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Abstract Background: In congenital heart surgery, low cardiac output syndrome (LCOS) is a major cause of morbidity in the immediate post-operative period. A decrease in cardiac output leads to an increase in tissue oxygen consumption. Several biomarkers such as venous oxygen saturation (SvO2), arteriovenous oxygen difference (DavO2), and lactate can assess tissue perfusion in the presence of LCOS. Recently, central venous to arterial CO2 difference (ΔCO2) has been proposed as a biomarker of tissue ischemia that could be used as a predictor of death in neonatal patients. This study aimed to analyze the relationship between ΔCO2 and immediate post-operative outcomes in pediatric patients undergoing congenital heart surgery and its correlation with DavO2, SvO2, and lactate. Methods: We conducted a longitudinal study of patients aged 0-18 years who underwent congenital heart surgery with or without cardiopulmonary bypass at the Instituto Nacional de Pediatría, from March 2019 to March 2021. Results: Eighty-two patients were included; the median age was 17 months. About 59% had a ΔCO2 ≥ 6 mmHg. Patients with ΔCO2 ≥ 6 mmHg had a vasoactive-inotropic score > 5 (p < 0.001), DavO2 > 5 mL/dL (p = 0.048), and lactate > 2 mmol/L (p = 0.027), as well as a longer hospital stay (p = 0.043). Patients with ΔCO2 > 6 mmHg and vasoactive-inotropic score ≥ 10 were 12.6 times more likely to die. Conclusion: ΔCO2 is a good marker of tissue hypoperfusion and outcome in the post-operative period of congenital heart surgery.
Resumen Introducción: En la cirugía cardiaca de malformaciones congénitas, el síndrome de bajo gasto cardiaco (SBGC) es una de las principales causas de morbilidad en el postoperatorio inmediato. La caída del gasto cardiaco aumenta el consumo de oxígeno en los tejidos. Varios biomarcadores, como la saturación venosa de oxígeno (SvO2), la diferencia arteriovenosa de oxígeno (DavO2) y el lactato han sido utilizados como indicadores hipoperfusión tisular en presencia de SBGC. Recientemente, la diferencia arteriovenosa de CO2 (ΔCO2) se ha propuesto como otro biomarcador de isquemia tisular que podría utilizarse como predictor de muerte en pacientes en edad neonatal. El objetivo de este estudio fue analizar la relación entre la ΔCO2 y la evolución postoperatoria de pacientes pediátricos operados de cardiopatías congénitas y correlacionarlo con la DavO2, SvO2 y lactato. Métodos: Se realizó un estudio longitudinal en pacientes de 0 a 18 años operados de corazón con empleo de bomba de circulación extracorpórea en el Instituto Nacional de Pediatría. Resultados: Se incluyeron 82 pacientes; la mediana de edad fue de 17 meses. El 59% presentó un ΔCO2 > 6 mmHg. Los pacientes con un ΔCO2 > 6 mmHg mostraron un puntaje de inotrópicos > 5 (p < 0.001), DavO2 > 5 mL/dL (p = 0.048) y lactato > 2 mmol/L (p = 0.027), así como mayor estancia hospitalaria (p = 0.043). Los pacientes con ΔCO2 > 6 mmHg y un puntaje de inotrópicos ≥ 10 presentaron una probabilidad de muerte 12.6 veces mayor. Conclusiones: El ΔCO2 en el periodo postoperatorio de una cirugía cardiaca congénita es un buen marcador de hipoperfusión tisular y de desenlace.
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Objective:To explore the protective effects and mechanisms of L-carnitine (LCAR) on cognitive dysfunction in chronic cerebral hypoperfusion rats.Methods:Totally 90 SD male rats (SPF class) aged 3-4 months were divided into four groups according to random number talbe: sham operated control group (SHAM group, n=15), sham operated with L-carnitine treatment group (LCAR group, n=25), 2-vessel occlusion group (2VO group, n=25), and 2-vessel occlusion with L-carnitine treatment group (2VO+ LCAR group, n=25). The chronic cerebral hypoperfusion model was established by bilateral common carotid artery ligation, and the carotid arteries from SHAM group and LCAR group were only separated without ligation.L-carnitine was administered intraperitoneally (300 mg·kg -1·d -1) for 30 days after surgery in the LCAR and 2VO+ LCAR groups.After 30 days of L-carnitine intervention, Morris water maze was performed to test the spatial cognitive function of the rats, the ATP level of hippocampal tissue was detected by chemiluminescence, the mitochondrial structure and synaptic structure of hippocampal neurons were observed by transmission electron microscopy, the degree of mitochondrial damage was scored, the vesicle density was counted and measured, the level of N-methyl-D-aspartate receptor subunit 2A or 2B(NR2A/B) and postsynaptic density 95(PSD95) in hippocampal tissue were detected by Western blot.The expression and distribution levels of transcription factor cAMP response element-binding protein(CREB) in brain tissues were observed by immunofluorescence.SPSS 16.0 software was used for statistical analysis.The escape latency data of repeated learning training in Morris water maze was conducted by repetitive measurement ANOVA, while other data were adopted by one-way ANOVA, and Dunnett's t test was used for further pairwise comparison. Results:(1)Morris water maze results showed that the time and group interaction of escape latency was not significant among the 4 groups of rats ( F=1.4, P>0.05), but the time main effect and group main effect were significant( F=21.6, 15.2, both P<0.05). Morris water maze results showed that platform position learning from 3rd to 7th day, the escape latencies in 2VO group were longer than those in SHAM group and 2VO+ LCAR group (all P<0.05). The results of short-term memory showed that the escape latency in 2VO group was longer than those in SHAM group and 2VO+ LCAR group (all P<0.05). Meanwhile, the retention time and crossing times in the platform area of 2VO group were less than those in SHAM group and 2VO+ LCAR group (all P<0.05). (2) The absolute and relative levels of ATP in hippocampus showed that the difference among the 4 groups were statistically significant ( F=14.6, 13.2, both P<0.05). ATP level of hippocampus in 2VO group was lower than those in SHAM group and 2VO+ LCAR group (both P<0.05). Electron microscopic observation of mitochondrial morphology showed that the Flameng score of mitochondrial damage in the hippocampus of rats in 2VO group (2.82±0.17) was higher than those in SHAM group (0.25±0.07) and 2VO+ LCAR group (1.76±0.09) (both P<0.05). (3) The density of synaptic vesicles in the hippocampus of rats in 2VO group ((289.09±22.41)/μm 2)was lower than those in SHAM group ((497.49±28.89)/μm 2)and 2VO+ LCAR group ((401.23±45.09)/μm 2) (both P<0.01). Western blot results showed that the relative levels of synaptic proteins NR2A/B, PSD95 and CREB in 2VO group were lower than those in SHAM group and 2VO+ LCAR group (all P<0.05). Immunofluorescence results showed that the relative level of CREB expression in hippocampal subregions and cortex in 2VO group was lower than those in SHAM group and 2VO+ LCAR group (both P<0.01). Conclusion:L-carnitine can improve spatial learning and memory dysfunction in rats with chronic cerebral hypoperfusion, which are related with promoting ATP production and protecting mitochondrial morphology, and promoting synaptic vesicle synthesis and synaptic protein expression.
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Objective:To explore the roles and mechanisms of metformin in the improvement of cognitive dysfunction induced by chronic cerebral hypoperfusion in rats.Methods:Total 82 SD male rats (SPF grade) aged 3-4 months were randomly divided into four groups: sham operation control group (Con group, n=15), sham operation with metformin treatment group (Met group, n=20), 2-vessel occlusion group (2VO group, n=22), and 2-vessel occlusion with metformin administration group (2VO+ Met group, n=25). The chronic cerebral hypoperfusion model was established by bilateral common carotid artery ligation, and the carotid arteries of rats in Con group and Met group were only separated without ligation.After 2VO operation, rats in 2VO+ Met group and Met group were given metformin solution in drinking water at a dose of 100 mg/kg per day for 4 weeks.After 4-week continuous intervention with metformin, Morris water maze was performed to test the spatial cognitive function of the rats, in vivo electrophysiological technology was used to detect the long-term potential of the rats, and enzyme-linked immunosorbent assay(ELISA) was used to detect the concentrations of inflammatory factor tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β) and interleukin-6(IL-6) in the hippocampus.The density of dendritic spines of hippocampal neurons was observed by Golgi staining, and the synaptic structure of hippocampal neurons, especially the vesicle density, was observed by transmission electron microscopy.SPSS 16.0 software was used for statistical analysis.Repetitive measurement ANOVA was used for the escape latency data of 7 days repeated learning training in water maze.One-way ANOVA was used for the comparison of other data among multiple groups, and Dunnett's t test was used for further pairwise comparison. Results:Morris water maze results showed that during 7 days of learning training, the time and group interaction for escape latency was not significant in the 4 groups of rats ( F=0.93, P>0.05), but the time main effect ( F=25.90, P<0.05) and group main effect ( F=13.20, P<0.05) were significant.Morris water maze test showed that from the 3rd to 7th day, the escape latencies in 2VO group were significantly longer than those in Con group and 2VO+ Met group(all P<0.05). The short-term memory of rats was detected after 1 day of rest.The results showed that the escape latency in 2VO group was significantly longer than that in Con group and 2VO + Met group( P<0.01). The retention time and crossing times in the platform area of 2VO rats were less than those in Con group and 2VO + Met group ( P<0.01). Electrophysiological results showed that the relative field excitatory postsynaptic potential slope of 2VO group (1.29±0.09) was significantly lower than that in Con group (2.07±0.09) and 2VO + Met group (1.69±0.08)( P<0.01). ELISA results showed that TNF-α level in hippocampal tissue of 2VO group was significantly higher than that in Con group and 2VO+ Met group; IL-1β and IL-6 levels in hippocampal tissue of 2VO group were significantly higher than those in Con group and 2VO + Met group.Density of dendritic spines in hippocampal neurons of 2VO group was significantly lower than that in Con group and 2VO+ Met group.The density and proportion of immature dendritic spines in hippocampal neurons of 2VO group were significantly higher than those in Con group and 2VO + Met group.Synaptic vesicle density of neurons in CA1 area of hippocampus in 2VO group ((230.29±19.44) vescicles/μm 2) was significantly lower than that in the Con group ((414.52±13.17) vescicles/μm 2) and 2VO+ Met group ((313.19±12.42) vescicles/μm 2). Conclusion:Metformin can reduce neuroinflammation of hippocampus with chronic cerebral hypoperfusion and improve synaptic plasticity and cognitive dysfunction.It may have potential application value in the treatment of vascular cognitive dysfunction.
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Septic shock is the most critical stage of sepsis, and the core of the treatment is improving tissue hypoperfusion.In addition to the improvement of large circulation by fluid resuscitation, the microcirculation also need to be improved, then proper vasoactive drugs should be applied to different types of shock to meet the needs of the body for perfusion.The condition of septic shock progresses rapidly, and the microcirculation in different pathophysiological stages is different, which increases the difficulty of rational use of vasoactive drugs.Monitoring and accurate evaluation of peripheral microcirculation may provide guidance for individualized treatment of septic shock.
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Cognitive impairment caused by chronic cerebral hypoperfusion (CCH) is associated with white matter injury (WMI), possibly through the alteration of autophagy. Here, the autophagy-lysosomal pathway (ALP) dysfunction in white matter (WM) and its relationship with cognitive impairment were investigated in rats subjected to two vessel occlusion (2VO). The results showed that cognitive impairment occurred by the 28th day after 2VO. Injury and autophagy activation of mature oligodendrocytes and neuronal axons sequentially occurred in WM by the 3rd day. By the 14th day, abnormal accumulation of autophagy substrate, lysosomal dysfunction, and the activation of mechanistic target of rapamycin (MTOR) pathway were observed in WM, paralleled with mature oligodendrocyte death. This indicates autophagy activation was followed by ALP dysfunction caused by autophagy inhibition or lysosomal dysfunction. To target the ALP dysfunction, enhanced autophagy by systemic rapamycin treatment or overexpression of Beclin1 (BECN1) in oligodendrocytes reduced mature oligodendrocyte death, and subsequently alleviated the WMI and cognitive impairment after CCH. These results reveal that early autophagy activation was followed by ALP dysfunction in WM after 2VO, which was associated with the aggravation of WMI and cognitive impairment. This study highlights that alleviating ALP dysfunction by enhancing oligodendrocyte autophagy has benefits for cognitive recovery after CCH.
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The glymphatic system plays a pivotal role in maintaining cerebral homeostasis. Chronic cerebral hypoperfusion, arising from small vessel disease or carotid stenosis, results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction. However, whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown. Here, we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis. We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glymphatic system function. The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization. Treatment of digoxin rescued changes in glymphatic transport, white matter structure, and cognitive function. Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury. Our research yields new insight into the relationship between hemodynamics, glymphatic transport, white matter injury, and cognitive changes after chronic cerebral hypoperfusion.
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Animals , Mice , Brain Ischemia , Carotid Stenosis/drug therapy , Cognitive Dysfunction/etiology , Digoxin , Disease Models, Animal , Mice, Inbred C57BL , White MatterABSTRACT
Objective:To explore the role and mechanism of kidney brain protein (KIBRA) down-regulation in cognitive dysfunction caused by chronic cerebral hypoperfusion.Methods:Ninety male SPF grade Sprague Dawley (SD) rats were divided into four groups according to random number table: sham operation group ( n=15), chronic hypoperfusion group (2VO group, n=25), chronic hypoperfusion stereotaxic injection of AAV-KIBRA group (2VO+ AAV-KIBRA group, n=25), chronic hypoperfusion stereotaxic injection of AAV-Vector group (2VO+ AAV-vector group, n=25). Chronic cerebral hypoperfusion model was established by bilateral ligation of common carotid artery, and stereotactic injection of 2 μL AAV-KIBRA or AAV-vector was performed for 30 days.Morris water maze, in vitro electrophysiology, p21-activated kinase 3(PAK3) activity detection, Western blot, immunoprecipitation and Golgi staining were used to detect spatial learning and memory ability, long-term potentiation(LTP), KIBRA level expression, PAK3 activity changes and the distribution of dendritic spines.SPSS 16.0 statistical software was used for statistical data.One-way ANOVA was used to compare the differences between groups.LSD test was used to compare the significance of data differences between the two groups.Welch test was used for uneven variance. Results:After 1 month of chronic cerebral hypoperfusion, the level of KIBRA in the hippocampus of rats was detected by homogenate and Western blot, and it was found that the level of KIBRA in 2VO group was lower than that of sham group(73.49±4.12)% ( P<0.01). AAV-KIBRA injection in hippocampal CA1 region significantly up-regulated the level of KIBRA to (91.91±7.01)% over 2VO group ( P<0.01). Morris water maze test showed that the latency of the 2VO group(3rd-7th day trail data: (48.18±2.82)s, (43.45±2.27)s, (32.27±2.22)s, (26.55±2.37)s, (17.18±2.67)s) were significantly longer than those of the sham group((41.67±2.74)s, (32.58±2.57)s, (22.50±2.94)s, (16.91±2.39)s, (8.75±1.52)s) (all P<0.05), and the latencies of the 2VO+ AAV-KIBRA group 3rd-7th day trail data: (43.83±2.95)s, (35.25±2.15)s, (26.58±2.03)s, (19.92±2.17)s, (17.75±1.35)s) was significantly shorter than that of the 2VO group ((all P<0.01). The Morris water maze test with the platform removed showed that the latency of rats in the 2VO group to reach the platform region was significantly longer than that of the sham group, while the latency of rats in the 2VO+ AAV-KIBRA group to reach the platform region was significantly shorter than that in the 2VO group ( P<0.01). At the same time, the retention time and the crossing times in the platform region of 2VO group were less than those of the sham group ( P<0.01), but the retention time and the crossing times in the platform region of 2VO+ AAV-KIBRA group were significantly higher than those in the 2VO group ( P<0.01). The electrophysiological records of the brain slices showed that the relative excitatory postsynaptic field potential of 2VO group (1.43±7.43) was significantly lower than that of sham group (2.21±6.54) after high frequency stimulation, while the relative excitatory postsynaptic field potential of 2VO+ AAV-KIBRA group (1.90±8.15) was higher than that of 2VO group ( P<0.01). Immunoprecipitation in rat hippocampus revealed that PAK3 could be detected by Western blot assay when KIBRA was precipitated.The results showed that the relative enzyme activity of PAK3 in 2VO hippocampal tissue (0.64±0.04) was significantly lower than that in sham group (1.02±0.07), while the relative enzyme activity of PAK3 in 2VO+ AAV-KIBRA group (0.86±0.03) was significantly higher than that in 2VO group.Golgi staining showed that the density of dendritic spines in 2VO hippocampal neurons((6.85±0.43)/10 μm) was significantly lower than that in sham group((11.83±0.58)/10 μm), while the density of dendritic spines in 2VO+ AAV-KIBRA group((10.22±0.39)/10 μm) was significantly higher than that in 2VO group. Conclusion:The down-regulated of KIBRA after chronic cerebral hypoperfusion plays a key role in cognitive dysfunction and is also involved in the decrease of synaptic functional plasticity.The downregulation of KIBRA is involved in the structural plasticity of dendrites through the regulation of PAK3 activity.Therefore, KIBRA may be an important target for the prevention and treatment of cognitive function of chronic cerebral hypoperfusion.
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ObjectiveBased on the protective effect of Dengzhan Shengmai capsules （DZSM） on chronic cerebral hypoperfusion （CCH）， network pharmacology was employed to investigate the molecular mechanism. MethodCCH model was established by right common carotid artery ligation. The mice were divided into sham operation group， model group， ginaton group （48 mg·kg-1）， DZSM low- and high-dose groups （0.040 5， 0.162 g·kg-1）. The efficacy was evaluated by the Morris water maze test and open-field test. The underlying mechanism of DZSM for CCH was analyzed by network pharmacology and verified by molecular biology experiments. PubChem， GeneCards， Metascape and other databases were used for targets collection and enrichment analysis. Besides， the association of ingredients targets of DZSM with disease targets of CCH， core target network and chemical components-core targets-pathways network were constructed by STRING 11.0 and Cytoscape 3.7.1. ResultThe escape latency of CCH mice significantly shortened on the 3rd to 5th day after DZSM low-dose treatment， the crossing times， time spent in the target quadrant， movement distance and distance in the central region of CCH mice significantly increased after DZSM low-dose and high-dose treatment. The results of network pharmacology indicated that DZSM might play a key role by regulating inflammatory response， phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt） signaling pathway， cytokine-cytokine receptor interaction， tumor necrosis factor （TNF） signaling pathway， blood circulation， angiogenesis， extracellular matrix and other related biological processes and pathways， and acting as targets such as interleukin-6 （IL-6）， TNF， insulin-like growth factor 1 （IGF1）， vascular endothelial growth factor A （VEGFA）， epidermal growth factor （EGF）. The results of biological experiments showed that DZSM could reduce the expression of IL-6 in brain tissue of CCH mice. ConclusionDZSM provides a protective effect during CCH， and its multi-component， multi-pathway， multi-target mechanism is also revealed， which provides a basis for further study of the mechanism.
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Objective:To observe the expression of noggin mRNA in the hippocampus of rats with chronic cerebral hypoperfusion, and explore the effect of electroacupuncture (EA) at the " baihui" and " dazhui" acupoints on their learning and memory and on hippocampal neurogenesis.Methods:In total, 120 Sprague-Dawley rats had cerebral hypoperfusion induced by permanent bilateral ligation of the common carotid artery. The 104 successfully induced were divided at random into a model group and an EA group, each of 52. The EA group was given EA on the baihui and dazhui acupoints for 20 minutes daily for seven days followed by a two-day break. The output current was 1mA at 15Hz. No special treatment was given to the model group. After one, two, four and six weeks of treatment, 6 rats were given BrdU injections to observe the proliferation and differentiation of neural stem cells. Learning and memory were assessed using the Morris Water Maze. The expression of noggin mRNA and neurogenesis in the dentate gyrus of the hippocampus were measured using reverse-transcription polymerase chain reactions and immunohistochemistry.Results:After one, two and five weeks of intervention, the average learning and memory ability of the EA group were significantly better than those of the control group. The average expression of noggin mRNA was significantly higher in the EA group than in the model group at the same time points. Compared with the model group, there were more BrdU-positive cells in the hippocampal dentate gyrus in the EA group, and the number decreased with the prolongation of ischemia. Pearson correlation analysis showed that the levels of noggin mRNA in the hippocampus of both groups were positively correlated with their number of BrdU-positive cells. The correlation was stronger in the EA group than in the model group.Conclusions:Electroacupuncture can promote hippocampal neurogenesis in rats with chronic cerebral hypoperfusion by regulating the expression of hippocampal noggin mRNA, thereby improving their spatial learning and memory ability.
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Objective:To investigate the effect of GluA2-3Y which is an inhibitor of AMPA(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptor internalization on cognitive function and hippocampal postsynaptic protein expression in rats with chronic cerebral hypoperfusion.Methods:Forty-eight adult male SD rats were randomly divided into Sham group, 2VO group, high-dose GluA2-3Y group and low-dose GluA2-3Y group according to random number table, with 12 rats in each group.The chronic cerebral hypoperfusion model of rat was established by two vessel occlusion (2VO) while the Sham operation was performed in rats of Sham group.The rats in high dose GluA2-3Y group and low dose GluA2-3Y group were intraperitoneal injected with 3 μmol/kg and 0.03 μmol/kg GluA2-3Y respectively once a day for 2 weeks. Rats in 2VO group and Sham group were intraperitoneally injected with control peptide. Morris water maze test and new object recognition test were performed to evaluate the learning and memory ability of rats, and Western blot was used to evaluate the expression of Akt1、GSK3β、p-GSK3β、GluA2 and PSD-95 in rat hippocampus. The expressions of GluA2 and PSD-95 in rat hippocampus were evaluated by immunofluorescence. SPSS 23.0 software was used for data analysis. The comparison between multiple groups was analyzed by one-way ANOVA and repeated measurement ANOVA was used to analyze Morris water maze results. And independent-samples t-test was used for pairwise comparisons. Results:(1)In Morris water maze trials, the results of repeated measurement ANOVA showed that the interaction between group and time of escape latency of rats in each group was not significant ( F=0.79, P>0.05), and the group main effect and time main effect were significant ( F=24.44, 40.42, both P<0.05). On the 5th day of navigation trials, the escape latency of rats in 2VO group was longer than that in sham group ( t=5.87, P<0.05). The escape latency of rats in low dose GluA2-3Y group and high dose GluA2-3Y group were significantly shorter than that in 2VO group ( t=2.20, 3.41, both P<0.05), but there was no significant difference between low dose GluA2-3Y group and high dose GluA2-3Y group ( t=1.37, P>0.05). The target quadrant residence time and resolution coefficient ((14.57±1.40)s, (0.15±0.10)) in 2VO group were significantly lower than those in Sham group ((23.71±2.57)s, (0.40±0.06)) ( t=3.23, 2.24, both P<0.05), while the target quadrant residence time in high dose GluA2-3Y group ((20.19±1.53)s) and low dose GluA2-3Y group ((20.31±2.06)s) were longer than that in 2VO group( t=2.71, 2.35, both P<0.05). The discrimination coefficients in high dose GluA2-3Y group (0.47±0.10) and low dose GluA2-3Y group (0.59±0.06) were higher than that of 2VO group ( t=2.21, 3.94, both P<0.05). (2)The Western blot results showed that the expression of PSD-95 and GluA2 in hippocampus of rats in 2VO group were significantly lower than those in Sham group ( t=2.31, 2.20, both P<0.05), and the expression of PSD-95 in high dose GluA2-3Y group (1.026±0.056) was significantly higher than that in 2VO group ((0.760±0.061), t=2.49, P<0.05), while there was no significant difference between low-dose GluA2-3Y group and 2VO group( t=0.96, P>0.05). The expression of GluA2 in low-dose GluA2-3Y group was higher than that in 2VO Group ((1.130±0.087), (0.766±0.080), t=2.37, P<0.05), but there was no significant difference between high-dose GluA2-3Y group and 2VO group( t=1.06, P>0.05). (3) Immunofluorescence showed that compared with Sham group, the expression of PSD-95 and GluA2 in 2VO group decreased ( t=4.23, 2.57, P<0.05). Compared with 2VO group, the expression of PSD-95 and GluA2 in high dose GluA2-3Y group and low dose GluA2-3Y group increased significantly, and the differences were statistically significant (PSD-95: (7.757±0.578), (12.057±0.578), t=3.14, 6.96, both P<0.05; (9.721±0.950), (16.610±0.950), t=4.56, 9.34, both P<0.05). (4) The results of Western blot showed that the expression GSK3β in hippocampus of rats in each group were not statistically different( F=2.03, P>0.05). There were significant differences in the expression of Akt1, p-GSK3β and the percentage of p-GSK3β/GSK3β in hippocampus of rats in each group ( F=8.30, 4.76, 3.57, all P<0.05). Compared with Sham group, the levels of Akt1, p-GSK3β and the percentage of p-GSK3β/GSK3β in 2VO group were significantly lower ( t=3.00, 2.81, 3.17, all P<0.05). Compared with 2VO group, the levels of Akt1, p-GSK3β and p-GSK3β/GSK3β percentage in low dose GluA2-3Y group and high-dose GluA2-3Y group were significantly higher (Akt1: t=2.05, 5.20, both P<0.05; p-GSK3β: t=2.49, 4.15, both P<0.05; p-GSK3β/GSK3β percentage: t=2.30, 2.97, both P<0.05). Conclusion:GluA2-3Y, an AMPA receptor internalization inhibitor, can alleviate the cognitive impairment in rats with chronic cerebral hypoperfusion, which may be related to the increased expression of Akt1, p-GSK3β and postsynaptic proteins.
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Objective:To investigate the protective effect of Naoxin'an capsule （NC） against glial cell activation and inflammatory damage in brain of rats with chronic cerebral hypoperfusion-induced vascular cognitive impairment （VCI）. Method:One hundred and fifty rats were randomly divided into a sham operation group （<italic>n</italic>=20） and a modeling group （<italic>n</italic>=130）. Following the modeling with the two vessels occlusion （2-VO） technique， 87 successfully modeled rats were randomly divided into the model group， positive drug group （aricept， 0.5 mg·kg<sup>-1</sup>）， and low-， medium-， and high-dose （0.18， 0.36， 0.72 g·kg<sup>-1</sup>） NC groups， with 17-18 rats in each group. After intragastric administration of NC for eight weeks， the Morris water maze test and passive avoidance test were conducted to detect the effects of NC on learning and memory ability of VCI rats. Changes in neuronal structure of rat hippocampal CA1 area were observed by hematoxylin-eosin （HE） staining， and the neuronal apoptosis in hippocampus by terminal deoxynucleotidyl transferase （TdT）-mediated dUTP nick end labeling （TUNEL） staining. Western blot assay was used to detect the expression levels of glial fibrillary acidic protein （GFAP）， ionized calcium-binding adapter molecule 1 （Iba-1）， phosphorylated p38 mitogen-activated protein kinase （p38 MAPK）， and phosphorylated nuclear factor <italic>κ</italic>B （NF-<italic>κ</italic>B）， followed by the measurement of interleukin-1<italic>β</italic> （IL-1<italic>β</italic>） and tumor necrosis factor-<italic>α</italic> （TNF-<italic>α</italic>） in the brain by enzyme-linked immunosorbent assay （ELISA）. Result:Compared with the sham operation group， the model group displayed obviously decreased spatial learning and memory ability and memory retention ability （<italic>P</italic><0.05， <italic>P</italic><0.01）， neuronal damage in hippocampal CA1 area， enhanced neuronal apoptosis （<italic>P</italic><0.01）， up-regulated GFAP and Iba-1 （<italic>P</italic><0.01）， elevated phosphorylation of p38 MAPK and NF-<italic>κ</italic>B （<italic>P</italic><0.01）， and increased IL-1<italic>β</italic> and TNF-<italic>α</italic> （<italic>P</italic><0.01）. Compared with the model group， NC at each dose significantly improved the spatial learning and memory ability and memory retention ability of VCI rats （<italic>P</italic><0.05， <italic>P</italic><0.01）， ameliorated the neuronal damage in hippocampus CA1 area， reduced the apoptosis rate of nerve cells （<italic>P</italic><0.05， <italic>P</italic><0.01）， down-regulated the expression of GFAP and Iba-1 （<italic>P</italic><0.01）， decreased the phosphorylation levels of p38 MAPK and NF-<italic>κ</italic>B （<italic>P</italic><0.05， <italic>P</italic><0.01）， and lowered TNF-<italic>α</italic> and IL-1<italic>β</italic> levels （<italic>P</italic><0.01）. Conclusion:NC alleviates the inflammatory damage of the central nervous system caused by activated p38 MAPK and NF-<italic>κ</italic>B and improves chronic cerebral hypoperfusion-induced VCI in rats by inhibiting the activation of microglia and astrocytes.
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Ginkgo biloba and Panax notoginseng are both herb medicines for cerebrovascular disease, and play an active role in treating ischemic cerebrovascular disease(ICVD). Their mechanisms of action include antioxidant stress, nerve protection, vascular protection. According to the comparative study of literatures, G. biloba has a certain protective effect from the early stage of free radical formation throughout the whole process of causing cell inflammation and apoptosis in antioxidant stress; while P. notoginseng has mainly anti-inflammatory, anti-apoptosis effects. In the nerve protection and repair of nerve damage caused by glutamate, both could promote neurogenesis, repair damaged axons and protect nerve cells. In addition, G. biloba could also relieve neurotoxicity caused by glutamate damage, while P. notoginseng have a unique effect in repairing blood-brain barrier(BBB) and blood vessel regeneration. In clinic, they are used as auxiliary drugs in combination with thrombolytic therapy, and play curative effects in alleviating inflammation, eliminating edema, improving the cure rate and the prognosis. For cerebral diseases caused by chronic cerebral hypoperfusion, G. biloba could reduce inflammation and improve cognition. In addition, G. biloba could protect neurocyte by adjusting the secretion of dopamine in vivo, and has a certain effect on antidepressant diseases, which however needs further studies.
Subject(s)
Humans , Brain Ischemia , Drug Therapy , Ginkgo biloba , Panax notoginseng , Phytotherapy , Plant Extracts , Therapeutic Uses , Plants, MedicinalABSTRACT
BACKGROUND: Chronic cerebral hypoperfusion is significantly associated with cognitive decline. Our previous studies have found that mitochondrial aging, increased silent synapses and α-synuclein are important pathological changes of chronic cerebral hypoperfusion. Simvastatin is a traditional lipid regulation agent that can traverse the blood brain barrier, and exerts anti-atherosclerosis, anti-thrombosis and anti-inflammatory effects to improve cognitive function. OBJECTIVE: To observe the effect of continuous oral simvastatin for 3 months on cognitive function of chronic cerebral hypoperfusion male Sprague-Dawley rats, and explore the clinical significance of simvastatin in preventing and treating vascular cognitive impairment and dementia. METHODS: Sprague-Dawley rats were randomly divided into model group, sham group, solvent group and simvastatin group. In the model group, rats were subjected to bilateral common carotid artery occlusion. In the sham group, the bilateral common carotid arteries were not ligated. In the solvent group, the model rats were intragastrically treated with 0.5% carboxymethyl cellulose sodium. In the simvastatin group, the model rats were intragastrically treated with simvastatin suspension. Interventions in each group lasted for 3 months. Behavioral tests were then used to evaluate the learning and memory ability of rats in each group. The expressions of synaptophysin and post-synaptic density 95, key proteins of presynaptic and postsynaptic membrane, were detected by western blot. Ethical approval was obtained from the Animal Experimental Ethics Committee of the General Hospital of Western Theater Command with approval No. 2019ky79. RESULTS AND CONCLUSION: Compared with the sham group, the learning and memory functions of the rats in the model group were significantly impaired. In the open-field test, the moving distance within 5 minutes was significantly reduced in the model group compared with the sham group (P < 0.05), suggesting that autonomous exploration behavior was impaired. In the place navigation test, escape latency was significantly shortened in the model group, implicating the reference memory was damaged. In the spatial probe test, the frequency of passing through the platform and the time for passing through target quadrant were reduced, indicating that the space exploration ability was reduced. In the simvastatin group, however, these indexes were all improved. Western blot results showed that the protein expression of synaptophysin and post-synaptic density 95 decreased significantly in the model group (P < 0.05), but increased in the simvastatin group as compared with the solvent group. Therefore, chronic cerebral hypoperfusion can significantly impair learning and memory function and reduce cognitive level in rats. Continuous oral simvastatin for 3 months can improve cognitive function in chronic cerebral hypoperfusion rats, which indicates that simvastatin may be used as an adjunctive drug to improve the prognosis of patients with vascular cognitive impairment and dementia.
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BACKGROUND: Previous studies have found that chronic cerebral hypoperfusion can cause changes in the intestinal mucosal barrier in rats, and Occludin and Claudin are important components of the intestinal mucosal barrier.OBJECTIVE: To explore the effect of chronic cerebral hypoperfusion on the ileum mucosal barrier. METHODS: Twenty male Sprague-Dawley rats were randomly divided into sham operation (sham) group and chronic cerebral hypoperfusion model group. Animal model of chronic cerebral hypoperfusion was built by permanent bilateral common carotid artery ligation. The bilateral common carotid arteries of the sham group were isolated without ligation. The animals were killed at 4 weeks after operation, and their ileums were isolated for morphological observation and pathological scoring using hematoxylin-eosin staining. Apoptosis in the ileum cells was detected using TUNEL. Western blot was used to detect the expression of Claudin-2 and Occludin. immunohistochemical staining was used to detect the expression of Occludin. The study protocol was approved by the Animal Experiment Ethics Committee of General Hospital of Western Theater Command. RESULTS AND CONCLUSION: Compared with the sham group, hematoxylin-eosin staining showed that the ileum in the model group did not develop obvious injury with no higher pathological scores (P > 0.05). Western blot results indicated that compared with the sham group, the expression of claudin-2 was increased in the ileum tissue of the rats with chronic cerebral hypoperfusion, while the expression of Occludin was decreased (P < 0.05). TUNEL fluorescence staining showed that the apoptotic rate in the model group was significantly increased compared with the sham group (P < 0.05). Immunohistochemical results showed that the expression of Occludin in the ileum tissue of the chronic cerebral hypoperfusion group was significantly reduced (P < 0.05). These findings indicate that chronic cerebral hypoperfusion may damage the intestinal mucosal barrier by downregulating Occludin expression and upregulating Claudin-2 expression.
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@#Introduction: Preclinical studies have reported that Murraya koenigii leaves (MKL) could enhance memory. MKL is also known for its antioxidant activity. The current study was to assess the possible neuroprotective potential of MKL methanolic extract in a two vessel occlusion (2VO) rat model of partial global cerebral ischaemia. Methods: Rats were divided into memory and learning groups. Each group was subdivided into sham control, untreated 2VO and MKL-treated 2VO subgroups. The Morris water maze test was implemented to assess the rats’ cognitive function postoperatively. Brain samples were histopathologically examined for viable neurons within the CA1 hippocampal region. Results: Water maze test findings showed that MKL positively improved memory and learning impairments. However, this improvement in memory test for the treated group was still significantly inferior to that of the healthy control group. Additionally, MKL treated group exhibited insignificant difference in the number of viable hippocampal CA1 pyramidal neurons from that of the untreated 2VO group, whereas both MKL treated and untreated 2VO groups showed significantly less viable neurons when compared with the control group. Conclusion: MKL extract modestly improved memory without providing substantial neuroprotective action to the hippocampal neurons in rats with chronic partial global cerebral ischaemia.
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PURPOSE: Colon perfusion status is one of the most important factors for the determination of postoperative anastomotic complications. Colonic hypoperfusion can be induced by inferior mesenteric artery (IMA) ligation in some patients. This study aimed to evaluate atherosclerotic risk assessment and vascular parameters of CT angiography as predictors of colonic hypoperfusion. METHODS: This prospective study was conducted at a tertiary referral hospital and included 46 rectosigmoid colon cancer patients undergoing laparoscopic anterior resection between August 2013 to July 2014. Atherosclerotic risk scores were assessed using the Framingham cardiovascular risk score system. The IMA length, branching pattern, atherosclerotic calcification, and intermesenteric artery and mesenteric vascular diameters were evaluated using CT angiography. Mesenteric marginal artery pressures were measured before and after IMA clamping. The mean arterial pressure (MAP) index was calculated by dividing the mesenteric marginal MAP into the systemic MAP to determine the mesenteric hypoperfusion status after IMA clamping. A critically low MAP index was defined as <0.4. RESULTS: Critically low MAP index (<0.4) was observed in 6 cases (13.0%) after IMA clamping. Atherosclerotic calcification of the IMA and superior mesenteric artery occurred in 11 (23.9%) and 5 patients (10.9%), respectively. Low MAP index was associated with high atherosclerotic risk score and short IMA length, rather than atherosclerotic calcification and other vascular parameters of the major mesenteric arteries. Multivariate analysis indicated that high atherosclerotic risk and short IMA length were independent predictors of critically low MAP index. CONCLUSION: Atherosclerotic risk assessment and IMA length were useful predictors of the mesenteric hypoperfusion status following IMA ligation during laparoscopic rectosigmoid colon surgery.
Subject(s)
Humans , Angiography , Arterial Pressure , Arteries , Atherosclerosis , Colon , Colonic Neoplasms , Constriction , Ligation , Mesenteric Arteries , Mesenteric Artery, Inferior , Mesenteric Artery, Superior , Multivariate Analysis , Perfusion , Prospective Studies , Risk Assessment , Tertiary Care CentersABSTRACT
Objective To investigate serum p75 neurotrophin receptor-extracellular domain (p75NTR-ECD) level in patients with chronic cerebral hypoperfusion-vascular cognitive impairment (CCH-VCI) and its relationship with tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6. Methods The clinical data of patients with CCH-VCI (n＝34) were collected from Changhai Hospital, Naval Medical University (Second Military Medical University) from Aug. to Dec. 2018. Enzyme linked immunosorbent assay was applied for detection of serum levels of p75NTR-ECD, TNF-α, IL-1β and IL-6; and the results were then compared with those of ischemic stroke participants (n＝34) and healthy controls (n＝36), who were all in the same age range. Spearman correlation analysis was used to analyze the relationship between serum p75NTR-ECD level and the above-mentioned inflammatory factors in CCH-VCI patients. Results The serum p75NTR-ECD level in the CCH-VCI group was significantly higher than those in the healthy control group and the ischemic stroke group (544.36 [440.88, 628.50] pg/mL vs 276.49 [262.59, 313.87] pg/mL and 366.87 [337.09, 450.43] pg/mL, U＝87.500 and 335.500, both P0.05). The serum levels of TNF-α, IL-1β and IL-6 were 196.02 (141.20, 280.35) pg/mL, 68.23 (60.79, 91.94) pg/mL and 51.04 (40.24, 65.26) pg/mL in the CCH-VCI group, respectively, and 218.67 (143.76, 281.28) pg/mL, 76.87 (59.10, 99.91) pg/mL and 64.45 (43.13, 86.76) pg/mL in the ischemic stroke group, respectively, which were all significantly higher than those in the healthy control group (73.71 [56.94, 79.81] pg/mL, 42.98 [34.52, 51.34] pg/mL and 14.97 [11.76, 21.19] pg/mL, respectively; U＝ 31.000 and 4.000, 106.000 and 132.000, and 48.000 and 13.000; all P0.05). Serum p75NTR-ECD level in the CCH-VCI patients was correlated with TNF-α level (r＝0.391, P＝0.022), but not with IL-1β or IL-6 levels (r＝0.032 and 0.164, P＝ 0.855 and 0.355). Conclusion Serum p75NTR level may be related to inflammatory factors (TNF-α) after chronic cerebral hypoperfusion, and they may jointly participate in the pathogenesis of CCH-VCI.
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Context: Hyperglycemia has been found to occur during myocardial infarction and cardiac surgery even in nondiabetic patients. These being essentially stressful processes associated with hypoperfusion, we decided to find a possible relationship between the occurrence of global tissue hypoperfusion (GTH) and elevated blood glucose level in adult nondiabetic patients undergoing elective off-pump coronary artery bypass grafting (CABG). Aims: This study aims to observe for the occurrence of global tissue hypoperfusion and its effect on blood glucose level and whether raised blood glucose level can be used as a marker for GTH. Design: Prospective, observational study. Settings: Cardiothoracic operation theater and intensive care unit of a tertiary care teaching hospital. Materials and Methods: The occurrence of global tissue hypoperfusion were detected with the help of combined markers of mixed venous oxygen saturation and arterial lactate level at various perioperative study points together with arterial blood glucose level. Blood glucose level compared between the patients with and without GTH. Statistical Analysis Used: Numerical variables were compared between groups by Student's t-test and categorical variables by Fisher's exact test. Two-tailed P ≤ 0.05 was considered for statistically significant. Results: The incidence of GTH was 67%. Blood glucose level was raised in patients with GTH at some study time points but with poor sensitivity and specificity values. Conclusions: Global tissue hypoperfusion is a common occurrence in even nondiabetic patients undergoing elective off-pump CABG. A relationship exists between rise in blood glucose level and global tissue hypoperfusion in such patients, although it cannot be viewed as marker of the same.
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In dogs with congestive heart failure, the upregulated sympathetic tone causes vasoconstriction that impairs peripheral blood supply, therefore causing the accumulation of lactate. In this prospective cross-sectional study with a longitudinal component, blood lactate was quantified in 10 healthy and 34 myxomatous mitral valve disease (MMVD) dogs to investigate its potential use as a diagnostic and prognostic biomarker. While there were no differences in lactate concentration between control animals and stages B1 (3.31±0.62mmol/L) and B2 (3.32±0.46mmol/L) dogs, significant differences were found between healthy (2.50±0.69mmol/L) and both C (3.99±0.47mmol/L) and D (6.97±1.23mmol/L) animals. When a cut-off of 3.35mmol/L was used, lactate was able to distinguish dogs with normal and remodeled hearts with a sensitivity of 78.2% and specificity of 63.6%. Also, significant correlations existed between lactate and indicators of cardiac remodeling. Finally, animals with blood lactate <3.5mmol/L carried a better prognosis when compared with dogs in which lactate was >5.0mmol/L. Our results suggest that the progression of MMVD results in accumulation of lactate within the bloodstream, which is likely attributable to the impaired peripheral tissue perfusion. In MMVD dogs, blood lactate may be used as a surrogate for cardiac remodeling, and an increased concentration is associated with a worse prognosis regarding the time to evolve into congestive heart failure.(AU)
Em cães com insuficiência cardíaca congestiva, o tônus simpático hiperregulado causa vasoconstrição e interfere com o suprimento sanguíneo periférico, resultando no acúmulo de lactato. Neste estudo prospectivo transversal com um componente longitudinal, o lactato sanguíneo foi quantificado em 10 cães saudáveis e 34 cães com doença mixomatosa da valva mitral (DMVM) para investigar seu potencial como biomarcador diagnóstico e prognóstico. Embora não tenham sido identificadas diferenças na concentração de lactato entre animais controle e cães com DMVM nos estágios B1 (3,31±0,62mmol/L) e B2 (3,32±0,46mmol/L), diferenças significativas foram constatadas entre os cães saudáveis (2,50±0,69mmol/L) e cães com DMVM estágio C (3,99±0,47mmol/L) ou D (6,97±1,23mmol/L). Quando utilizado o valor de corte de 3,35mmol/L, o lactato foi capaz de diferenciar cães com corações normais daqueles com corações remodelados com sensibilidade de 78,2% e especificidade de 63,6%. Além disso, correlações significativas foram encontradas entre o lactato e os indicadores de remodelamento cardíaco. Por fim, os animais com lactato sanguíneo <3,5mmol/L tiveram prognóstico melhor comparativamente aos cães com concentrações >5,0mmol/L. Nossos resultados sugerem que a progressão da DMVM resulta no acúmulo de lactato na corrente sanguínea, fato que é provavelmente atribuído à perfusão periférica prejudicada. Em cães com DMVM, o lactato sanguíneo pode ser utilizado como indicador de remodelamento cardíaco, cuja concentração elevada está associada com pior prognóstico relativo ao tempo para evoluir para insuficiência cardíaca congestiva.(AU)
Subject(s)
Animals , Dogs , Lactic Acid/administration & dosage , Dogs/blood , Hyperlactatemia/veterinary , Mitral ValveABSTRACT
BACKGROUND: Cardiopulmonary bypass (CPB) can cause systemic hypoperfusion, which remains undetected by routine monitoring of physiological parameters. Noninvasive tissue perfusion monitoring offers a clinical benefit by detecting low systemic perfusion. In this study, we tried to evaluate whether regional tissue perfusion saturation reflects systemic hypoperfusion during CPB. METHODS: This retrospective study included 29 patients with American Society of Anesthesiologists physical status II–III, who required cardiac surgery with CPB. We evaluated the correlations of serum lactate and delivery oxygen with organ perfusion values of peripheral tissue oxygen saturation and cerebral oxygen saturation. Data were recorded at different stages of CPB: T1 (pre-CPB), T2 (cooling), T3 (hypothermia), T4 (rewarming), and T5 (post-CPB). RESULTS: Lactate levels were elevated after CPB and up to weaning (P < 0.05). The levels of peripheral and tissue oxygen saturation decreased after the start of CPB (P < 0.05). Lactate levels were negatively correlated with peripheral tissue oxygen saturation levels at T4 (R = −0.384) and T5 (R = −0.370) and positively correlated with cerebral oxygen saturation at T3 (R = 0.445). Additionally, delivery oxygen was positively correlated with peripheral tissue oxygen saturation at T4 (R = 0.466). CONCLUSIONS: In this study, we demonstrated that peripheral tissue oxygen saturation can be a reliable tool for monitoring systemic hypoperfusion during CPB period. We also believe that peripheral tissue oxygen saturation is a valuable marker for detecting early stages of hypoperfusion during cardiac surgery.