Abstract 16: Spatiotemporally-Controlled Ultrasound-Triggered Release of Nitric Oxide Using Nano Au-Polymersomes/S-Nitrosoglutathione Mitigates Post-Resuscitation Cerebral Vasoconstriction and Neuronal Apoptosis via Reciprocating Akt-eNOS-NO Signaling

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Wei-Tien Chang ◽  
Woan-Yi Wang ◽  
Min-Hsuan Hsu ◽  
Po-Tsung Kao ◽  
Chih-Hung Wang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Neuronal Apoptosis ◽  
Caspase 3 ◽  
Brain Perfusion ◽  
Tissue Perfusion ◽  
Triggered Release ◽  
Cerebral Vasoconstriction ◽  
No Release ◽  
No Signaling ◽  
The Brain

Introduction: Cerebral vasoconstriction in the post-resuscitation phase worsens neurological outcome. Nitric oxide (NO) plays important roles mediating vasodilatation and anti-apoptotic protection. We therefore designed an Au-polymersomes/S-nitrosoglutathione (Au-PLGA/GSNO) nanoparticle that can be triggered by ultrasound (US) to release NO, and investigated its roles in mitigating cerebral vasoconstriction and neuronal apoptosis post-CPR. Hypothesis: Spatiotemporally controlled, US-triggered NO release by Au-PLGA/GSNO improves post-CPR cerebral perfusion and confers anti-apoptotic neuroprotection. Methods: Using an established rat model of asphyxia cardiac arrest and CPR, Au-PLGA/GSNO (7500 PPM, 0.4 ml) was infused with simultaneous US (1 MHz) stimulation at the brain 10 min after ROSC. Brain tissue perfusion was continuously recorded by OxyFLO probe and cerebral vasculature videoed by CytoCam. The blood was sampled 2 h post-CPR for measurement of nitrate/nitrite, and the brain harvested for measurement of casepase-3, endothelial NO synthase (eNOS) and protein kinase B (Akt). In a subgroup the brain was harvested at 24 h for TUNEL stain. Results: After CPR, marked cerebral vasoconstriction was noted on CytoCam while brain perfusion significantly reduced to ~0.5 folds that of baseline. After Au-PLGA/GSNO infusion and US stimulation, cerebral vasoconstriction was ameliorated and the brain perfusion significantly enhanced ( P < 0.05 vs. CPR control). The plasma NO indicated by nitrate/nitrite 2 h post-CPR was significantly increased ( P < 0.01) while cleaved caspase-3/caspase-3 of the brain markedly reduced ( P < 0.001). TUNEL stain of the hippocampus CA1 and CA3 regions were also remarkably abrogated, suggesting anti-apoptotic neuroprotection. Specifically, the phosphorylated (p)-eNOS/eNOS and p-Akt/Akt were also increased ( P < 0.01 and 0.001, respectively), indicating reciprocating activation of Akt-eNOS signaling upstream of NO. Conclusion: Spatiotemporally controlled US-triggered NO release by Au-PLGA/GSNO mitigates cerebral vasoconstriction, improves brain perfusion and confers anti-apoptotic neuroprotection post-CPR via reciprocating Akt-eNOS-NO signaling.

Abstract 103: Propofol Infusion in the Early Post-Cardiac Arrest Phase Improves Cerebral Perfusion and Confers Anti-Apoptotic Neuroprotection via Akt-eNOS-NO Signaling

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Wei-Tien Chang ◽  
Min-Hsuan Hsu ◽  
Woan-Yi Wang ◽  
Chunpei Lee ◽  
Chih-Hung Wang ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Cerebral Perfusion ◽  
Neuronal Apoptosis ◽  
Caspase 3 ◽  
Neuroprotective Effect ◽  
Temperature Management ◽  
Target Temperature Management ◽  
Arterial Blood ◽  
No Signaling ◽  
The Brain

Introduction: Neurological outcome after cardiac arrest (CA) and CPR is usually unsatisfactory even in this era of target temperature management (TTM). Propofol is not only a useful sedative drug for TTM but confers neuroprotective effect. We previously showed that propofol combined with TTM improves survival in patients resuscitated from CA. In this study we aimed to explore the underlying mechanism focusing on cerebrovascular circulation and anti-apoptosis signaling. Hypothesis: Infusion of propofol in the early post-CA phase improves cerebral perfusion and mitigates neuronal apoptosis via Akt-eNOS signaling. Methods: Using an established rat model of asphyxia cardiac arrest and CPR, propofol infusion (20 mg/kg/h) was instituted after return of spontaneous circulation (ROSC) and continued in the first 2 h. Hemodynamics were monitored and the cerebral perfusion was continuously recorded by OxyFLO probe. The arterial blood was regularly sampled for measurement of reactive oxygen species (ROS, chemiluminescence method) and NO (demonstrated by nitrate/nitrite). Two hours after ROSC, the brain was harvested for measurement of casepase-3, endothelial NO synthase (eNOS) and protein kinase B (Akt). Results: After CA and CPR, the cerebral perfusion was significantly reduced to ~0.5 folds that of baseline. With the infusion of propofol, the cerebral perfusion was significantly increased from the beginning after ROSC ( P < 0.01 vs. CPR control). The plasma NO indicated by nitrate/nitrite 2 h post-CPR was significantly increased ( P < 0.01) while ROS abrogated ( P < 0.05). The cleaved caspase-3/caspase-3 of the brain was markedly reduced ( P < 0.001), suggesting anti-apoptotic neuroprotection. When exploring the mechanism, the phosphorylated (p)-eNOS/eNOS and p-Akt/Akt were significantly increased (both P < 0.001), indicating activation of Akt-eNOS-NO signaling. Conclusions: Infusion of propofol in the early post-CA phase reduces oxidative stress, improves cerebral perfusion, and ameliorates neuronal apoptosis. The protection is, at least in part, mediated via activation of Akt-eNOS-NO signaling.

scholarly journals Hydropersulfides (RSSH) and Nitric Oxide (NO) Signaling: Possible Effects on S-Nitrosothiols (RS-NO)

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 169
Author(s):  
Jon M. Fukuto ◽  
Cristina Perez-Ternero ◽  
Jessica Zarenkiewicz ◽  
Joseph Lin ◽  
Adrian J. Hobbs ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Steady State ◽  
Protein Function ◽  
Physiological Mechanisms ◽  
No Formation ◽  
No Release ◽  
No Signaling ◽  
Thiol Protein ◽  
Proteins And Peptides

S-Nitrosothiol (RS-NO) formation in proteins and peptides have been implicated as factors in the etiology of many diseases and as possible regulators of thiol protein function. They have also been proposed as possible storage forms of nitric oxide (NO). However, despite their proposed functions/roles, there appears to be little consensus regarding the physiological mechanisms of RS-NO formation and degradation. Hydropersulfides (RSSH) have recently been discovered as endogenously generated species with unique reactivity. One important reaction of RSSH is with RS-NO, which leads to the degradation of RS-NO as well as the release of NO. Thus, it can be speculated that RSSH can be a factor in the regulation of steady-state RS-NO levels, and therefore may be important in RS-NO (patho)physiology. Moreover, RSSH-mediated NO release from RS-NO may be a possible mechanism allowing RS-NO to serve as a storage form of NO.

scholarly journals Desoxyrhapontigenin attenuates neuronal apoptosis in an isoflurane-induced neuronal injury model by modulating the TLR-4/cyclin B1/Sirt-1 pathway

AMB Express ◽  
2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Feng Liang ◽  
Xin Fu ◽  
Yunpengfei Li ◽  
Fanglei Han
Keyword(s):  
Oxidative Stress ◽  
Cognitive Function ◽  
Protein Expression ◽  
Protective Effect ◽  
Neuronal Apoptosis ◽  
Caspase 3 ◽  
Neuronal Injury ◽  
Cyclin B1 ◽  
The Brain ◽  
And Oxidative Stress

Abstract This study investigated the protective effect of desoxyrhapontigenin (DOP) against isoflurane (ISF)-induced neuronal injury in rats. Neuronal injury was induced in pups by exposing them to 0.75% ISF on postnatal day 7 with 30% oxygen for 6 h. The pups were treated with DOP 10 mg/kg, i.p., for 21 days after ISF exposure. The protective effect of DOP was estimated by assessing cognitive function using the neurological score and the Morris water maze. Neuronal apoptosis was assessed in the hippocampus using the TUNEL assay, and protein expression of caspase-3, Bax, and Bcl-2 was measured by Western blotting. The levels of cytokines and oxidative stress parameters were assessed by ELISA. Western blotting and RT-PCR were performed to measure the expression of NF-kB, TLR-4, Sirt-1, and cyclin B1 protein in the brain. The cognitive function and neurological function scores were improved in the DOP group compared with the ISF group. Moreover, DOP treatment reduced the number of TUNEL-positive cells and the expression of caspase-3, Bax, and Bcl-2 protein in the brains of rats with neuronal injury. The levels of mediators of inflammation and oxidative stress were reduced in the brain tissue of the DOP group. Treatment with DOP attenuated the protein expression of TLR-4, NF-kB, cyclin B1, and Sirt-1 in the brain tissue of rats with neuronal injury. In conclusion, DOP ameliorates neuronal apoptosis and improves cognitive function in rats with ISF-induced neuronal injury. Moreover, DOP treatment can prevent neuronal injury by regulating the TLR-4/cyclin B1/Sirt-1 pathway.

scholarly journals Influence of miR-1 on Nerve Cell Apoptosis in Rats with Cerebral Stroke via Regulating ERK Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Yuanding Jiang ◽  
Tao Wang ◽  
Jian He ◽  
Quan Liao ◽  
Jingjing Wang
Keyword(s):  
Infarct Size ◽  
Neuronal Apoptosis ◽  
Caspase 3 ◽  
Sham Group ◽  
Cerebral Infarct ◽  
Erk Signaling ◽  
Model Group ◽  
Protein Levels ◽  
The Brain ◽  
Brain Tissues

To explore the effect of miR-1 on neuronal apoptosis in rats with stroke through the ERK signaling pathway. Methods. Forty male rats (180-220 g) were selected and randomly divided into the sham, model, miR-1 inhibitor, and miR-1 mimic groups (10 rats per group) by average body weight. Cerebral ischemia/reperfusion (I/R) models were established using a modified middle cerebral artery wire thrombosis (MCAO) method in rats in the model group, miR-1 inhibitor group, and miR-1 mimic group. After the successful model establishment, the miR-1inhibitor group and miR-1 mimic group were intravenously injected with miR-1 inhibitor and miR-1 mimic, respectively, once a day for 3 days. The sham and model groups were given the same dose of normal saline. TTC staining was applied to detect the cerebral infarct size and calculate the infarct volume. Histopathological changes in the hippocampus of rat brains were observed by HE staining. Flow cytometry was used to detect neuronal apoptosis in rat brains. The mRNA expressions of miR-1, ERK1/2, Bcl-2, and Bax in rat brain tissues were determined by QRT PCR, and the protein levels of ERK1/2, Bcl-2, Bax, and caspase-3 were determined by Western blot analysis. Results. Compared with the sham group, the neurological impairment score, cerebral infarct size, and volume of rats in the model group were significantly increased ( p < 0.05 ). Compared with the model group, the neurological impairment score, cerebral infarct size, and volume were significantly increased in the miR-1 mimic group and significantly decreased in the miR-1 inhibitor group ( p < 0.05 ). In the model group, the hippocampal tissue of rats had malaligned cells, neuron cell atrophy became smaller, the intercellular spaces became larger, and vacuoles appeared. Compared with the model group, the miR-1 inhibitor group could effectively alleviate the pathological changes in the hippocampus, and the miR-1 mimic group could significantly add to the pathological changes in the rat hippocampus. Compared with the sham group, the mRNA expression of miR-1 and Bax in the brain of model rats increased significantly ( p < 0.05 ), and the mRNA expression of ERK1/2 decreased significantly; Compared with the model group, the miR-1 and Bax mRNA expressions in the brain tissues of rats in the miR-1 inhibitor group were significantly decreased, the ERK1/2 and bcl-2 mRNA expressions were significantly increased, and the miR-1 and Bax mRNA expressions in the brain tissues of rats in the miR-1 inhibitor group were significantly decreased, and the Bcl-2 mRNA expression was significantly increased ( p < 0.05 ). Compared with the sham group, neuronal apoptosis was increased in the brain tissues of rats in the model group and miR-1 mimic group. Compared with the model group, neuronal apoptosis was decreased in the brain tissues of rats in the miR-1 inhibitor group. Compared with the sham group, the ERK1/2 proteins in the model group were significantly decreased, the Bcl-2, Bax, and caspase-3 proteins were significantly increased, and the ERK1/2, Bcl-2, Bax, and caspase-3 proteins in the miR-1 inhibitor group and miR-1 mimic group were significantly increased. Compared with the model group, the protein levels of ERK1/2 and Bcl-2 in the miR-1 inhibitor group were significantly increased, the proteins of Bax and caspase-3 were significantly decreased, and the protein levels of ERK1/2 and Bcl-2 in the miR-1 inhibitor group were significantly increased ( p < 0.05 ). Conclusions. miR-1 can interfere with neuronal apoptosis in rats with stroke through the ERK signaling pathway.

Blood flow and relative tissue PO2 of brain and muscle: effect of various gas mixtures

1976 ◽  
Vol 230 (3) ◽  
pp. 839-844 ◽  
Author(s):  
HR Weiss ◽  
JA Cohen ◽  
LA McPherson
Keyword(s):  
Biceps Brachii ◽  
Brain Perfusion ◽  
Tissue Perfusion ◽  
Gas Mixtures ◽  
Cerebral White Matter ◽  
Experimental Conditions ◽  
Co2 Gas ◽  
High Co2 ◽  
Tissue Po2 ◽  
The Brain

The effects of inspiring low O2 or high CO2, or low-O2-high-CO2 gas mixtures on tissue perfusion and tissue Po2 of brain and muscle were studied in 76 anesthetized rats. Under control conditions, relative tissue Po2 of cerebral white matter measured polarographically averaged 16.4 mmHg and 18.7 mmHg in the biceps brachii. With low-O2 gas mixtures, tissue Po2 declined in both brain and muscle, but more in muscle. Tissue Po2 increased under high-CO2 conditions, with the brain increasing to a greater extent. Control cerebral cortex tissue perfusion averaged 23.5 ml/min per 100 g and muscle was 18.3 ml/min per 100 g measured by H2 clearance. Brain perfusion increased under all experimental conditions. Muscle perfusion did not change with low O2 alone, but increased with low-O2-high-CO2 or high-CO2 gas mixtures. Brain perfusion increased under all conditions significantly more than muscle. The brain appeared better protected compared to skeletal muscle in terms of tissue Po2 and perfusion under the stress of hypoxia and hypoxic-hypercapnia. The effects of hypercapnia are also greater on the brain.

scholarly journals Administration of Curcumin Protects Kidney Tubules Against Renal Ischemia-Reperfusion Injury (RIRI) by Modulating Nitric Oxide (NO) Signaling Pathway

2017 ◽  
Vol 44 (1) ◽  
pp. 401-411 ◽  
Author(s):  
Fuhe Liu ◽  
Wenjuan Ni ◽  
Jiajia Zhang ◽  
Guokang Wang ◽  
Fanzhu Li ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Tissue ◽  
Renal Tubules ◽  
Kidney Tubules ◽  
Model Group ◽  
No Signaling

Background/Aims: To explore the protective effect of curcumin on renal ischemia-reperfusion injury (RIRI) in rats, and its influence on nephridial tissue’s NO and cGMP levels as well as downstream signaling pathway, to elucidate the possible mechanism of curcumin on RIRI. Methods: 36 Sprague Dawley rats (SD rats) were randomly divided into Sham group, Model group, curcumin (CUR +) Model group, 12 rats per group. They were all given RIRI model preparation by unilateral artery occlusion method. All groups’ β2-MG in urine in 24h, serum Cr and BUN were compared, and UAER were calculated. Nitric oxide synthase (NOS), cGMP-dependent protein kinase (PKG), Caspase-3 expression were all determined by western blot. Nitric oxide (NO), NOS and cGMP levels were also examined by using ELISA. All groups’ nephridial histomorphology and kidney tubules score were evaluated and compared. Results: β2-MG and UAER in urine, serum Cr and BUN, in renal tissue were all elevated in Model of RIRI, indicating the success of animal model of RIRI establishment, and above index in CUR + Model group were all lower than those in Model group. Furthermore, iNOS, NO, cGMP, PKG and Caspase-3 in renal tissue were all increased in Model of RIRI, indicating the NO signaling pathway was activated, which is one of the pathogenesis of RIRI, and above index in CUR + Model group were all lower than those in Model group, suggesting that inactivation of iNOS/NO/cGMP/PKG signaling pathway is one of the reasons that explain the protective effect of curcumin in RIRI. Conclusion: The activation of iNOS/NO/cGMP/PKG signaling pathway and the consequent promoted apoptosis of renal tubules are significantly involved in the pathogenesis of development of RIRI, and curcumin treatment could protect renal tubules against RIRI, at least partially, by suppressing the activated iNOS/NO/cGMP/PKG signaling pathway.

scholarly journals Sugammadex-Enhanced Neuronal Apoptosis following Neonatal Sevoflurane Exposure in Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Maiko Satomoto ◽  
Zhongliang Sun ◽  
Yushi U. Adachi ◽  
Koshi Makita
Keyword(s):  
Neuronal Apoptosis ◽  
Caspase 3 ◽  
Neuronal Damage ◽  
Intraperitoneal Administration ◽  
Binding Agent ◽  
Learning Deficits ◽  
Neonatal Mice ◽  
Transmission Electron ◽  
Pass Through ◽  
The Brain

In rodents, neonatal sevoflurane exposure induces neonatal apoptosis in the brain and results in learning deficits. Sugammadex is a new selective neuromuscular blockade (NMB) binding agent that anesthesiologists can use to achieve immediate reversal of an NMB with few side effects. Given its molecular weight of 2178, sugammadex is thought to be unable to pass through the blood brain barrier (BBB). Volatile anesthetics can influence BBB opening and integrity. Therefore, we investigated whether the intraperitoneal administration of sugammadex could exacerbate neuronal damage following neonatal 2% sevoflurane exposure via changes in BBB integrity. Cleaved caspase-3 immunoblotting was used to detect apoptosis, and the ultrastructure of the BBB was examined by transmission electron microscopy. Exposure to 2% sevoflurane for 6 h resulted in BBB ultrastructural abnormalities in the hippocampus of neonatal mice. Sugammadex alone without sevoflurane did not induce apoptosis. The coadministration of sugammadex with sevoflurane to neonatal mice caused a significant increase (150%) in neuroapoptosis in the brain compared with 2% sevoflurane. In neonatal anesthesia, sugammadex could influence neurotoxicity together with sevoflurane. Exposure to 2% sevoflurane for 6 h resulted in BBB ultrastructural abnormalities in the hippocampus of neonatal mice.

Abstract 2046: Hypercapnic Resuscitation Improves Survival and Neurological Outcomes by Nitric Oxide Synthase-Mediated Enhancement of Brain Perfusion

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Wei-Tien Chang ◽  
Lay-San Gan ◽  
Chiang-Ting Chien ◽  
Chien-Hua Huang ◽  
Huei-Wen Chen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Cardiac Arrest ◽  
Apoptotic Cell ◽  
Brain Perfusion ◽  
No Synthase ◽  
Neurological Injury ◽  
Neurological Outcomes ◽  
Arterial Blood ◽  
The Brain

Neurological injury is one of the major causes of morbidity and mortality following cardiac arrest and cardiopulmonary resuscitation (CPR). Brain perfusion is usually compromised in the post-resuscitation phase, which inevitably lengthens the ischemic insult of the brain. Hypercapnia has been reported to cause cerebral vasodilatation. We therefore sought to study the potentials of hypercapnic resuscitation in improving the brain perfusion as well as survival and neurological prognoses. Using an established rat model of asphyxial cardiac arrest (6 min) and CPR, we employed hypercapnic (5% CO 2 , 95% O 2 ) ventilation during CPR and the first 2 h post-resuscitation, and compared the brain perfusion with normocapnia (5% N 2 , 95% O 2 ) control. The blood pressure was continuously monitored, with arterial blood sampled regularly for gas analysis. The tissue perfusion of the brain was measured by OxyLyte 2000E perfusion sensor. In a subgroup the survival and neurological outcomes were monitored up to 3 days. TdT-mediated dUTP nick-ends labeling (TUNEL) stain and Bax/Bcl2 of the brain were assessed as indicators of apoptotic cell death. The PaCO 2 was significantly higher ( P <0.001) and pH significantly lower ( P <0.001) in hypercapnia group during the first 2 h post-resuscitation. No difference was noted in PaO 2 or blood pressure. In normocapnia control, the brain perfusion was significantly reduced in the first 30 min post-resuscitation. Hypercapnic ventilation enhanced brain perfusion during this period ( P <0.05). The survival and neurological outcomes were also improved (LogRank P <0.05), which was consistent with the decrease in TUNEL stain and Bax/Bcl2. If nitric oxide (NO) synthase inhibitor N ω -nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) was cotreated with hypercapnia, the increased brain perfusion and reduced TUNEL and Bax/Bcl2 were reversed. The improved survival and neurological outcomes were also abrogated. Hypercapnic ventilation during CPR and early post-resuscitation phase improves brain perfusion and hence survival and neurological outcomes. This is in part mediated by NO synthase-related vasodilatation.

scholarly journals Increased tissue perfusion promotes capillary dysplasia in the ALK1-deficient mouse brain following VEGF stimulation

2008 ◽  
Vol 295 (6) ◽  
pp. H2250-H2256 ◽  
Author(s):  
Qi Hao ◽  
Hua Su ◽  
Douglas A. Marchuk ◽  
Radoslaw Rola ◽  
Yongqiang Wang ◽  
...  
Keyword(s):  
Brain Perfusion ◽  
Tissue Perfusion ◽  
Angiogenic Factor ◽  
Vascular Endothelial ◽  
Loss Of Function ◽  
Vascular Flow ◽  
Receptor Like Kinase ◽  
Endothelial Growth Factor ◽  
The Brain

Loss-of-function activin receptor-like kinase 1 gene mutation (ALK1+/−) is associated with brain arteriovenous malformations (AVM) in hereditary hemorrhagic telangiectasia type 2. Other determinants of the lesional phenotype are unknown. In the present study, we investigated the influence of high vascular flow rates on ALK1+/− mice by manipulating cerebral blood flow (CBF) using vasodilators. Adult male ALK1+/− mice underwent adeno-associated viral-mediated vascular endothelial growth factor (AAVVEGF) or lacZ (AAVlacZ as a control) gene transfer into the brain. Two weeks after vector injection, hydralazine or nicardipine was infused intraventricularly for another 14 days. CBF was measured to evaluate relative tissue perfusion. We analyzed the number and morphology of capillaries. Results demonstrated that hydralazine or nicardipine infusion increased focal brain perfusion in all mice. It was noted that focal CBF increased most in AAVVEGF-injected ALK1+/− mice following hydralazine or nicardipine infusion (145 ± 23% or 150 ± 11%; P < 0.05). There were more detectable dilated and dysplastic capillaries (2.4 ± 0.3 or 2.0 ± 0.4 dysplasia index; P < 0.01) in the brains of ALK1+/− mice treated with AAVVEGF and hydralazine or nicardipine compared with the mice treated with them individually. We concluded that increased focal tissue perfusion and angiogenic factor VEGF stimulation could have a synergistic effect to promote capillary dysplasia in a genetic deficit animal model, which may have relevance to further studies of AVMs.

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