

Antinociceptive effects of dexmedetomidine via spinal substance P and CGRP.

The aim of this study was to examine the role played by substance P and calcitonin gene-related peptide (CGRP) within the dorsal horn of the spinal cord in engagement of antinociception evoked by dexmedetomidine (DEX). Paw withdrawal threshold (PWT) to mechanical stimulation was determined after chronic intrathecal infusion of DEX and enzyme-linked immunosorbent assay (ELISA) was employed to examine the levels of spinal substance P and CGRP. Our results show that PWT was significantly increased by intrathecal administration of DEX in rats (P < 0.05 vs. vehicle control, n = 20 in each group). Also, intrathecal infusion of DEX significantly decreased the concentrations of substance P and CGRP as compared with vehicle control (P < 0.05 DEX vs. vehicle control, n = 20 in each group). Blocking α2-adrenoreceptors (α2-AR) blunted the decreases of substance P and CGRP levels and the enhancement of PWT evoked by DEX. Additionally, a linear relationship was observed between PWT and the levels of spinal substance P (r = 0.87; P < 0.005) and CGRP (r = 0.85; P < 0.005). Moreover, blocking individual substance P and CGRP receptors amplified PWT without altering substance P and CGRP levels. Thus, DEX plays a role in stimulating α2-AR receptors, which thereby decreases substance P and CGRP levels within the dorsal horn. This contributes to DEX-evoked antinociception.

Effects of conditioning with sevoflurane before reperfusion on hippocampal ischemic injury and insulin-like growth factor-1 expression in rats.

Sevoflurane pre-conditioning before ischemia can reduce ischemia-reperfusion injuries in cardiac, pulmonary and cerebral tissues. It is uncertain whether sevoflurane conditioning before reperfusion has similar protective effects on neuronal injuries. In this study, we explored the effect of sevoflurane conditioning (at concentrations of 1.5%, 2.4% or 3.0%) on the morphology and molecular mechanisms of the hippocampal CA1 region in male Sprague-Dawley rats subjected to global cerebral ischemia. We determined the pathological results by hematoxylin and eosin (H&E) staining and examined the mRNA levels of insulin-like growth factor-1 (IGF-1) and protein levels of p-JNK1/2 and p-Akt1 in the hippocampus at 24 h, 48 h and 72 h after global cerebral ischemia-reperfusion. Our data showed that O2 post-conditioning and lower dose (1.5%) of sevoflurane did not ameliorate ischemia-induced CA1 injury. However, higher doses of 2.4% and 3.0% sevoflurane post-conditioning alleviated the CA1 injury and enhanced the expression levels of IGF-1 mRNA. Furthermore, sevoflurane post-conditioning inhibited the activations of p-JNK1/2 and enhanced activation of p-Akt1. In conclusion, these results suggest that post-conditioning with sevoflurane at 2.4% and 3.0% ameliorates global cerebral ischemia induced hippocampal CA1 injury by up-regulating the expression of IGF-1 mRNA followed by the activation of p-Akt1 and inhibition of the activation of p-JNK1/2.

Effect of ondansetron in preventing postoperative nausea and vomiting under different conditions of general anesthesia: a preliminary, randomized, controlled study.

METHODS: Two hundred and forty patients were randomly allocated into six groups: Group I, anesthesia was maintained with sevoflurane; Group II, anesthesia was maintained with sevoflurane and 8 mg of ondansetron; Group III, anesthesia was maintained with propofol; Group IV, anesthesia was maintained with propofol and 8 mg of ondansetron; Group V, anesthesia was maintained with sevoflurane and propofol; Group VI, anesthesia was maintained with sevoflurane combined with propofol and 8 mg of ondansetron. RESULTS: We found that the incidence of vomiting was lower in group II (17.5%), group IV (7.5%), and group VI (10%) compared with group I (55%), group III (27.5%), and group V (30%), respectively (P < 0.05). The incidence of vomiting was also lower in group III (27.5%) and group V (30%) when compared with group I (55%) (P < 0.05). The incidence of nausea was 55% in group I, 42.5% in group II, 30% in group III, 27.5% in group IV, 30% in group V, and 30% in group VI. Groups III and V had a lower incidence of nausea than group I (P < 0.05). CONCLUSIONS: We conclude that compared with sevoflurane anesthesia alone, anesthesia with either propofol alone or propofol combined with sevoflurane resulted in a reduced incidence of vomiting and nausea during the first 24 h after surgery. Administration of ondansetron effectively reduced the incidence of vomiting but not that of nausea for all three types of general anesthesia.

The effect of sevoflurane on the expression of M1 acetylcholine receptor in the hippocampus and cognitive function of aged rats.

Our aim is to investigate the effect of 1.5 and 3.0% sevoflurane on the expression of M(1) acetylcholine receptor (mAChR M(1)) in the hippocampus and the cognitive function of aged rats. Forty Sprague-Dawley (SD) rats of 12-month old were randomly divided into five groups. All SD rats received 1.5 or 3.0% sevoflurane in a special glass anesthesia box for 2 h, respectively, except for the normal control group. Y-maze was used to test the ability of learning and memory after being received sevoflurane for 1 or 7 days at the same moment portion. The expression of mAChR M(1) in the hippocampus of rats was tested by RT-PCR. The results showed that 3% sevoflurane induced the decline of cognitive function and significantly decreased the mAChR M(1) expression at mRNA levels at 1 day in the 3.0% sevoflurane I group when compared with the normal control group. However, there was no significant difference among the other groups when compared with normal control group. Therefore, administration of sevoflurane might temporally affect the ability of cognitive function of rats through suppressing the mAChR M(1) expression at mRNA levels in hippocampus.

Sevoflurane postconditioning ameliorates oxygen-glucose deprivation-reperfusion injury in the rat hippocampus.

INTRODUCTION: Sevoflurane is well known to exert a neuroprotective effect through anesthetic preconditioning. However, its effects on postconditioning, a neuroprotective phenomenon following an insult, have not been well studied. AIMS: In this study, we examined the ability of sevoflurane to induce postconditioning in rat hippocampal slices, in vitro. RESULTS: 2%, 4%, and 6% sevoflurane reduced neurophysiologic and morphologic neuronal injury following oxygen-glucose deprivation (OGD) and reperfusion. The quantity of damaged neurons was significantly reduced on immunofluorescence staining; excitatory amino acids (Asp, Glu) increased and inhibitory amino acids (GABA) decreased significantly. The effect was concentration-dependent. CONCLUSION: Postconditioning with sevoflurane reduces neuronal damage after OGD-reperfusion injury in the CA1 area of rat hippocampus, in vitro.

The effect of sevoflurane anesthesia on cognitive function and the expression of Insulin-like Growth Factor-1 in CA1 region of hippocampus in old rats.

To investigate the effects of sevoflurane on cognitive function in old Sprague-Dawley (SD) rats and the expression of insulin-like growth factor-1 (IGF-1) in CA1 region of hippocampus. Forty Sprague-Dawley rats of 12 months old were randomly divided into five groups: the normal control group; 1.5% sevoflurane I group (be tested after received 1.5% sevoflurane for 1 day); 1.5% sevoflurane II group (be tested after received 1.5% sevoflurane for 7 day); 3.0% sevoflurane I group (be tested after received 3.0% sevoflurane for 1 day) and 3.0% sevoflurane II group (be tested after received 3.0% sevoflurane for 7 day). All SD rats were received 1.5 or 3.0% sevoflurane in a special glass anesthesia box for 2 h respectively, except for the normal control group. Y-maze was used to test the ability of learning and memory after being received sevoflurane for 1 or 7 days at the same moment portion. The altered expression level of IGF-1 in the hippocampus was tested to compare its transcripts by RT-PCR analysis. The results showed that 3% sevoflurane induced the decline of cognitive function and significantly deceased the IGF-1 expression at mRNA levels at 1 day in the 3.0% sevoflurane I group when compared with the normal control group. However, there were no significant difference among the other groups when compared with normal control group. Therefore, administration of sevoflurane might temporally affect the ability of cognitive function of rats through suppressing the IGF-1 expression at mRNA levels in hippocampus.