RESUMEN
BACKGROUND: The relationship between Alzheimer's disease biomarkers and postoperative complications, such as postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), remains a subject of ongoing debate. OBJECTIVE: This meta-analysis aimed to determine whether there is an association between perioperative Alzheimer's disease biomarkers and postoperative complications. DESIGN: We conducted a meta-analysis of observational clinical studies that explored the correlation between Alzheimer's disease biomarkers and POD or POCD in patients who have undergone surgery, following PRISMA guidelines. The protocol was previously published (INPLASY: INPLASY202350001). DATA SOURCES: A comprehensive search was conducted across PubMed, Embase, Web of Science, and Cochrane databases until March 2023. ELIGIBILITY CRITERIA: Surgical patients aged at least 18 years, studies focusing on POD or POCD, research involving Alzheimer's disease biomarkers, including Aß or tau in blood or cerebrospinal fluid (CSF), and availability of the full text. RESULTS: Our meta-analysis included 15 studies: six focusing on POD and nine on POCD. The findings revealed a negative correlation between preoperative CSF ß-amyloid 42 (Aß42) levels and the onset of POD [mean difference -86.1, 95% confidence interval (CI), -114.15 to -58.05, I2 : 47%]; this association was strongly supported by trial sequential analysis (TSA). A similar negative correlation was discerned between preoperative CSF Aß42 levels and the incidence of POCD (-165.01, 95% CI, -261.48 to -68.53, I2 : 95%). The TSA also provided robust evidence for this finding; however, the evidence remains insufficient to confirm a relationship between other Alzheimer's disease biomarkers [ß-amyloid 40 (Aß40), total tau (T-tau), phosphorylated tau (P-tau), and Aß42/T-tau ratio] and POD or POCD. CONCLUSION: The study results indicate a negative correlation between preoperative CSF Aß42 levels and the occurrence of both POD and POCD. Future investigations are warranted to identify the predictive cutoff value of preoperative CSF Aß42 for POD and POCD.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Delirio del Despertar , Complicaciones Cognitivas Postoperatorias , Humanos , Adolescente , Adulto , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Estudios Prospectivos , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Cognitivas Postoperatorias/diagnóstico , Complicaciones Cognitivas Postoperatorias/epidemiología , Complicaciones Cognitivas Postoperatorias/etiología , Biomarcadores/líquido cefalorraquídeo , Fragmentos de PéptidosRESUMEN
This work attempts to discuss whether dexmedetomidine (Dex) can protect rats from postoperative cognitive dysfunction (POCD) through regulating the γ-aminobutyric acid-B receptor (GABAB R)-mediated cyclic adenosine monophosphate (cAMP) - protein kinase A (PKA) - cAMP-response element binding (cAMP-PKA-CREB) signaling pathway. Sprague-Dawley rats were divided into a non-surgical group (Control), a surgical group (Model), a surgical group treated with Dex (Model + Dex), a surgical group treated with GABAB R antagonist (Model + CGP 35348) and a surgical group treated with Dex and GABAB R agonist (Model + Dex + Baclofen). Cognitive and memory functions were evaluated by Y-maze test and open-field test. The neuronal morphology of the hippocampus was observed by hematoxylin and eosin staining and neuronal apoptosis was by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling method. Inflammatory factors and cAMP levels were detected by enzyme-linked immunosorbent assay while expressions of GABAB R and PKA-CREB pathway-related molecules by Western blot. Compared with control rats, the model rats exhibited reduced alternation rates with a prolonged time spent in the central zone; meanwhile, levels of tumor necrosis factor-α and interleukin-1ß and the apoptotic index, as well as GABAB R1 and GABAB R2 expressions were increased in the model rats, but the cAMP-PKA-CREB pathway was inhibited (all P < 0.05). When treated with either Dex or CGP 35348, the surgical rats displayed an opposite tendency concerning the above factors as compared to the model rats (all P < 0.05). Furthermore, Baclofen, the agonist of GABAB R, could reverse the protective effect of Dex against POCD in rats. Dex protects rats from POCD possibly via suppressing GABAB R to up-regulate the cAMP-PKA-CREB signaling pathway, thereby alleviating the hippocampal inflammation caused by surgical trauma.
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Disfunción Cognitiva/prevención & control , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Dexmedetomidina/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Complicaciones Posoperatorias , Receptores de GABA-B/metabolismo , Animales , Apoptosis/efectos de los fármacos , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Encefalitis/complicaciones , Encefalitis/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Masculino , Neuronas/efectos de los fármacos , Neuronas/patología , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
Propofol is widely used in clinical practice, including non-obstetric surgery in pregnant women. Previously, we found that propofol anaesthesia in maternal rats during the third trimester (E18) caused learning and memory impairment to the offspring rats, but how about the exposure during early pregnancy and the underlying mechanisms? Histone acetylation plays an important role in synaptic plasticity. In this study, propofol was administered to the pregnant rats in the early pregnancy (E7). The learning and memory function of the offspring were tested by Morris water maze (MWM) test on post-natal day 30. Two hours before each MWM trial, histone deacetylase 2 (HDAC2) inhibitor, suberoylanilide hydroxamic acid (SAHA), Senegenin (SEN, traditional Chinese medicine), hippyragranin (HGN) antisense oligonucleotide (HGNA) or vehicle were given to the offspring. The protein levels of HDAC2, acetylated histone 3 (H3) and 4 (H4), cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), N-methyl-D-aspartate receptor (NMDAR) 2 subunit B (NR2B), HGN and synaptophysin in offspring's hippocampus were determined by Western blot or immunofluorescence test. It was discovered that infusion with propofol in maternal rats on E7 leads to impairment of learning and memory in offspring, increased the protein levels of HDAC2 and HGN, decreased the levels of acetylated H3 and H4 and phosphorylated CREB, NR2B and synaptophysin. HDAC2 inhibitor SAHA, Senegenin or HGN antisense oligonucleotide reversed all the changes. Thus, present results indicate exposure to propofol during the early gestation impairs offspring's learning and memory via inhibiting histone acetylation. SAHA, Senegenin and HGN antisense oligonucleotide might have therapeutic value for the adverse effect of propofol.
Asunto(s)
Memoria , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Propofol/efectos adversos , Acetilación/efectos de los fármacos , Anestesia , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Histona Desacetilasa 2/metabolismo , Histonas/metabolismo , Memoria/efectos de los fármacos , Oligonucleótidos Antisentido/farmacología , Fosforilación/efectos de los fármacos , Embarazo , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Sinaptofisina/genética , Sinaptofisina/metabolismo , Vorinostat/farmacologíaRESUMEN
The brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) (BDNF-TrkB) signalling pathway plays a crucial role in regulating learning and memory. Synaptophysin provides the structural basis for synaptic plasticity and depends on BDNF processing and subsequent TrkB signalling. Our previous studies demonstrated that maternal exposure to propofol during late stages of pregnancy impaired learning and memory in rat offspring. The purpose of this study is to investigate whether the BDNF-TrkB signalling pathway is involved in propofol-induced learning and memory impairments. Propofol was intravenously infused into pregnant rats for 4 hrs on gestational day 18 (E18). Thirty days after birth, learning and memory of offspring was assessed by the Morris water maze (MWM) test. After the MWM test, BDNF and TrkB transcript and protein levels were measured in rat offspring hippocampus tissues using real-time PCR (RT-PCR) and immunohistochemistry (IHC), respectively. The levels of phosphorylated-TrkB (phospho-TrkB) and synaptophysin were measured by western blot. It was discovered that maternal exposure to propofol on day E18 impaired spatial learning and memory of rat offspring, decreased mRNA and protein levels of BDNF and TrkB, and decreased the levels of both phospho-TrkB and synaptophysin in the hippocampus. Furthermore, the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) reversed all of the observed changes. Treatment with 7,8-DHF had no significant effects on the offspring that were not exposed to propofol. The results herein indicate that maternal exposure to propofol during the late stages of pregnancy impairs spatial learning and memory of offspring by disturbing the BDNF-TrkB signalling pathway. The TrkB agonist 7,8-DHF might be a potential therapy for learning and memory impairments induced by maternal propofol exposure.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Memoria/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Propofol/efectos adversos , Receptor trkB/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Animales Recién Nacidos , Análisis de los Gases de la Sangre , Factor Neurotrófico Derivado del Encéfalo/genética , Regulación hacia Abajo/efectos de los fármacos , Femenino , Flavonas/farmacología , Hipocampo/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Fosforilación , Embarazo , Ratas Sprague-Dawley , Receptor trkB/genética , SinaptofisinaRESUMEN
Some pregnant women have to experience non-obstetric surgery during pregnancy under general anesthesia. Our previous studies showed that maternal exposure to sevoflurane, isoflurane, propofol, and ketamine causes cognitive deficits in offspring. Histone acetylation has been implicated in synaptic plasticity. Propofol is commonly used in non-obstetric procedures on pregnant women. Previous studies in our laboratory showed that maternal propofol exposure in pregnancy impairs learning and memory in offspring by disturbing histone acetylation. The present study aims to investigate whether HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) could attenuate learning and memory deficits in offspring caused by maternal surgery under propofol anesthesia during mid-pregnancy. Maternal rats were exposed to propofol or underwent abdominal surgery under propofol anesthesia during middle pregnancy. The learning and memory abilities of the offspring rats were assessed using the Morris water maze (MWM) test. The protein levels of histone deacetylase 2 (HDAC2), phosphorylated cAMP response-element binding (p-CREB), brain-derived neurotrophic factor (BDNF), and phosphorylated tyrosine kinase B (p-TrkB) in the hippocampus of the offspring rats were evaluated by immunofluorescence staining and western blot. Hippocampal neuroapoptosis was detected by TUNEL staining. Our results showed that maternal propofol exposure during middle pregnancy impaired the water-maze learning and memory of the offspring rats, increased the protein level of HDAC2 and reduced the protein levels of p-CREB, BDNF and p-TrkB in the hippocampus of the offspring, and such effects were exacerbated by surgery. SAHA alleviated the cognitive dysfunction and rescued the changes in the protein levels of p-CREB, BDNF and p-TrkB induced by maternal propofol exposure alone or maternal propofol exposure plus surgery. Therefore, SAHA could be a potential and promising agent for treating the learning and memory deficits in offspring caused by maternal nonobstetric surgery under propofol anesthesia.
Asunto(s)
Disfunción Cognitiva , Propofol , Humanos , Embarazo , Ratas , Animales , Femenino , Propofol/efectos adversos , Vorinostat/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Histonas/metabolismo , Aprendizaje por Laberinto , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/metabolismo , Hipocampo/metabolismo , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Anestesia GeneralRESUMEN
Recent evidence showed that general anesthesia produces long-term neurotoxicity and cognitive dysfunction. However, it remains unclear whether maternal non-obstetric surgery under ketamine anesthesia during second trimester causes cognitive impairment in offspring. The present study assigned pregnant rats into three groups: 1) normal control group receiving no anesthesia and no surgery, 2) ketamine group receiving ketamine anesthesia for 2â¯h on the 14th day of gestation but no surgery, and 3) surgery group receiving abdominal surgery under ketamine anesthesia on the 14th day of gestation. On postnatal day 1, the offspring rats in Ketamine group and surgery group were assigned to receive intra-peritoneal injection of Senegenin (15â¯mg/kg), once per day for consecutive 14 days. The offspring's spatial perception, anxiety-like behavior, and learning and memory were evaluated. Then the offspring's hippocampal tissues were collected. The offspring of the surgery group were impaired in the spatial perception in the cliff avoidance test and the spatial learning and memory in the Morris water maze test. Accordingly, the activity of histone deacetylases increased, the protein levels of NEDD9, BDNF, p-TrkB, Syn and PSD-95 decreased, and the density of dendritic spines reduced in the hippocampus of the offspring of the surgery group, and such effects were not seen in the offspring of the ketamine group, neither in the offspring of control group. Senegenin alleviated the learning and memory impairment, and increased the protein levels of NEDD9, BDNF, p-TrkB, Syn and PSD-95 and the density of dendritic spines in the offspring of the surgery group. ketamine anesthesia plus surgery during second trimester impairs hippocampus-dependent learning and memory, and the deficits could be rescued by treatment with Senegenin.
Asunto(s)
Anestesia , Ketamina , Embarazo , Femenino , Ratas , Animales , Ketamina/toxicidad , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Aprendizaje Espacial , Hipocampo , Dendritas , Aprendizaje por LaberintoRESUMEN
Postoperative cognitive dysfunction (POCD) affects millions of patients each year in the USA and has been recognized as a significant complication after surgery. Epigenetic regulation of learning and memory has been shown. For example, an increase of histone deacetylases (HDACs), especially HDAC2, which epigenetically regulates gene expression, impairs learning and memory. However, the epigenetic contribution to the development of POCD is not known. Also, the effects of living situation on POCD have not been investigated. Here, we showed that mice that lived alone before the surgery and lived in a group after the surgery and mice that lived in a group before surgery and lived alone after surgery had impairment of learning and memory compared with the corresponding control mice without surgery. Surgery increased the activity of HDACs including HDAC2 but not HDAC1 and decreased brain-derived neurotrophic factor (BDNF), dendritic arborization, and spine density in the hippocampus. Suberanilohydroxamic acid (SAHA), a relatively specific inhibitor of HDAC2, attenuated these surgery effects. SAHA did not change BDNF expression, dendritic arborization, and spine density in mice without surgery. Surgery also reduced the activity of nuclear histone acetyltransferases (HATs). This effect was not affected by SAHA. Our results suggest that surgery activates HDACs, which then reduces BDNF and dendritic arborization to develop POCD. Thus, epigenetic change contributes to the occurrence of POCD.
Asunto(s)
Dendritas/patología , Histona Desacetilasas/metabolismo , Laparotomía/efectos adversos , Aprendizaje , Trastornos de la Memoria/enzimología , Trastornos de la Memoria/patología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Dendritas/efectos de los fármacos , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/patología , Inhibidores de Histona Desacetilasas/farmacología , Aprendizaje/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Trastornos de la Memoria/complicaciones , Trastornos de la Memoria/fisiopatología , Ratones , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/fisiopatología , Receptor trkB/metabolismo , Vorinostat/farmacologíaRESUMEN
Recent studies have shown that sevoflurane can cause long-term neurotoxicity and learning and memory impairment in developing and progressively neurodegenerative brains. Sevoflurane is a widely used volatile anesthetic in clinical practice. Late gestation is a rapidly developing period in the fetal brain, but whether sevoflurane anesthesia during late gestation affects learning and memory of offspring is not fully elucidated. Histone deacetylase 2 (HDAC2) plays an important regulatory role in learning and memory. This study examined the effect of maternal sevoflurane exposure on learning and memory in offspring and the underlying role of HDAC2. The Morris water maze (MWM) test was used to evaluate learning and memory function. Q-PCR and immunofluorescence staining were used to measure the expression levels of genes related to learning and memory. The results showed that sevoflurane anesthesia during late gestation impaired learning and memory in offspring rats (e.g., showing increase of the escape latency and decrease of the platform-crossing times and target quadrant traveling time in behavior tests) and upregulated the expression of HDAC2, while downregulating the expression of the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the N-methyl-D-aspartate receptor 2 subunit B (NR2B) mRNA and protein in the hippocampus of offspring in a time-dependent manner. HDAC2 inhibitor suberoylanilide hydroxamic acid (SAHA) treatment alleviated all of these changes in offspring rats. Therefore, the present study indicates that sevoflurane exposure during late gestation impairs offspring rat's learning and memory via upregulation of the expression of HDAC2 and downregulation of the expression of CREB and NR2B. SAHA can alleviate these impairments.
Asunto(s)
Anestésicos por Inhalación/toxicidad , Inhibidores de Histona Desacetilasas/farmacología , Aprendizaje/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/prevención & control , Sevoflurano/toxicidad , Vorinostat/farmacología , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Histona Desacetilasa 2/antagonistas & inhibidores , Histona Desacetilasa 2/genética , Masculino , Intercambio Materno-Fetal , Embarazo , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genéticaRESUMEN
OBJECTIVE: To study the effect of growth hormone (Gh) on Clara cell in acute lung injury (ALI) rats during stress responsive stage. METHODS: One hundred and twelve male Sprague-Dawley (SD) rats were randomly divided into ALI group and recombinant human Gh (rhGh) group. The rats in two groups were subdivided into seven subgroups of different time intervals after lipopolysaccharide (LPS) injection:0 (pre-injection of LPS, acted as control group), 0.5, 1, 2, 4, 6 and 24 hours subgroups respectively. Immunohistochemistry and electron microscope were used to investigate the number and morphological changes in Clara cells in ALI rats. RESULTS: Half of an hour after LPS injection, ALI was induced. The extent of lung injury increased with the time increased after LPS injection,peaked at 6 hours, then the extent of lung injury began to recess. The dynamic changes in lung injury of rats in rhGh group were similar to those in ALI group, but the extent of injury was more severe than that in ALI group at different time intervals. The Clara cell counts decreased significantly 1 hour after LPS injection, reaching the lowest at 6 hours, then began to recover 24 hours after LPS injection with statistically significant difference (all P<0.01). The counts of Clara cells in rhGh group decreased more significantly than that in ALI group at different time intervals after LPS injection, especially at 24 hours.The ultrastructure of Clara cell showed significant damage 24 hours after LPS injection. Compared with ALI group,the ultrastructure of Clara cell in rhGh group were more damaged 24 hours after LPS injection. CONCLUSION: rhGh could deteriorate the damage of Clara cell in acute lung injury rats induced by endotoxemia during stress response stage.
Asunto(s)
Lesión Pulmonar Aguda/patología , Hormona de Crecimiento Humana/farmacología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Lipopolisacáridos/toxicidad , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/farmacologíaRESUMEN
OBJECTIVE: To observe the effects of low-intensity pulsed ultrasound (LIPUS) pretreatment on pulmonary expression of high mobility group box-1 (HMGB1) in a rat model of lung ischemia-reperfusion (IR). METHODS: Thirty-two male SpragueDawley rats weighing 250-300 g were randomly divided (n=8) into sham-operated group, lung IR group, LIPUS pretreatment group and pretreatment with α7-nicotinic cholinergic receptor (α7nAChR) antagonist group. In the sham-operated group, the left pulmonary hilum was dissociated without occlusion; in the other 3 groups, the left pulmonary hilum was occluded for 45 min followed by reperfusion for 180 min; LIPUS pretreatment for 30 min and intraperitoneal injection of methyllycaconitine (2 mg/kg), an α7nAChR antagonist, were administered before the operation. The wet/dry weight ratio (W/D) and pulmonary permeability index (LPI) of the lung tissue were measured, and the lung histopathology was observed and scored. The contents of interleukin-1 (IL-1) and IL-6 in the lung tissues were measured using ELISA, and the pulmonary expression of HMGB1 protein was detected using immunofluorescence assay and Western blotting. RESULTS: Compared with those in the sham-operated group, the W/D of the lung tissue, LPI, pathological scores, IL-1 and IL-6 contents in the lung tissue, and pulmonary HMGB1 expression all significantly increased in the other 3 groups (P < 0.05). LIPUS preconditioning significantly lowered the W/D values, LPI, pathological score, IL-1 and IL-6 contents and HMGB1 expression in the lung tissues following lung IR, and these effects were significantly inhibited by administration of methyllycaconitine. CONCLUSIONS: LIPUS preconditioning can reduce lung IR injury possibly by activating α7nAChR-dependent cholinergic anti-inflammatory pathway to reduce lung tissue HMGB1 expression.
Asunto(s)
Proteína HMGB1/metabolismo , Pulmón/irrigación sanguínea , Daño por Reperfusión/terapia , Terapia por Ultrasonido/métodos , Receptor Nicotínico de Acetilcolina alfa 7/antagonistas & inhibidores , Aconitina/análogos & derivados , Aconitina/farmacología , Animales , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Pulmón/metabolismo , Pulmón/patología , Masculino , Antagonistas Nicotínicos/farmacología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Ondas UltrasónicasRESUMEN
Preclinical studies suggest that propofol may cause neuronal injury to the developing brain. A previous study demonstrated that, in a rat model, maternal exposure to propofol during early or late pregnancy caused learning and memory impairment in the offspring. However, whether propofol exposure during middle pregnancy can cause longterm behavioral deficits in the offspring remains to be elucidated. NmethylDaspartate receptor 2B subunit (NR2B) serves a critical role in memory modulation. To exert its function, NR2B must be transported to the neuronal membrane by kinesin family member 17 (KIF17). The aim of the present study was to investigate the role of KIF17 in learning and memory impairment in rat offspring caused by propofol exposure during middle pregnancy. Pregnant rats were exposed to propofol on gestational day 14 (G14) for 4 and 8 h, with control pregnant rats receiving an equal volume of normal saline. The learning and memory of the offspring was assessed using Morris water maze tests from postnatal day 30 (P30) to P36. The levels of KIF17 protein, total NR2B (TNR2B) and membrane NR2B (MNR2B) in the hippocampus were detected using western blotting. The results demonstrated that propofol exposure caused learning and memory deficits and decreased KIF17 and MNR2B protein levels in the hippocampus; however, no but changes in the expression of TNR2B were observed. These results indicate that maternal propofol exposure during middle pregnancy impairs learning and memory in offspring rats by suppressing the expression of KIF17 and inhibiting the translocation of NR2B to the neuronal membrane.
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Cinesinas/genética , Discapacidades para el Aprendizaje/etiología , Exposición Materna/efectos adversos , Trastornos de la Memoria/etiología , Efectos Tardíos de la Exposición Prenatal , Propofol/efectos adversos , Animales , Biomarcadores , Modelos Animales de Enfermedad , Femenino , Hipocampo/metabolismo , Hipocampo/fisiopatología , Cinesinas/metabolismo , Discapacidades para el Aprendizaje/fisiopatología , Masculino , Trastornos de la Memoria/fisiopatología , Fenotipo , Embarazo , Ratas , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Increasing evidence indicates that most general anesthetics can harm developing neurons and induce cognitive dysfunction in a dose- and time-dependent manner. Histone deacetylase 2 (HDAC2) has been implicated in synaptic plasticity and learning and memory. Our previous results showed that maternal exposure to general anesthetics during late pregnancy impaired the offspring's learning and memory, but the role of HDAC2 in it is not known yet. In the present study, pregnant rats were exposed to 1.5% isoflurane in 100% oxygen for 2, 4 or 8 hours or to 100% oxygen only for 8 hours on gestation day 18 (E18). The offspring born to each rat were randomly subdivided into 2 subgroups. Thirty days after birth, the Morris water maze (MWM) was used to assess learning and memory in the offspring. Two hours before each MWM trial, an HDAC inhibitor (SAHA) was given to the offspring in one subgroup, whereas a control solvent was given to those in the other subgroup. The results showed that maternal exposure to isoflurane impaired learning and memory of the offspring, impaired the structure of the hippocampus, increased HDAC2 mRNA and downregulated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) mRNA, N-methyl-D-aspartate receptor 2 subunit B (NR2B) mRNA and NR2B protein in the hippocampus. These changes were proportional to the duration of the maternal exposure to isoflurane and were reversed by SAHA. These results suggest that exposure to isoflurane during late pregnancy can damage the learning and memory of the offspring rats via the HDAC2-CREB -NR2B pathway. This effect can be reversed by HDAC2 inhibition.
Asunto(s)
Anestésicos por Inhalación/efectos adversos , Histona Desacetilasa 2/genética , Isoflurano/efectos adversos , Exposición Materna/efectos adversos , Memoria/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Aprendizaje Espacial/efectos de los fármacos , Animales , Femenino , Aprendizaje por Laberinto/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba/efectos de los fármacosRESUMEN
OBJECTIVE: To study the effect of growth hormone (GH) on acute lung injury (ALI) induced by endotoxemia, and its potential therapeutic mechanism. METHODS: One hundred and twelve male Sprague-Dawley rats were randomly divided into ALI group and GH group. The rats in two groups were further divided into seven subgroups determined by the length of interval after lipopolysaccharide (LPS) challenge: 0 (before injection of LPS, served as control group), 0.5, 1, 2, 4, 6 and 24 hours subgroups respectively. Pulmonary alveolar septum area density (PASAD) and the number of neutrophil in lungs of rats were analyzed morphometrically. The levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) were determined by radioimmunoassay. The expression and activation of nuclear factor-kappaB (NF-kappaB) were analyzed, NF-kappaB positive cells in lungs were counted after immunofluorescence staining, and the levels of NF-kappaB inhibition (I-kappaB alpha) in lung homogenates of rats were assayed by Western blot. RESULTS: Half an hour after intravenous injection of LPS, both the PASAD and the number of neutrophil in lungs of ALI rats began to increase, and peaked at 6 hours post-injury, then began to recover and reached the normal levels at 24 hours. The content of TNF in lung homogenates showed immediate elevation after LPS injection, becoming higher than that of the control after 0.5 hour, reaching the peak value at 1 hour, maintaining high levels until 6 hours, then gradually recovered. The content of TNF in lung homogenates of the GH group increased significantly more than that in the LPS group. The contents of IL-6 in rats' lung homogenates began to increase significantly 1 hour post-injury, peaked at 4 hours, then gradually returned to normal level 6 hours post-injury. The content of IL-6 in the lung homogenates of GH group was higher than that in the LPS group at different time intervals post-injury, showing significant difference at 0.5, 6 and 24 hours (P<0.05 or P<0.01). The number of NF-kappaB positive cells increased dramatically at 0.5 hour post-injury. The intensity of fluorescence was enhanced. Both of them peaked at 4 hours post-injury. The number of NF-kappaB positive cells and the enhanced intensity of fluorescence began to decrease at 6 hours post-injury. But the number of NF-kappaB cells at 24 hours post-injury was still larger than that in the control group. The number of NF-kappaB cells in lungs of GH group was significantly larger than that in the LPS group at different time intervals post-injury (P<0.05 or P<0.01). I-kappaB alpha contents in lung homogenates of ALI rats decreased dramatically 0.5 hour post-injury, nadir at 4 hours, and then began to recover. Correlation analysis indicated that PASAD, the levels of TNF and IL-6 and the extent of neutrophil infiltration in lung were positively correlated to the extent of the expression and the activation of NF-kappaB. CONCLUSION: The application of GH during early stage of endotoxin challenge can deteriorate the lung injury induced by LPS through enhancing the expression and activation of NF-kappaB, thus enhances the inflammatory response in lungs.
Asunto(s)
Lesión Pulmonar Aguda/metabolismo , Hormona del Crecimiento/farmacología , Pulmón/metabolismo , FN-kappa B/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patología , Animales , Modelos Animales de Enfermedad , Proteínas I-kappa B/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/toxicidad , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Neutrófilos/patología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Factores de Necrosis Tumoral/metabolismoRESUMEN
BACKGROUND: Clara cell secretory protein (CC16) is an important lung derived protective factor and may play an important role on the pathogenesis of acute lung injury (ALI) induced by endotoxemia. Growth hormone (GH) is an important anabolism hormone secreted by GH cells of the hypophysis. Previous research showed that GH would significantly exacerbate ALI induced by endotoxemia, but the mechanism is not very clear yet. Whether the effects are related to CC16 or not is undetermined. METHODS: One hundred and twelve male Sprague-Dawley rats were randomly divided into an ALI group and a GH group. The rats in the two groups were subdivided into seven subgroups, according to injection with lipopolysaccharides (LPS) or not, then according to different intervals of time after LPS injection; 0 hour (pre-injection of LPS, acted as control group), 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours for subgroups. Pulmonary alveolar septa area density (PASAD) and ploymorphonuclear cells (PMN) in the lungs were analyzed morphometrically. The levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6) were determined by radioimmunoassay. To analyze the expression and activation of nuclear factor kappa B (NF-κB), the numbers of NF-κB positive cells in lungs were counted after immunofluorescence staining, and the levels of NF-κB inhibitory protein-α (IκB-α) in lung homogenates of rats were detected by Western blotting. The expression levels of CC16 mRNA in lungs of the rats with ALI were determined by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). The levels of CC16 protein in lung homogenates were detected by Western blotting. RESULTS: Half an hour after LPS injury both the PASAD and PMN numbers in lungs of the rats with ALI began to increase significantly and peaked at 6-hour post-injury. They then began to recover and reached normal levels at 24-hour post-injury. Both the PASAD and PMN numbers in the GH group increased more significantly than those in the ALI group. The levels of TNF in lungs of the rats with ALI homogenates increased significantly 0.5-hour post-injury, peaked at 1-hour and maintained a high level until 6 hours then gradually recovered. The content of TNF in the GH group lung homogenates increased more significantly than in the ALI group post-injury. The contents of IL-6 in rat lung homogenates began to increase significantly at 1-hour post-injury, peaked at 4 hours then gradually returned to normal levels by 6 hours post-injury. The levels of IL-6 in the lung homogenates of the GH group were higher than in the ALI group at different time intervals post-injury. The number of NF-κB positive cells increased dramatically at 0.5-hour post-injury, and the fluorescence intensity was enhanced. Both peaked at 4-hour post-injury. The number of NF-κB positive cells and the enhanced intensity of fluorescence began to decrease from 6-hour post-injury, but the number of NF-κB cells at 24 hours post-injury was still higher than in the control group. The number of NF-κB cells in lungs in the GH group was significantly higher than in the LPS group at the different time intervals post-injury. The IκB-α expression in lungs of the rats with ALI homogenates decreased dramatically 0.5-hour post-injury, reaching a nadir at 4-hour post-injury and then began to recover. The levels of IκB-α in GH group were significantly lower than those in ALI group. Both the levels of CC16 mRNA and protein in lungs of the rats with ALI began to decrease significantly 0.5-hour post-injury, reached a nadir at 6 hours, and then began to recover. Both the expression of CC16 mRNA and CC16 protein in the GH group were significantly lower than those in the ALI group at the different time intervals post-injury. Correlation analysis indicates that CC16 correlates significantly with all the indices mentioned above. CONCLUSIONS: Down-regulation of CC16 expression plays a critical role in the pathogenesis of acute lung injury induced by endotoxemia. The application of GH can exacerbate the lung injury induced by endotoxemia through down-regulating the expression of CC16.
Asunto(s)
Lesión Pulmonar Aguda/genética , Hormona del Crecimiento/farmacología , Pulmón/metabolismo , Uteroglobina/genética , Lesión Pulmonar Aguda/metabolismo , Animales , Líquido del Lavado Bronquioalveolar , Interleucina-6/metabolismo , Pulmón/efectos de los fármacos , Masculino , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
This work aims to study the pathogenesis of learning and memory impairment in offspring rats resulting from maternal enflurane anesthesia by focusing on the expression of the N-methyl-d-aspartic acid receptor subunit 2B (NR2B) in the hippocampus of the offspring. Thirty female Sprague-Dawley rats were randomly divided into three groups: control (C group), 4 h enflurane exposure (E1 group), and 8 h enflurane exposure (E2 group) groups. Eight to ten days after the initiation of pregnancy, rats from the E1 and E2 groups were allowed to inhale 1.7% enflurane in 2 L/min oxygen for 4 h and 8 h, respectively. Rats from the C group were allowed to inhale 2 L/min of oxygen only. The Morris water maze was used to assay the learning and memory function of the offspring on postnatal days 20 and 30. RT-PCR and immunohistochemistry assays were then used to measure the mRNA levels and protein expression of NR2B, respectively. Relative to offspring rats from the C group, those from the E1 and E2 groups exhibited longer escape latencies, lesser number of crossings over the platform, and less time spent in the target quadrant in the spatial exploration test (P < 0.05). In addition, the mRNA and protein expression levels of NR2B in the hippocampus of offspring rats in the E1 and E2 groups were down-regulated (P < 0.05). No significant differences between the E1 and E2 groups were observed (P > 0.05) in terms of mRNA levels and protein expression of NR2B. The cognitive function of the offspring is impaired when maternal rats are exposed to enflurane during early pregnancy. A possible mechanism of this effect is related to the down-regulation of NR2B expression.
Este trabalho objetiva o estudo da patogênese de deficiência no aprendizado e memória de prole de ratos resultante da anestesia maternal por enflurano, por meio da expressão da subunidade 2B do receptor do ácidoN-metil-D-aspártico (NR2B) no hipocampo dos filhotes. Dividiram-se, aleatoriamente, 30 fêmeas de ratos Sprague-Dawley em três grupos: controle (grupo C), exposição ao enflurano por 4 h (grupo E1) e por 8 h (grupo E2). De oito a 10 dias após o início da gravidez, os ratos dos grupos E1 e E2 inalaram enflurano 1,7% em 2 L/min de oxigênio, por 4 h e 8 h, respectivamente. Ratos do grupo C inalaram apenas 2 L/min de oxigênio. O labirinto de água de Morris foi empregado para analisar as funções de aprendizado e memória da cria em 20 e 30 dias após o nascimento. Utilizaram-se ensaios de RT-PCR e de imuno-histoquímica para medir os níveis de mRNA e expressão da proteína do NR2B, respectivamente. Em comparação com os ratos controle do grupo C, aqueles dos grupos E1 e E2 exibiram latências de escape mais longas, menor número de travessias na plataforma e menos tempo gasto no quadrante alvo no teste de exploração espacial (P < 0,05). Adicionalmente, os níveis de expressão de mRNA e de proteína do NR2B no hipocampo dos filhotes nos grupos E1 e E2 estavam reduzidos (P < 0,05). Não se observaram diferenças significativas entre os grupos E1 e E2 (P < 0,05) quanto aos níveis de mRNA e à expressão de proteína de NR2B. A função cognitiva dos filhotes é prejudicada quando as mães são expostas ao enflurano durante o início da gravidez. O mecanismo possível para esse efeito está relacionado à diminuição na expressão de NR2B.