Isoflurane-induced Cognitive Dysfunction Research Articles

ANGPTL2 Deletion Attenuates Neuroinflammation and Cognitive Dysfunction Induced by Isoflurane in Aged Mice through Modulating MAPK Pathway.

Postoperative cognitive dysfunction (POCD) is a well-known complication after surgery with cognitive impairments. Angiopoietin-like protein 2 (ANGPTL2) has been found to be associated with inflammation. However, the role of ANGPTL2 in inflammation of POCD is unclear. Here, mice were subjected into isoflurane anesthesia. It was demonstrated that isoflurane increased ANGPTL2 expression and promoted pathological change in brain tissues. However, downregulation of ANGPTL2 alleviated the pathological change and elevated learning and memory abilities, improving isoflurane-induced cognitive dysfunction in mice. In addition, isoflurane-induced cell apoptosis and inflammation were repressed via ANGPTL2 knockdown in mice. Downregulation of ANGPTL2 was also verified to suppress isoflurane-induced microglial activation, evidenced by a decrease of Iba1 and CD86 expressions and an increase of CD206 expression. Further, the isoflurane-induced MAPK signaling pathway was repressed through downregulation of ANGPTL2 in mice. In conclusion, this study proved that downregulation of ANGPTL2 attenuated isoflurane-induced neuroinflammation and cognitive dysfunction in mice via modulating the MAPK pathway, which provided a new therapeutic target for POCD.

HSF-1 attenuates isoflurane-induced cognitive dysfunction by inhibiting TLR2 expression

Purpose: To investigate the regulatory effects of heat shock factor 1 (HSF-1) in the progression of postoperative cognitive dysfunction (POCD).
 Methods: Isoflurane (ISO)-induced POCD model in rats was established to determine the role of HSF-1 in POCD. Morris water maze test was used to evaluate the learning and memory abilities of the POCD rats while mRNA and protein levels of HSF-1 were determined by RNA extraction/quantitative real-time polymerase chain reaction (RT-qPCR) and western blot analysis, respectively.
 Results: The mRNA and protein levels of HSF-1 were significantly reduced in ISO model, but OE-HSF-1 treatment significantly elevated HSF-1 level (p < 0.05). ISO treatment also significantly decreased escape latency but increased the decreased target quadrant of the rats, while HSF-1 upregulation reversed these effects (p < 0.05). Additionally, HSF-1 alleviated ISO-induced hippocampal injury, improved ISO-induced hippocampal inflammation, and inhibited ISO-induced hippocampal apoptosis. Furthermore, HSF-1 was modulated by POCD via TLR2/NF-κB pathway (p < 0.05).
 Conclusion: HSF-1 attenuates ISO-induced cognitive dysfunction by suppressing TLR2 expression. This activity provides a potential strategy to prevent POCD via HSF-1.

Neuroprotective effect of AGGF1 against isoflurane-induced cognitive dysfunction in aged rats through activating the PI3K/AKT signaling pathways.

This study aimed to evaluate and identify the value and explore the mechanisms of Angiogenic Factor with G-patch and FHA domains 1 (AGGF1) in postoperative cognitive dysfunction (POCD). Rats were separated into four different groups, namely sham, isoflurane, isoflurane + recombinant human Aggf1 (rh-Aggf1) (5 μg kg-1), and isoflurane + rh-Aggf1 (10 μg kg-1). qPCR and western blot assays were applied to detect the correlation between the expression of AGGF1 and isoflurane administration. Then, the Morris water maze (MWM) test was applied to evaluate the effect of AGGF1 on improving the POCD rats. Subsequently, TUNEL assay was applied and the cell apoptosis-related proteins were tested to reveal the anti-apoptotic effect of AGGF1 in POCD rats. Furthermore, the mRNA and protein levels of TNF-α, IL-6, and IL-1β were also detected by qPCR and ELISA to verify the anti-inflammatory effects of AGGF1 on POCD rats. Besides, the protein expression levels of PI3K, Akt, and NF-κB in each group were examined by western blot. In this study, the results revealed that isoflurane induced a decrease in AGGF1 expression in the hippocampus of aged rats. In addition, exogenous AGGF1 attenuated POCD in aged rats. Meanwhile, exogenous AGGF1 had anti-apoptotic and anti-inflammatory effects in POCD rats. Further research indicated that AGGF1 activated the PI3K/Akt pathway. AGGF1 has neuroprotective effect against isoflurane-induced cognitive dysfunction in aged rats via activating the PI3K/AKT signaling pathways.

Long non-coding RNA maternally expressed 3 (MEG3) regulates isoflurane-induced cognitive dysfunction by targeting miR-7-5p

This study aimed to investigate the role and mechanism of long non-coding RNA maternally expressed gene 3 (MEG3) in cognitive dysfunction induced by isoflurane (ISO). Morrier water maze analysis was performed to evaluate the cognitive function of rats. Modified modified neurological severity score (mNSS) scores were assessed for neurological damage. The levels of MEG3 in hippocampal tissues of rats and hippocampal neuron cell lines HT22 were examined by reverse transcription-quantitative polymerase chain reaction (qRT-PCR). Moreover, the cell viability and apoptosis were assessed by the Cell Counting Kit-8 (CCK-8) and flow cytometry assay. Indicators of inflammation and oxidative stress were determined using enzyme-linked immunosorbent assay (ELISA) and commercial assay kits. Relationship between MEG3 and microRNA (miR)-7-5p was verified by the dual-luciferase reporter gene assay. MEG3 was increased in hippocampal tissues and HT22 after ISO treatment (p < 0.05). MEG3 downregulation alleviated the increase in neurological severity score and cognitive dysfunction caused by ISO treatment (p < 0.05). In vitro, MEG3 downregulation alleviates the decrease in cell activity and increased apoptosis induced by ISO. What’s more, MEG3 reduction eliminated activation of neuroinflammation and oxidative stress promoted by ISO treatment in rats and HT22 (p < 0.05). MEG3 was confirmed to specifically bind to miR-7-5p. Inhibition of miR-7-5p eliminated the alleviating effects of MEG3 downregulation on cognitive dysfunction caused by ISO treatment. Decreased MEG3 alleviates cognitive dysfunction caused by ISO by targeting miR-7-5p and play a neuroprotective effect. We present a strategy for MEG3 as a potential target for brain protection during anesthesia.

Connexin 43 gap junction-mediated astrocytic network reconstruction attenuates isoflurane-induced cognitive dysfunction in mice

BackgroundPostoperative cognitive dysfunction (POCD) is a common complication following anesthesia and surgery. General anesthetic isoflurane has potential neurotoxicity and induces cognitive impairments, but the exact mechanism remains unclear. Astrocytes form interconnected networks in the adult brain through gap junctions (GJs), which primarily comprise connexin 43 (Cx43), and play important roles in brain homeostasis and functions such as memory. However, the role of the GJ-Cx43-mediated astrocytic network in isoflurane-induced cognitive dysfunction has not been defined.Methods4-month-old male C57BL/6 mice were exposure to long-term isoflurane to induce cognitive impairment. To simulate an in vitro isoflurane-induced cognitive dysfunction‐like condition, primary mouse astrocytes were subjected to long-term isoflurane exposure. Cognitive function was assessed by Y-maze and fear conditioning tests. Western blot was used to determine the expression levels of different functional configurations of Cx43. The morphology of the GJs-Cx43 was evaluated by immunofluorescence staining. Levels of IL-1β and IL-6 were examined by ELISA. The ability of GJs-Cx43-mediated intercellular communication was examined by lucifer yellow dye transfer assay. Ethidium bromide uptake assays were used to measure the activity of Cx43 hemichannels. The ultrastructural morphology of astrocyte gap junctions and tripartite synapse were observed by transmission electron microscopy.ResultsAfter long-term isoflurane anesthesia, the GJs formed by Cx43 in the mouse hippocampus and primary mouse astrocytes were significantly reduced, GJs function was impaired, hemichannel activity was enhanced, the levels of IL-1β and IL-6 were increased, and mice showed significant cognitive impairment. After treatment with the novel GJ-Cx43 enhancer ZP1609, GJ-Cx43-mediated astrocytic network function was enhanced, neuroinflammation was alleviated, and ameliorated cognition dysfunction induced by long-term isoflurane exposure. However, ZP1609 enhances the astrocytic network by promoting Cx43 to form GJs without affecting hemichannel activity. Additionally, our data showed that long-term isoflurane exposure does not alter the structure of tripartite synapse.ConclusionOur results reveal a novel mechanism of the GJ-Cx43-mediated astrocytic network involved in isoflurane-induced neuroinflammation and cognitive impairments, which provides new mechanistic insight into the pathogenesis of POCD and identifies potential targets for its treatment.

Neuroprotective Effect of HOTAIR Silencing on Isoflurane-Induced Cognitive Dysfunction via Sponging microRNA-129-5p and Inhibiting Neuroinflammation

Introduction: This article purposed to detect the function of the HOTAIR and HOTAIR/microRNA-129-5p (miR-129-5p) axis on the isoflurane (ISO)-injured cells and rat, and propounded a novel perspective in exploring the molecular pathogenesis of ISO damage. Methods: The expression of HOTAIR and miR-129-5p was tested by quantitative real-time PCR. The viable cells were identified using MMT, and the apoptotic cells were provided by flow cytometry. The concentration of proinflammatory indicators was revealed by enzyme-linked immunosorbent assay kits. The function of HOTAIR on oxidative stress was detected by commercial kits. A luciferase assay was performed to confirm the relationship between miR-129-5p and HOTAIR. The Morris water maze test was conducted to elucidate the cognition of SD rats. Results: The expression of HOTAIR was enhanced and the expression of miR-129-5p was lessened in the ISO-evoked SD rats and HT22 cells. The interference of HOTAIR reversed the injury of ISO on cell viability, apoptosis, inflammation, and oxidative stress. Besides, HOTAIR might be a target ceRNA of miR-129-5p. MiR-129-5p abrogated the function of silenced HOTAIR on cell viability, cell apoptosis, inflammation, and oxidative stress. Moreover, in vivo, the intervention of HOTAIR reversed the influence of ISO on cognition and oxidative stress by binding miR-129-5p. Discussion/Conclusion: Lowly expressed HOTAIR contributed to the recovery of the ISO-injured HT22 cell model from the abnormal viability, apoptosis, inflammation, and oxidative stress by regulating miR-129-5p. miR-129-5p mediated the function of HOTAIR on cognition and oxidative balance in the ISO-managed SD rat model.

Effect of LncRNA OIP5-AS1/microRNA-186-5p on isoflurane-induced cognitive dysfunction in aged rats.

Post-operative recognition dysfunction (POCD) is a kind of central nervous system complication that appears after operative anesthesia. Recent studies on the mechanism of long non-coding RNA (lncRNA) in neurodegenerative diseases are abundant. The study aimed to explore the expression pattern and role of lncRNA OIP5-AS1 in POCD and to investigate its underlying mechanism in old rats. The old rats were exposed to isoflurane to mimic the POCD in the elderly, and their cognitive function was tested via Morris water maze (MWM) test. Enzyme linked immunosorbent assay was applied for the concentration detection of inflammation and oxidative stress-related factors. Luciferase reporter assay was done for the target gene analysis. Downregulation of OIP5-AS1 was accompanied by isoflurane treatment in rats, overexpression of OIP5-AS1 induced the rats to spend more time in the target quadrant, and shorten escape latency time. OIP5-AS1 inhibited the release of TNF-α, IL-6 and IL-1β, GSH and superoxide dismutase, decreased the activation of caspase-3, but promoted malondialdehyde release. miR-186-5p was a target miRNA of OIP5-AS1, and exhibited high expression in rats after isoflurane exposure. miR-186-5p can abolish the beneficial role of OIP5-AS1 against cognitive impairment, inflammatory response, oxidative stress and neuron apoptosis. OIP5-AS1 plays a neuroprotective role in elderly POCD rats through sponging miR-186-5p, and it is related to OIP5-AS1/miR-186-5p mediated inflammatory response, oxidative stress and neuron apoptosis.

Ruscogenin alleviates cognitive dysfunction by inhibiting the activation of isoflurane-induced NLRP3 inflammasome in aged mice

Ruscogenin exerts an anti-inflammatory effect in the pathogenesis of various human diseases, including pulmonary hypertension, acute lung injury, acute pancreatitis and cerebral ischemia. Its role in isoflurane-induced rats with postoperative cognitive dysfunction (POCD) was investigated in this study. Aged rats were exposed to isoflurane for establishing a model of POCD, and administered with ruscogenin by gavage. Cognitive dysfunction was evaluated by the Morris water maze test. Hematoxylin and Eosin (H&amp;E) staining was designed to assess neuronal damage. Markers of brain damage and neuroinflammation were detected by enzyme-linked-immunosorbent serologic assay. Isoflurane exposure caused impaired cognitive function by increasing escape latency, decreasing the time taken for crossing target and time in target quadrant. However, administration of ruscogenin reversed these cognitive dysfunctions. Abnormal morphological phenomena on neurons and enhanced levels of serum calcium-binding protein β (S-100β) and neuron-specific enolase (NSE) were identified in mice post-isoflurane exposure. Administration of ruscogenin ameliorated the neuronal morphological damages and reduced the levels of S-100β and NSE in the hippocampi of isoflurane-induced aged mice. Ruscogenin also attenuated isoflurane-induced enhancements in the levels of Interleukin (IL)-1β, IL-6 and tumor necrosis factor-alpha in the hippocampi of mice. Isoflurane-induced enhancements in the mRNA expression levels of NLR family pyrin domain containing 3 (NLRP3), ASC, IL-1β and IL-18 proteins were also restored by administration of ruscogenin. Ruscogenin exerted neuroprotective effects against isoflurane-induced cognitive dysfunction and neuroinflammation through blocking of NLRP3 pathway.

Amelioration of Hippocampal Insulin Resistance Reduces Tau Hyperphosphorylation and Cognitive Decline Induced by Isoflurane in Mice.

General anesthetics can induce cognitive impairments and increase the risk of Alzheimer’s disease (AD). However, the underlying mechanisms are still unknown. Our previous studies shown that long-term isoflurane exposure induced peripheral and central insulin resistance (IR) in adult mice and aggravated IR in type 2 diabetes mellitus (T2DM) mice. Clinical and preclinical studies revealed an association between impaired insulin signaling and tau pathology in AD and other tauopathies. We investigated if alleviation of hippocampal IR by the antidiabetic agent metformin could reduce tau hyperphosphorylation and cognitive decline induced by isoflurane in mice. The effects of prolonged (6 h) isoflurane anesthesia on hippocampal IR, hippocampal tau hyperphosphorylation, and hippocampus-dependent cognitive function were evaluated in wild type (WT) adult mice and the high-fat diet plus streptozotocin (HFD/STZ) mouse model of T2DM. Here we shown that isoflurane and HFD/STZ dramatically and synergistically induced hippocampal IR and fear memory impairment. Metformin pretreatment strongly ameliorated hippocampal IR and cognitive dysfunction caused by isoflurane in WT mice, but was less effective in T2DM mice. Isoflurane also induced hippocampal tau hyperphosphorylation and metformin reversed this effect. In addition, isoflurane significantly increased blood glucose levels in both adult and T2DM mice, and metformin reversed this effect as well. Administration of 25% glucose to metformin-pretreated mice induced hyperglycemia, but surprisingly did not reverse the benefits of metformin on hippocampal insulin signaling and fear memory following isoflurane anesthesia. Our findings show hippocampal IR and tau hyperphosphorylation contribute to acute isoflurane-induced cognitive dysfunction. Brief metformin treatment can mitigate these effects through a mechanism independent of glycemic control. Future studies are needed to investigate whether long-term metformin treatment can also prevent T2DM-induced hippocampal IR and cognitive decline.

Anti-Inflammatory, Antioxidant and Neuroprotection Effect of Thiopental Sodium on Isoflurane-Induced Cognitive Dysfunction in Rats

Anti-Inflammatory, Antioxidant and Neuroprotection Effect of Thiopental Sodium on Isoflurane-Induced Cognitive Dysfunction in Rats

Neuroprotective effect of miR-212-5p on isoflurane-induced cognitive dysfunction by inhibiting neuroinflammation

Background Isoflurane is a commonly used inhalation anesthetic in the clinic, which can induce cognitive dysfunction and neuroinflammation. miR-212-5p has been demonstrated to be involved in the neuronal system and play vital roles in memory formation. Its function in the learning and memory impairment and neuroinflammation induced by isoflurane was investigated in this study. Methods Cognitive dysfunction rat models were established by 3% isoflurane inhalation. The neurological function was evaluated by the modified Neurological Severity Scale. The learning and memory ability of rats was assessed by the Morris water maze test. The expression level of miR-212-5p was analyzed by RT-qPCR, and the protein levels of proinflammatory cytokines were detected by ELISA. Results Isoflurane induced cognitive dysfunction in rats with the neurological scores and the escape latency increased, and time spent in the target quadrant decreased. The protein levels of IL-1β, IL-6, and TNF-α were increased in isoflurane treated rats. miR-212-5p was downregulated in cognitive impairment rats. The upregulation of miR-212-5p by the agomir injection decreased the neurological scores of rats and increased the learning and memory ability of impaired rats. Moreover, the neuroinflammation was inhibited by the overexpression of miR-212-5p. Conclusion miR-212-5p showed a neuroprotective effect in isoflurane-induced cognitive dysfunction rats by inhibiting neuroinflammation.

Tetramethylpyrazine ameliorates isoflurane-induced cognitive dysfunction by inhibiting neuroinflammation via miR-150 in rats.

Tetramethylpyrazine (TMP) has neuroprotective effects in the pathogenesis of some human diseases, such as Parkinson's disease. The present study aimed to investigate the role of TMP in isoflurane-induced cognitive dysfunction in rats, and further identify the mechanisms involved in the protective effects of TMP. The Morris water maze test was used to evaluate the cognitive function of rats exposed to isoflurane or treated with TMP. ELISA was conducted to evaluate the effects of isoflurane or TMP on neuroinflammation. The expression of microRNA-150 (miR-150) was measured using reverse transcription-quantitative PCR, and the potential target genes of miR-150 were predicted and verified. The impaired cognitive function induced by isoflurane in the rats was significantly ameliorated by treatment with TMP. In addition, TMP treatment in rats attenuated neuroinflammation caused by isoflurane. The expression of miR-150 was inhibited by isoflurane exposure, but was enhanced by TMP treatment in rats. Furthermore, the overexpression of miR-150 alleviated the isoflurane-induced cognitive dysfunction and neuroinflammation, while the neuroprotective effects of TMP were significantly abrogated by the knockdown of miR-150. AKT3 was a direct target of miR-150, and its mRNA expression was significantly decreased by the overexpression of miR-150 in isoflurane- and TMP-treated rats. These results demonstrated the protective effects of TMP against isoflurane-induced cognitive dysfunction, which were achieved by attenuating neuroinflammation via the regulation of the miR-150/AKT3 pathway. In addition, miR-150 may serve as a novel therapeutic target for the alleviation of cognitive dysfunction induced by anesthetics.

Protective effects of grape seed procyanidin on isoflurane-induced cognitive impairment in mice

Context Oxidative imbalance-induced cognitive impairment is among the most urgent clinical concerns. Isoflurane has been demonstrated to impair cognitive function via an increase in oxidative stress. GSP has strong antioxidant capacities, suggesting potential cognitive benefits. Objective This study investigates whether GSP pre-treatment can alleviate isoflurane-induced cognitive dysfunction in mice. Materials and methods C57BL/6J mice were pre-treated with either GSP 25–100 mg/kg/d for seven days or GSP 100–400 mg/kg as a single dose before the 6 h isoflurane anaesthesia. Cognitive functioning was examined using the fear conditioning tests. The levels of SOD, p-NR2B and p-CREB in the hippocampus were also analysed. Results Pre-treatment with either a dose of GSP 50 mg/kg/d for seven days or a single dose of GSP 200 mg/kg significantly increased the % freezing time in contextual tests on the 1st (72.18 ± 12.39% vs. 37.60 ± 8.93%; 78.27 ± 8.46% vs. 52.72 ± 2.64%), 3rd (93.80 ± 7.62% vs. 52.94 ± 14.10%; 87.65 ± 10.86% vs. 52.89 ± 1.73%) and 7th (91.36 ± 5.31% vs. 64.09 ± 14.46%; 93.78 ± 3.92% vs. 79.17 ± 1.79%) day after anaesthesia. In the hippocampus of mice exposed to isoflurane, GSP 200 mg/kg increased the total SOD activity on the 1st and 3rd day and reversed the decreased activity of the NR2B/CREB pathway. Discussion and conclusions These findings suggest that GSP improves isoflurane-induced cognitive dysfunction by protecting against perturbing antioxidant enzyme activities and NR2B/CREB pathway. Therefore, GSP may possess a potential prophylactic role in isoflurane-induced and other oxidative stress-related cognitive decline.

GLYX-13 pretreatment ameliorates long-term isoflurane exposure-induced cognitive impairment in mice.

Accumulating evidence indicates that inhalation anesthetics induce or increase the risk of cognitive impairment. GLYX-13 (rapastinel) acts on the glycine site of N-methyl-D-aspartate receptors (NMDARs) and has been shown to enhance hippocampus-dependent learning and memory function. However, the mechanisms by which GLYX-13 affects learning and memory function are still unclear. In this study, we investigated these mechanisms in a mouse model of long-term anesthesia exposure. Mice were intravenously administered 1 mg/kg GLYX-13 at 2 hours before isoflurane exposure (1.5% for 6 hours). Cognitive function was assessed using the contextual fear conditioning test and the novel object recognition test. The mRNA expression and phosphorylated protein levels of NMDAR pathway components, N-methyl-D-aspartate receptor subunit 2B(NR2B)-Ca2+/calmodulin dependent protein kinase II (CaMKII)-cyclic adenosine monophosphate response element binding protein (CREB), in the hippocampus were evaluated by quantitative RT-PCR and western blot assay. Pretreatment with GLYX-13 ameliorated isoflurane exposure-induced cognitive impairment and restored NR2B, CaMKII and CREB mRNA and phosphorylated protein levels. Intracerebroventricular injection of KN93, a selective CaMKII inhibitor, significantly diminished the effect of GLYX-13 on cognitive function and NR2B, CaMKII and CREB levels in the hippocampus. Taken together, our findings suggest that GLYX-13 pretreatment alleviates isoflurane-induced cognitive dysfunction by protecting against perturbation of the NR2B/CaMKII/CREB signaling pathway in the hippocampus. Therefore, GLYX-13 may have therapeutic potential for the treatment of anesthesia-induced cognitive dysfunction. This study was approved by the Experimental Animal Ethics Committee of Drum Tower Hospital affiliated to the Medical College of Nanjing University, China (approval No. 20171102) on November 20, 2017.

Adiponectin improves isoflurane-induced cognitive dysfunction in elderly rats via inhibiting p38-MAPK signal pathway in hippocampus.

To investigate the intervention of exogenous adiponectin in the elderly rats with cognitive dysfunction induced by isoflurane through mitogen-activated protein kinase (MAPK) signaling pathway in hippocampus. A total of 60 healthy elder Sprague Dawley (SD) rats aged 15-20 months and weighing 400-500 g were selected. These rats were randomly divided into four groups, i.e., the control group, the anesthetic group, adiponectin intervention group, and p38-MAPK antagonist group, in which the rats in the control group were treated through inhalation of pure oxygen for 4 h at a rate of 4 L/min, while the rats in the other 3 groups were treated through inhalation of isoflurane for 4 h. During the inhalation of isoflurane, the concentration of isoflurane was 3.5% at the beginning and decreased to 2.2% at 1 h, and 1.7% between 2 h and 4 h. Then, the intraperitoneal injection of 0.5 mL normal saline was performed for the rats in the control group and the anesthetic group, while adiponectin (300 mg/kg) was injected into the rats in the adiponectin intervention group and p38-MAPK antagonist group. Simultaneously, the antagonist (20 mg/kg) diluted to 0.5 mL was given to the rats in the p38-MAPK antagonist group, once/day for 3 days. Morris water maze test was carried out respectively in the 1st, 3rd, and 7th day, and 5 rats participated in the test at each time point, during which we recorded the escape latency, as well as the length of the swimming route of rats. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting were employed to detect the mRNA and protein expressions of p38 in the hippocampus. The escape latency and the length of the swimming route at any time point after the intervention in the anesthetic group were significantly longer than those in the control group (p<0.05), and they were significantly shorter in the adiponectin intervention group than those in the anesthetic group (p<0.05), but there were no differences between the p38-MAPK antagonist group and the anesthetic group (p>0.05). The mRNA and protein expressions of p38 at any time point after intervention in the anesthetic group were higher than those in the control group (p<0.05), and they were significantly lower in the adiponectin intervention group than those in the anesthetic group (p<0.05), but there were no differences between the p38-MAPK antagonist group and the anesthetic group (p>0.05). Exogenous adiponectin can improve the cognitive dysfunction of the elderly rats after anesthesia using isoflurane, possibly by inhibiting the p38-MAPK signal pathway in hippocampus.

Ulinastatin attenuates isoflurane-induced cognitive dysfunction in aged rats by inhibiting neuroinflammation and β-amyloid peptide expression in the brain

ABSTRACTObjective: Postoperative neurocognitive disease (PNCD) in the aged is a major clinical problem with unclear mechanisms. This study was designed to explore the mechanisms for ulinastatin (UTI) to attenuate isoflurane-induced cognitive decline in Fischer-344 rats.Methods: The rats were divided into four groups: Control (0.9% saline only), Isoflurane (exposure to 1.2% isoflurane), Isoflurane-plus-UTI (exposure to 1.2% isoflurane followed by 100,000 U/kg UTI injection i.v.) and UTI-plus-isoflurane (i.v. of 100,000 U/kg UTI followed by 1.2% isoflurane exposure). After respective tests, the concentrations of tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the brain were determined by ELISA the expression of β-amyloid peptide (Aβ) and cleaved caspase-3 were measured by Western blot. Ratio of apoptotic cells after Barnes maze challenge was assessed by TUNEL assay.Results: In both Barnes Maze training and challenge, results indicated isoflurane-impaired learning capacity, while pre-and post-treatment with UTI could attenuate this phenomenon. The ratio of apoptotic cells and the expression of cleaved caspase-3 were increased after isoflurane exposure, indicating that isoflurane could induce neuronal apoptosis, while both pre- and post-treatment with UTI could diminish these effects. Moreover, UTI inhibited the expression of TNF-α, IL-1β and Aβ induced by isoflurane in rat brain harvested at 16 h after isoflurane exposure.Conclusion: These results suggest that UTI inhibits neuronal apoptosis in rat brain by attenuating increased expression of Aβ42 and inflammatory cytokines, which may contribute to its alleviation of isoflurane-induced cognitive dysfunction in rats. Moreover, UTI pre-treatment before isoflurane exposure showed more effective than post-treatment.

Obesity caused by a high-fat diet regulates the Sirt1/PGC-1α/FNDC5/BDNF pathway to exacerbate isoflurane-induced postoperative cognitive dysfunction in older mice

ABSTRACT Objectives: To investigate the effects of obesity caused by high-fat diet (HFD) on postoperative cognitive dysfunction (POCD) and expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampus of older mice. Methods: Fifty-six 15-month-old male C57BL/6 mice were randomly divided into eight groups – ad libitum control (ALC), ad libitum surgery (ALS), ad libitum surgery with PBS (ALS + PBS), ad libitum surgery with resveratrol (ALS + Res), HFD control (HFC), HFD surgery (HFS), HFD surgery with PBS (HFS + PBS), HFD surgery with resveratrol (HFS + Res). Surgery group mice were exposed to isoflurane before tibial fracture internal fixation. Open field tests and fear conditioning were performed to test motor ability and memory. The levels of expression of Sirt1, PGC-1α, FNDC5, and BDNF were detected using western blot and immunofluorescence. Results: The results of the open field tests indicated there were no between-group differences in motor ability and anxiety. The results of the fear conditioning indicated that the memory of the HFC group and HFS group mice were significantly worse compared with the ALC group and ALS group mice, respectively. There were parallel decreases in expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampi of the HFC and HFS group mice. Resveratrol treatment attenuated the memory loss by increasing hippocampal Sirt1 expression. Expression of the PGC-1α/FNDC5/ BDNF pathway in the CA1 area of the hippocampus was upregulated after resveratrol treatment. Conclusion: An HFD exacerbates POCD in older mice. This change was related to HFD inhibition of expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampus. Resveratrol pretreatment reversed the memory loss via upregulation of this pathway.

Eleutheroside E attenuates isoflurane-induced cognitive dysfunction by regulating the α7-nAChR-NMDAR pathway.

There is growing evidence that cognitive dysfunction induced by anesthetics is adversely affecting a large number of elderly surgical patients. Eleutheroside E (EE), a principal component of Eleutherococcus senticosus, exerts obvious protective effects on cognition. The aim of this study was to investigate the neuroprotective effect of EE on isoflurane (ISO)-induced cognitive dysfunction and explore the possible mechanisms. Learning and memory are assessed in novel object recognition and Morris water maze. We found that with ISO exposure, aged rats had a lower preference for the new object and spent less time in the target quarter. However, the amnesia can be alleviated by EE (50 mg/kg, intraperitoneally). Further research focused on the possible protective molecules associated with learning and memory, such as acetylcholine (ACh) and choline acetyltransferase (ChAT), nicotinic acetylcholine receptors (α7-nAChR), and NR2B, is required. The ACh in the hippocampus and serum was decreased after ISO exposure; meanwhile, the expression of ChAT, α7-nAChRs, and NR2B was downregulated. This abnormal state can be reversed by the administration of EE. Here, our results suggested that EE may be a potential therapeutic agent against ISO-induced cognitive dysfunction. The possible mechanism can be attributed to its neuroprotection through enhancing ChAT, which promotes the synthesis of ACh, further influencing the expression of the α7-nAChR-NR2B complex.

Effects of ADAM2 silencing on isoflurane-induced cognitive dysfunction via the P13K/Akt signaling pathway in immature rats

Volatile anesthetics, including isoflurane, have been reported to have negative effects on cognitive dysfunction characterized by cognitive deficits following anesthesia. The aim of the current study was to investigate the effects involved with disintegrin and metallopeptidase domain 2 (ADAM2) silencing on isoflurane-induced cognitive dysfunction via the P13 K/Akt signaling pathway in immature rats. One week old healthy Sprague-Dawley (SD) rats were recruited and administered isoflurane anesthesia. The rats were then subjected to shADAM2 or wortmannin (PI3K/Akt signaling pathway inhibitor) to identify the effects of ADAM2 and the PI3K/Akt signaling pathway on the cognitive function of rats. Morris water maze and passive-avoidance tests were performed to examine the cognitive function of the rats. TUNEL staining was conducted to detect neuronal apoptosis in the hippocampal CA1 region. The obtained experimental results demonstrated that isoflurane anesthesia led to increased escape latency, reaction time, number of errors and TUNEL-positive neurons, along with a decreased latency time. In response to treatment with shADAM2, escape latency, reaction time, number of errors and TUNEL-positive cells were all noted to have decreased, in addition to elevated latency time, while contrasting trends were observed in regard to treatment with wortmannin. Taken together, the key findings of the present study revealed that shADAM2 activated the PI3K/Akt signaling pathway, resulting in elevated expressions of PI3K and Akt. Our study ultimately identified that ADAM2 silencing alleviates isoflurane-induced cognitive dysfunction by activating the P13 K/Akt signaling pathway in immature rats.

Circadian rhythm resynchronization improved isoflurane-induced cognitive dysfunction in aged mice

Postoperative cognitive dysfunction (POCD) is a common clinical phenomenon characterized by cognitive deficits in patients after anesthesia and surgery. Advanced age is a significant independent risk factor for POCD. We previously reported that in young mice, sleep–wake rhythm is involved in the isoflurane-induced memory impairment. In present study, we sought to determine whether advanced age increased the risk of POCD through aggravated and prolonged post-anesthetic circadian disruption in the elderly. We constructed POCD model by submitting the mice to 5-h 1.3% isoflurane anesthesia from Zeitgeber Time (ZT) 14 to ZT19. Under novel object recognition assay (NOR) and Morris water maze (MWM) test, We found 5-h isoflurane anesthesia impaired the cognition of young mice for early 3 days after anesthesia but damaged the aged for at least 1 week. With Mini-Mitter continuously monitoring, a 3.22 ± 0.75 h gross motor activity acrophase delay was manifested in young mice on D1, while in the aged mice, the gross motor activity phase shift lasted for 3 days, consistent with the body temperature rhythm trends of change. Melatonin has been considered as an effective remedy for circadian rhythm shift. In aged mice, melatonin was pretreated intragastrically at the dose of 10 mg/kg daily for 7 consecutive days before anesthesia. We found that melatonin prevented isoflurane-induced cognitive impairments by restoring the locomotor activity and temperature circadian rhythm via clock gene resynchronization. Overall, these results indicated that Long-term isoflurane anesthesia induced more aggravated and prolonged memory deficits and circadian rhythms disruption in aged mice. Melatonin could prevent isoflurane-induced cognitive impairments by circadian rhythm resynchronization.