Neonatal Repeated Exposure to Isoflurane not Sevoflurane in Mice Reversibly Impaired Spatial Cognition at Juvenile-Age.
Liu Jianhui,Zhao Yanhong,Yang Junjun,Zhang Xiaoqing,Zhang Wei,Wang Peijun
Neurochemical research
Inhalation anesthetics facilitate surgical procedures in millions of children each year. However, animal studies demonstrate that exposure to the inhalation anesthetic isoflurane may cause neuronal cell death in developing brains. The long-term cytotoxic effects of sevoflurane, the most popular pediatric anesthetic, have not been compared with isoflurane. Thus, this study was designed to compare the effects of equipotent doses of these two anesthetics on neonatal long-term neurotoxicity. Postnatal 7-day-old (P7) C57/BL male mice were exposed to 1.5% isoflurane or 2.2% sevoflurane 2 h a day for 3 days. Non-anesthetized mice served as controls. The effects of anesthesia on learning and memory were assessed using the Morris Water Maze (MWM) at Postnatal days 30 (P30) and P60 respectively. The hippocampal content of N-methyl-D-aspartate receptor subunits (NMDA), brain-derived neurotrophic factor (BDNF), and synaptophysin (Syn) were determined by Western Blot. Neuron structure and apoptosis were assessed via Nissl and TUNEL staining, respectively. The isoflurane group exhibited cognitive impairment at P30. Repeated inhalation of isoflurane or sevoflurane caused different degrees of apoptosis and damaged hippocampal neurons in neonatal mice, particularly isoflurane. In neonatal mice, repeated exposure to isoflurane, but not sevoflurane, caused spatial cognitive impairments in juvenile mice. Our findings suggest that isoflurane induces significantly greater neurodegeneration than an equipotent minimum alveolar concentration of sevoflurane.
10.1007/s11064-016-2114-7
Elamipretide Attenuates Pyroptosis and Perioperative Neurocognitive Disorders in Aged Mice.
Zuo Youmei,Yin Lei,Cheng Xinqi,Li Jun,Wu Hao,Liu Xuesheng,Gu Erwei,Wu Jing
Frontiers in cellular neuroscience
Pyroptosis is a recently characterized inflammatory form of programmed cell death that is thought to be involved in the pathogenesis of perioperative neurocognitive disorders (PND). Elamipretide (SS-31), a mitochondrial-targeted peptide with multiple pharmacological properties, including anti-inflammatory activity, has been demonstrated to protect against many neurological diseases. However, the effect of elamipretide on pyroptosis in PND has not been studied. We established an animal model of PND by performing an exploratory laparotomy on mice under isoflurane anesthesia and examined the effects of elamipretide on cognitive function, synaptic integrity, neuroinflammation, mitochondrial function, and signaling controlling pyroptosis. Our results showed that anesthesia and surgery caused mitochondrial dysfunction and abnormal morphology, activation of canonicalnod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-caspase-1 dependent pyroptosis, and downregulation of synaptic integrity-related proteins in the hippocampus in aged mice, thus leading to learning and memory deficits in behavioral tests. Remarkably, treatment with the mitochondrial-targeted peptide elamipretide not only had protective effects against mitochondrial dysfunction but also attenuated surgery-induced pyroptosis and cognitive deficits. Our results provide a promising strategy for the treatment of PND involving mitochondrial dysfunction and pyroptosis.
10.3389/fncel.2020.00251
Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca/calpain might contribute to postoperative cognitive dysfunction in aging mice.
Qiu Li-Li,Pan Wei,Luo Dan,Zhang Guang-Fen,Zhou Zhi-Qiang,Sun Xiao-Yun,Yang Jian-Jun,Ji Mu-Huo
Journal of neuroinflammation
BACKGROUND:Postoperative cognitive decline (POCD) is a recognized clinical phenomenon characterized by cognitive impairments in patients following anesthesia and surgery, yet its underlying mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory via activation of TrkB-full length (TrkB-FL) receptors. It has been reported that an abnormal truncation of TrkB mediated by calpain results in dysregulation of BDNF/TrkB signaling and is associated with cognitive impairments in several neurodegenerative disorders. Calpains are Ca-dependent proteases, and overactivation of calpain is linked to neuronal death. Since one source of intracellular Ca is N-methyl-d-aspartate receptors (NMDARs) related and the function of NMDARs can be regulated by neuroinflammation, we therefore hypothesized that dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca/calpain might be involved in the pathogenesis of POCD. METHODS:In the present study, 16-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to establish the POCD animal model. For the interventional study, mice were treated with either NMDAR antagonist memantine or calpain inhibitor MDL-28170. Behavioral tests were performed by open field, Y maze, and fear conditioning tests from 5 to 8 days post-surgery. The levels of Iba-1, GFAP, interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), NMDARs, calpain, BDNF, TrkB, bax, bcl-2, caspase-3, and dendritic spine density were determined in the hippocampus. RESULTS:Anesthesia and surgery-induced neuroinflammation overactivated NMDARs and then triggered overactivation of calpain, which subsequently led to the truncation of TrkB-FL, BDNF/TrkB signaling dysregulation, dendritic spine loss, and cell apoptosis, contributing to cognitive impairments in aging mice. These abnormities were prevented by memantine or MDL-28170 treatment. CONCLUSION:Collectively, our study supports the notion that NMDAR/Ca2+/calpain is mechanistically involved in anesthesia and surgery-induced BDNF/TrkB signaling disruption and cognitive impairments in aging mice, which provides one possible therapeutic target for POCD.
10.1186/s12974-019-1695-x
α7 Nicotinic Acetylcholine Receptor May Be a Pharmacological Target for Perioperative Neurocognitive Disorders.
Frontiers in pharmacology
The α7 nicotinic acetylcholine receptor (α7nAChR) is a promising therapeutic target in neurodegenerative diseases. This study examined the effects of surgery and anesthesia on α7nAChR expression in the central nervous system and determined the mechanisms by which α7nAChR mediates neuroprotection in perioperative neurocognitive disorders (PNDs) in aged mice. Eighteen-month-old male C57BL/6J mice underwent aseptic laparotomy under isoflurane anesthesia, maintaining spontaneous ventilation to establish the PNDs model. Agonists and antagonists of the α7nAChR and tropomyosin receptor kinase B (TrkB) receptors were administered before anesthesia. The α7nAChR expression, peripheral as well as hippocampal interleukin-1β (IL-1β), and the brain-derived neurotrophic factor (BDNF) levels were assessed. Separate cohorts of aged mice were tested for cognitive decline using the Morris water maze (MWM). Surgery and anesthesia significantly suppressed α7nAChR expression in the hippocampus and cortex. Surgery-induced IL-1β upregulation in the serum as well as hippocampus and hippocampal microglial activation were reversed by the α7nAChR agonist A significant reduction in the hippocampal BDNF levels were also observed. The α7nAChR stimulation reversed, and α7nAChR suppression promoted BDNF reduction in the hippocampus. Blocking the BDNF/TrkB signaling pathway abolished α7nAChR-induced neuroprotection in PNDs, as evidenced by poor cognitive performance in the MWM test. These data reveal that α7nAChR plays a key role in PNDs. The mechanisms of the anti-inflammatory pathway and BDNF/TrkB signaling pathways are involved in α7nAChR-meidiated neuroprotection in PNDs.
10.3389/fphar.2022.907713
D30 Alleviates β2-Microglobulin-Facilitated Neurotoxic Microglial Responses in Isoflurane/Surgery-Induced Cognitive Dysfunction in Aged Mice.
Laboratory investigation; a journal of technical methods and pathology
Postoperative cognitive dysfunction (POCD) is a common complication with no effective treatment in elderly patients. POCD, Alzheimer disease (AD), and many other cognitive diseases mostly involve neurotoxic microglia response, and recently, β2-microglobulin (B2M) has been suggested to play a pivotal role. A novel pyromeconic acid-styrene hybrid compound D30 was synthesized by our team and shown to be safe and effective in some neurodegenerative mouse models. In this study, we evaluated D30 on POCD and its potential mechanism. Fourteen- to 18-month-old male C57BL/6 mice were used to establish POCD through isoflurane anesthesia and surgery. The plasma of elderly patients was collected pre- and postoperatively. Primary mouse microglia were subjected to various stimulations in multiple experimental designs to imitate in vivo POCD-like conditions. Morris water maze, fear conditioning, western blot, immunofluorescent staining, and blood-brain barrier (BBB) permeability tests were conducted in this study. D30 administration significantly improved learning and memory in aged mice following POCD. Neurotoxic M1 microglia cells were dramatically increased following POCD, manifested as morphologically changing into fewer and shorter branches, enlarged somatic areas, and upregulated expression of iNOS and C1q. Notably, following POCD, B2M was significantly upregulated in the plasma and the brain. D30 treatment significantly suppressed these pathologic changes, by inhibiting the POCD-induced BBB breakdown while suppressing the surge of plasma B2M levels. D30 treatment suppressed POCD-induced surge of B2M and Aβ plaques in the brain and preserved adult hippocampal neurogenesis vulnerable to POCD. Furthermore, postoperative levels of B2M were significantly elevated over the preoperative levels in patients aged 80 years and over. In parallel with mouse plasma after POCD, the postoperative patient plasma was also much more effective at activating M1 microglia. Of note, this POCD plasma-induced activation of M1 microglia was largely prevented by D30 treatment. Taken together, by inhibiting the surge of plasma B2M, protecting BBB integrity, and reducing inflammatory response, D30 protected aged mice from B2M-facilitated POCD.
10.1016/j.labinv.2024.102190
Caffeic Acid Phenethyl Ester Suppresses Oxidative Stress and Regulates M1/M2 Microglia Polarization via Sirt6/Nrf2 Pathway to Mitigate Cognitive Impairment in Aged Mice following Anesthesia and Surgery.
Antioxidants (Basel, Switzerland)
Postoperative cognitive dysfunction (POCD) is a severe neurological complication after anesthesia and surgery. However, there is still a lack of effective clinical pharmacotherapy due to its unclear pathogenesis. Caffeic acid phenethyl ester (CAPE), which is obtained from honeybee propolis and medicinal plants, shows powerful antioxidant, anti-inflammatory, and immunomodulating properties. In this study, we aimed to evaluate whether CAPE mitigated cognitive impairment following anesthesia and surgery and its potential underlying mechanisms in aged mice. Here, isoflurane anesthesia and tibial fracture surgery were used as the POCD model, and H2O2-induced BV2 cells were established as the microglial oxidative stress model. We revealed that CAPE pretreatment suppressed oxidative stress and promoted the switch of microglia from the M1 to the M2 type in the hippocampus, thereby ameliorating cognitive impairment caused by anesthesia and surgery. Further investigation indicated that CAPE pretreatment upregulated hippocampal Sirt6/Nrf2 expression after anesthesia and surgery. Moreover, mechanistic studies in BV2 cells demonstrated that the potent effects of CAPE pretreatment on reducing ROS generation and promoting protective polarization were attenuated by a specific Sirt6 inhibitor, OSS_128167. In summary, our findings opened a promising avenue for POCD prevention through CAPE pretreatment that enhanced the Sirt6/Nrf2 pathway to suppress oxidative stress as well as favor microglia protective polarization.
10.3390/antiox12030714
Isoflurane has no effect on cognitive or behavioral performance in a mouse model of early-stage Alzheimer's disease.
Frontiers in neuroscience
Background:Patients with Alzheimer's disease show a sex-dependent decline of cognitive and behavioral performance. It is controversially discussed whether general anesthesia itself can aggravate or even cause this neurocognitive decline. Therefore, we investigated the effect of general anesthesia on neurocognitive and behavioral function and amyloidopathy in a mouse model of early-stage Alzheimer's disease with respect to sex. Methods:After governmental approval 10 months old Tg2576 mice and wild type (total 85 mice) either underwent general anesthesia with 1.0 minimal alveolar concentration of isoflurane for 2 h or were not exposed to isoflurane (controls). Following cognitive and behavioral testing using the modified hole board test (mHBT), brains were investigated regarding amyloidopathy, inflammation, and apoptosis. Data were analyzed using repeated measure analysis of variance (ANOVA) and univariate analysis of variance (UNIANOVA). Results:Tg2576 mice showed a decline in memory function ( < 0.001), less anxiety ( = 0.022 and = 0.024), increased locomotor activity ( = 0.025), and impaired fine motor skills ( < 0.001). Amyloid precursor protein ( < 0.001), soluble amyloid-beta ( < 0.001) and insoluble amyloid deposits ( < 0.001) were increased in Tg2576 animals. Neither sex nor exposure to isoflurane had an effect on cognitive or behavioral testing or expression of amyloid-related biomarkers. Discussion and conclusion:We found that 10 months old Tg2576 showed typical signs of early-stage Alzheimer's disease and corresponding histopathological alterations. Relevant sex-specific differences or an effect of isoflurane anesthesia could not be detected at this early stage of the disease.
10.3389/fnins.2022.1033729
Sarm1 is Essential for Anesthesia-Induced Neuroinflammation and Cognitive Impairment in Aged Mice.
Cellular and molecular neurobiology
Postoperative cognitive dysfunction (POCD) is a common phenomenon among elderly patients with unclear etiology. Sterile alpha and TIR motif-containing 1 (Sarm1) plays important roles in neuroinflammation and cognitive function, and activates Calpain which has been shown to promote POCD through TrkB cleavage. This study aims to test the hypothesis that Sarm1 is involved in POCD through regulating Calpain activity. Wild type and Sarm1 knock out mice were exposed to isoflurane. Mouse cognitive function was determined by Morris water maze test. Neuroinflammation was determined by Iba1 and GFAP protein levels and mRNA expression of proinflammatory cytokines. Calpain activation was determined by αII-spectrin degradation and TrkB cleavage. Mitogen-activated protein kinase (MAPK) signaling was determined by c-Jun N-terminal kinase and cJun phosphorylation both in vivo and in vitro by Western blot and immunofluorescence staining. We found that Sarm1 deletion suppressed isoflurane induced cognitive impairment and neuroinflammation. Deletion of Sarm1 inhibited isoflurane induced αII-spectrin degradation and TrkB cleavage, which indicates suppression of Calpain activation. Finally, deletion of Sarm1 suppressed isoflurane induced MAPK signaling both in vivo and in vitro. Our findings suggest that isoflurane anesthesia induced cognitive impairment is prevented by Sarm1 deletion in mice, making Sarm1 a potent therapeutic target for treating or preventing POCD.
10.1007/s10571-020-01037-4
Post-Anesthesia Cognitive Dysfunction in Mice Is Associated with an Age-Related Increase in Neuronal Intracellular [Ca]-Neuroprotective Effect of Reducing Intracellular [Ca]: In Vivo and In Vitro Studies.
Cells
Postoperative cognitive dysfunction (POCD) is a common disorder after general anesthesia in elderly patients, the precise mechanisms of which remain unclear. We investigated the effect of isoflurane with or without dantrolene pretreatment on intracellular calcium concentration ([Ca]), reactive oxygen species (ROS) production, cellular lactate dehydrogenase (LDH) leak, calpain activity, and cognitive function using the Morris water maze test of young (3 months), middle-aged (12-13 months), and aged (24-25 months) C57BL6/J mice. Aged cortical and hippocampal neurons showed chronically elevated [Ca] compared to young neurons. Furthermore, aged hippocampal neurons exhibited higher ROS production, increased LDH leak, and elevated calpain activity. Exposure to isoflurane exacerbated these markers in aged neurons, contributing to increased cognitive deficits in aged mice. Dantrolene pretreatment reduced [Ca] for all age groups and prevented or significantly mitigated the effects of isoflurane on [Ca], ROS production, LDH leak, and calpain activity in aged neurons. Dantrolene also normalized or improved age-associated cognitive deficits and mitigated the cognitive deficits caused by isoflurane. These findings suggest that isoflurane-induced cytotoxicity and cognitive decline in aging are linked to disruptions in neuronal intracellular processes, highlighting the reduction of [Ca] as a potential therapeutic intervention.
10.3390/cells13030264
Physical activity compensates for isoflurane-induced selective impairment of neuronal progenitor cell proliferation in the young adult hippocampus.
Behavioural brain research
General anesthesia is considered a risk factor for postoperative cognitive dysfunction. However, it is unclear what the neuronal and cognitive consequences of general anesthesia are and whether they can be treated. One possible pathomechanism is hippocampal neurogenesis. We investigated how the anesthetic isoflurane affects adult hippocampal neurogenesis and associated cognitive functions and whether the neurogenic stimulus of physical activity reverses isoflurane-induced changes. We exposed young adult mice to isoflurane (ISO) - half had access to a running wheel (ISO-RW). Both groups were compared with a control condition (CTR; CTR-RW). Cell proliferation and survival in the dentate gyrus of the hippocampus were quantified histologically 48 h and 3 weeks after anesthesia by bromodeoxyuridine incorporation. Cell phenotype was determined by expression of neuronal markers, and the extent of continuous endogenous neuronal proliferation was estimated from the number of doublecortin-positive cells. The Morris water maze was used to test hippocampus-dependent functions. We found that isoflurane decreased proliferation of neuronal progenitor cells, whereas survival of mature neurons remained intact. Consistent with intact neuronal survival, spatial memory associated with neurogenesis also proved intact in the Morris water maze despite isoflurane exposure. Physical activity attenuated the observed neuronal changes by preventing the decrease in newborn neuronal progenitor cells and the decline in continuous endogenous neuronal proliferation in isoflurane-treated animals. In conclusion, isoflurane selectively impairs neuronal proliferation but not survival or neurogenesis-linked cognition in adult mice. The observed adverse effects can be attenuated by physical activity, a cost-effective means of preventing the neurogenic consequences of general anesthesia.
10.1016/j.bbr.2023.114675
The differential effects of isoflurane and sevoflurane on neonatal mice.
Zhao Shuai,Fan Ziqi,Hu Jing,Zhu Yueli,Lin Caixiu,Shen Ting,Li Zheyu,Li Kaicheng,Liu Zhirong,Chen Yanxing,Zhang Baorong
Scientific reports
Previous research has shown that exposure to volatile anesthetics can induce acute neuroinflammation and neuroapoptopsis in neonatal rodents and that these events can lead to cognitive dysfunction at later stages. Isoflurane and sevoflurane are two of the most popular anesthetics used in the field of pediatrics. However, the relative impact of these two anesthetics on the developing brain at distinct time points after the induction of anesthesia has not been compared. In the present study, we exposed 7-day-old mice to clinically equivalent doses of isoflurane (1.5%) and sevoflurane (2.5%) for 4 h and then investigated consequential changes in the brains of these mice at six different time points. We analyzed the levels of proteins that are directly related to neuroapoptosis, neuroinflammation, synaptic function, and memory, in the brains of neonatal mice. Exposure of neonatal mice to isoflurane and sevoflurane resulted in acute neuronal apoptosis. Our analysis observed significant levels of neuroinflammation and changes in the expression levels of proteins associated with both synaptic transmission and memory in mice from the isoflurane group but not the sevoflurane group. Our results therefore indicate that isoflurane and sevoflurane induce differential effects in the brains of neonatal mice.
10.1038/s41598-020-76147-6
Isoflurane-induced neuroinflammation and NKCC1/KCC2 dysregulation result in long-term cognitive disorder in neonatal mice.
BMC anesthesiology
BACKGROUND:The inhalational anesthetic isoflurane is commonly utilized in clinical practice, particularly in the field of pediatric anesthesia. Research has demonstrated its capacity to induce neuroinflammation and long-term behavioral disorders; however, the underlying mechanism remains unclear [1]. The cation-chloride cotransporters Na-K-2Cl-1 (NKCC1) and K-2Cl-2 (KCC2) play a pivotal role in regulating neuronal responses to gamma-aminobutyric acid (GABA) [2]. Imbalances in NKCC1/KCC2 can disrupt GABA neurotransmission, potentially leading to neural circuit hyperexcitability and reduced inhibition following neonatal exposure to anesthesia [3]. Therefore, this study postulates that anesthetics have the potential to dysregulate NKCC1 and/or KCC2 during brain development. METHODS:We administered 1.5% isoflurane anesthesia to neonatal rats for a duration of 4 h at postnatal day 7 (PND7). Anxiety levels were assessed using the open field test at PND28, while cognitive function was evaluated using the Morris water maze test between PND31 and PND34. Protein levels of NKCC1, KCC2, BDNF, and phosphorylated ERK (P-ERK) in the hippocampus were measured through Western blotting analysis. Pro-inflammatory cytokines IL-1β, IL-6, and TNF-α were quantified using ELISA. RESULTS:We observed a decrease in locomotion trajectories within the central region and a significantly shorter total distance in the ISO group compared to CON pups, indicating that isoflurane induces anxiety-like behavior. In the Morris water maze (MWM) test, rats exposed to isoflurane exhibited prolonged escape latency onto the platform. Additionally, isoflurane administration resulted in reduced time spent crossing in the MWM experiment at PND34, suggesting long-term impairment of memory function. Furthermore, we found that isoflurane triggered activation of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α; downregulated KCC2/BDNF/P-ERK expression; and increased the NKCC1/KCC2 ratio in the hippocampus of PND7 rats. Bumetadine (NKCC1 specific inhibitors) reversed cognitive damage and effective disorder induced by isoflurane in neonatal rats by inhibiting TNF-α activation, normalizing IL-6 and IL-1β levels, restoring KCC2 expression levels as well as BDNF and ERK signaling pathways. Based on these findings, it can be speculated that BDNF, P-ERK, IL-1β, IL-6 and TNF - α may act downstream of the NKCC1/KCC2 pathway. CONCLUSIONS:Our findings provide evidence that isoflurane administration in neonatal rats leads to persistent cognitive deficits through dysregulation of the Cation-Chloride Cotransporters NKCC1 and KCC2, BDNF, p-ERK proteins, as well as neuroinflammatory processes.
10.1186/s12871-024-02587-6
The role and mechanism of TLR4-siRNA in the impairment of learning and memory in young mice induced by isoflurane.
Advances in clinical and experimental medicine : official organ Wroclaw Medical University
BACKGROUND:Isoflurane can significantly induce inflammation in children without surgical stress. The toll-like receptor 4 (TLR4) is closely related to noninfectious inflammation in the brain. OBJECTIVES:To investigate the role of TLR4-small interfering RNA (siRNA) in learning and memory impairment in young mice induced by isoflurane. MATERIAL AND METHODS:The C57 newborn mice were randomly allocated into normal control (control), isoflurane anesthesia (isoflurane), TLR4 interference empty vector+isoflurane anesthesia (siRNA-NC), and TLR4 interference+isoflurane anesthesia (TLR-siRNA) groups. Their behavior and pathological condition were detected using Morris water maze and hematoxylin and eosin (H&E) staining, respectively. The TLR4, brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate response element-binding protein 1 (CREB1) mRNA expressions were detected using quantitative real-time polymerase chain reaction (qRT-PCR). Serum tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 were detected by means of the enzyme-linked immunosorbent assay (ELISA). Apoptosis rate was detected with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). The TLR4, TNF-α, IL-6, BDNF, CREB1, extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK) protein expressions were detected using western blot (WB). RESULTS:Compared with the control group, the number of times the mice crossed the platform, and the time spent at the circumjacent area I and II of the platform were significantly decreased in the isoflurane group; the TLR4, TNF-α and IL-6 expressions were significantly increased in the isoflurane group, as compared to control; the results were reversed after the TLR4 interference. The hippocampal neurons in the isoflurane and siRNA-NC groups showed arrangement disorder and a high number of inflammatory infiltrates, while in the TLR-siRNA group they were closely and orderly arranged. Compared with the control group, the apoptosis rate and JNK protein expression in the isoflurane group were significantly increased, CREB1 protein expression was significantly decreased, and BDNF and ERK1/2 protein expressions showed no significant changes. Compared with the isoflurane group, the apoptosis rate of the TLR-siRNA group was significantly decreased, BDNF and CREB1 protein expressions were significantly increased, and ERK1/2 and JNK did not change significantly. CONCLUSIONS:Isoflurane stimulates the overexpression of inflammatory response factors, playing an important role in the cognitive impairment process. As a mediator of the innate immune inflammatory response, TLR4 plays an important role in the process of cell injury, which may be delayed by blocking the TLR4 signal.
10.17219/acem/147047
Mast cell stabilizer disodium cromoglycate improves long-term cognitive impairment after general anesthesia exposure in neonatal mice.
Frontiers in neuroscience
Background:Prolonged exposure to general anesthesia (GA) results in long-lasting cognitive impairment, especially during critical stages of brain development. An exaggerated neuroinflammation induced by anesthesia is generally considered to be a key cause of cognitive impairment. Materials and methods:Postnatal day 7 (PND 7) mice were exposed to GA by isoflurane inhalation for 6 h or mock anesthesia. Disodium cromoglycate (DSCG) was intraperitoneally injected daily for 2 weeks, beginning from 30 min before anesthesia. The post-anesthesia evaluation included behavioral tests, toluidine blue staining, immunofluorescence and western blot. Results:Our results demonstrated the long-term cognition were impaired after 6 h GA exposure in neonatal mice. DSCG treatment ameliorated early mast cells (MCs) degranulation and mast cell tryptase (MCT) expression, which helps to attenuate subsequent neuroinflammation, activation of microglia and astrocytes, and damage to oligodendrocytes and synapses to improve cognitive impairment. Conclusion:Disodium cromoglycate could effectively improve long-term cognitive impairment after GA exposure in neonatal mice.
10.3389/fnins.2022.990333
Protective effects of chlorogenic acid on isoflurane-induced cognitive impairment of aged mice.
Food science & nutrition
Postoperative cognitive dysfunction (POCD) is characterized by impairment in cognitive functions in patients following anesthesia and surgery. Chlorogenic acid (CGA) is a plant-derived compound possessing numerous bioactive properties. The aim of this study was to investigate the therapeutic potential of CGA in isoflurane (ISO)-induced cognitive dysfunction of aged mice, and further identify the mechanisms involved in the protective effects of CGA. A total of 80 male C57BL/6 mice, 20-month-old, were randomly divided into control group, isoflurane group (ISO), and ISO + 30 mg/kg CGA group and ISO + 60 mg/kg CGA. CGA was given orally once daily for 7 days to the mice and they were exposed to ISO (1.5%; 4 h). The open-field and Morris water maze tests were used to investigate the cognitive function of mice. Pretreatment with CGA significantly attenuated ISO-induced cognitive impairment. The levels of IL-1β, TNF-α, IL-6, nuclear p65 NF-kB, cleaved caspase-3, and Bax were significantly increased, while the levels of IkBα and Bcl-2 were decreased in the hippocampus 24 h after the ISO anesthesia. All the mentioned effects induced by ISO were reversed by CGA pretreatment. Furthermore, ISO exposure induced marked downregulation of SOD, CAT, HO-1, and NQO-1 and elevation of MDA and nuclear translocation of Nrf2 in the hippocampus tissue. All these parameters were reversed by CGA treatment. Importantly, the higher dose of CGA (60 mg/kg) showed a greater neuroprotective effect. In conclusion, these findings suggest that CGA attenuates the ISO-induced cognitive impairment via its anti-inflammatory, anti-oxidative, and anti-apoptotic properties in aged mice.
10.1002/fsn3.2952
Subsequent maternal sleep deprivation aggravates cognitive impairment by modulating hippocampal neuroinflammatory responses and synaptic function in maternal isoflurane-exposed offspring mice.
Brain and behavior
INTRODUCTION:Pregnant women may need to undergo non-obstetric surgery under general anesthesia owing to medical needs, and pregnant women frequently experience sleep disturbances during late gestation. Preclinical studies demonstrated that maternal isoflurane exposure (MISO) or maternal sleep deprivation (MSD) contributed to cognitive impairments in offspring. Research studies in mice have revealed that SD can aggravate isoflurane-induced cognitive deficits. However, it remains unclear whether MSD aggravates MISO-induced cognitive deficits in offspring. The purpose of this research was to explore the combined effects of MSD and MISO on offspring cognitive function and the role of neuroinflammation and synaptic function in the process of MSD + MISO. METHODS:Pregnant mice were exposed to 1.4% isoflurane by inhalation for 4 h on gestational day (GD) 14. Dams were then subjected to SD for 6 h (12:00-18:00 h) during GD15-21. At 3 months of age, the offspring mice were subjected to the Morris water maze test to assess cognitive function. Then the levels of inflammatory and anti-inflammatory markers and synaptic function-related proteins were assessed using molecular biology methods. RESULTS:The results of this study demonstrated that MISO led to cognitive dysfunction, an effect that was aggravated by MSD. In addition, MSD exacerbated the maternal isoflurane inhalation, leading to an enhancement in the expression levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha and a reduction in the hippocampal levels of IL-10, synaptophysin, post-synaptic density-95, growth-associated protein-43, and brain-derived neurotrophic factor. CONCLUSION:Our findings revealed that MSD aggravated the cognitive deficits induced by MISO in male offspring mice, and these results were associated with neuroinflammation and alternations in synaptic function.
10.1002/brb3.3610