scholarly journals Astrocyte-produced carbon monoxide and the carbon monoxide donor CORM-A1 protect against cerebrovascular dysfunction caused by prolonged neonatal asphyxia

2018 ◽  
Vol 315 (4) ◽  
pp. H978-H988 ◽  
Author(s):  
Helena Parfenova ◽  
Massroor Pourcyrous ◽  
Alex L. Fedinec ◽  
Jianxiong Liu ◽  
Shyamali Basuroy ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Carbon Monoxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Glutamate Excitotoxicity ◽  
Neonatal Asphyxia ◽  
Cerebrovascular Dysfunction ◽  
Tin Protoporphyrin ◽  
Newborn Pigs ◽  
Cerebral Vascular

Neonatal asphyxia leads to cerebrovascular disease and neurological complications via a mechanism that may involve oxidative stress. Carbon monoxide (CO) is an antioxidant messenger produced via a heme oxygenase (HO)-catalyzed reaction. Cortical astrocytes are the major cells in the brain that express constitutive HO-2 isoform. We tested the hypothesis that CO, produced by astrocytes, has cerebroprotective properties during neonatal asphyxia. We developed a survival model of prolonged asphyxia in newborn pigs that combines insults of severe hypoxia, hypercapnia, and acidosis while avoiding extreme hypotension and cerebral blood flow reduction. During the 60-min asphyxia, CO production by brain and astrocytes was continuously elevated. Excessive formation of reactive oxygen species during asphyxia/reventilation was potentiated by the HO inhibitor tin protoporphyrin, suggesting that endogenous CO has antioxidant effects. Cerebral vascular outcomes tested 24 and 48 h after asphyxia demonstrated the sustained impairment of cerebral vascular responses to astrocyte- and endothelium-specific vasodilators. Postasphyxia cerebral vascular dysfunction was aggravated in newborn pigs pretreated with tin protoporphyrin to inhibit brain HO/CO. The CO donor CO-releasing molecule-A1 (CORM-A1) reduced brain oxidative stress during asphyxia/reventilation and prevented postasphyxia cerebrovascular dysfunction. The antioxidant and antiapoptotic effects of HO/CO and CORM-A1 were confirmed in primary cultures of astrocytes from the neonatal pig brain exposed to glutamate excitotoxicity. Overall, prolonged neonatal asphyxia leads to neurovascular injury via an oxidative stress-mediated mechanism that is counteracted by an astrocyte-based constitutive antioxidant HO/CO system. We propose that gaseous CO or CO donors can be used as novel approaches for prevention of neonatal brain injury caused by prolonged asphyxia. NEW & NOTEWORTHY Asphyxia in newborn infants may lead to lifelong neurological disabilities. Using the model of prolonged asphyxia in newborn piglets, we propose novel antioxidant therapy based on systemic administration of low doses of a carbon monoxide donor that prevent loss of cerebral blood flow regulation and may improve the neurological outcome of asphyxia.

Vasopressin and prostanoid mechanisms in control of cerebral blood flow in hypotensive newborn pigs

1990 ◽  
Vol 258 (2) ◽  
pp. H408-H413 ◽  
Author(s):  
W. M. Armstead ◽  
C. W. Leffler ◽  
D. W. Busija ◽  
R. Mirro
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Metabolic Rate ◽  
Vascular Resistance ◽  
Brain Regions ◽  
Cerebral Metabolic Rate ◽  
Cerebral Vasoconstriction ◽  
Newborn Pigs ◽  
Cerebral Vascular Resistance ◽  
Cerebral Vascular

The interaction between vasopressinergic and prostanoid mechanisms in the control of cerebral hemodynamics in the conscious hypotensive newborn pig was investigated. Indomethacin treatment (5 mg/kg) of hypotensive piglets caused a significant decrease in blood flow to all brain regions within 20 min. This decrease in cerebral blood flow resulted from increased cerebral vascular resistances of 52 and 198% 20 and 40 min after treatment, respectively. Cerebral oxygen consumption was reduced from 2.58 +/- 0.32 ml.100 g-1.min-1 to 1.01 +/- 0.12 and 0.29 +/- 0.08 ml.100 g-1.min-1 20 and 40 min after indomethacin, respectively, in hemorrhaged piglets. Treatment with the putative vascular (V1) receptor antagonist [1-(beta-mercapto-beta, beta-cyclopentamethylene propionic acid-2-(O-methyl)tyrosine]arginine vasopressin (MEAVP) had no effect on regional cerebral blood flow, calculated cerebral vascular resistance, or cerebral metabolic rate either before or during hemorrhagic hypotension. However, decreases in cerebral blood flow and metabolic rate and increases in vascular resistance on treatment with indomethacin were blunted markedly in animals treated with MEAVP. These data are consistent with the hypothesis that the prostanoid system contributes to the maintenance of cerebral blood flow and cerebral metabolic rate during hypotension in the newborn pig, as reported previously, and implicate removal of vasopressinergic modulation by prostanoids as a potential mechanism for indomethacin-induced cerebral vasoconstriction in hypotensive newborn piglets.

scholarly journals Enteral Supplements of a Carbon Monoxide Donor CORM-A1 Protect against Cerebrovascular Dysfunction Caused by Neonatal Seizures

2014 ◽  
Vol 35 (2) ◽  
pp. 193-199 ◽  
Author(s):  
Jianxiong Liu ◽  
Alexander L Fedinec ◽  
Charles W Leffler ◽  
Helena Parfenova
Keyword(s):  
Carbon Monoxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Therapeutic Option ◽  
Neurovascular Unit ◽  
Neonatal Seizures ◽  
Quisqualic Acid ◽  
Effective Therapeutic Option ◽  
Pial Arterioles ◽  
Cerebral Vascular

Cerebral blood flow dysregulation caused by oxidative stress contributes to adverse neurologic outcome of seizures. A carbon monoxide (CO) donor CORM-A1 has antioxidant and cytoprotective properties. We investigated whether enteral supplements of CORM-A1 can improve cerebrovascular outcome of bicuculline-induced seizures in newborn piglets. CORM-A1 (2 mg/kg) was given to piglets via an oral gastric tube 10 minutes before or 20 minutes after seizure onset. Enteral CORM-A1 elevated CO in periarachnoid cerebrospinal fluid and produced a dilation of pial arterioles. Postictal cerebral vascular responses to endothelium-, astrocyte-, and vascular smooth muscle-dependent vasodilators were tested 48 hours after seizures by intravital microscopy. The postictal responses of pial arterioles to bradykinin, glutamate, the AMPA receptor agonist quisqualic acid, ADP, and heme were greatly reduced, suggesting that seizures cause injury to endothelial and astrocyte components of the neurovascular unit. In contrast, in the two groups of piglets receiving enteral CORM-A1, the postictal cerebral vascular responsiveness to these dilators was improved. Overall, enteral supplements of CORM-A1 before or during seizures offer a novel effective therapeutic option to deliver cytoprotective mediator CO to the brain, reduce injury to endothelial and astrocyte components of cerebral blood flow regulation and to improve the cerebrovascular outcome of neonatal seizures.

scholarly journals Comparison of Cerebrovascular Response to Hypoxic and Carbon Monoxide Hypoxia in Newborn and Adult Sheep

1984 ◽  
Vol 4 (1) ◽  
pp. 115-122 ◽  
Author(s):  
Raymond C. Koehler ◽  
Richard J. Traystman ◽  
Scott Zeger ◽  
Mark C. Rogers ◽  
M. Douglas Jones
Keyword(s):  
Carbon Monoxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Age Groups ◽  
Hypoxic Hypoxia ◽  
Dissociation Curve ◽  
Oxyhemoglobin Dissociation Curve ◽  
Adult Sheep ◽  
Control Value ◽  
Oxyhemoglobin Dissociation

Cerebral blood flow (CBF) responses to two types of isocapnic hypoxia, hypoxic hypoxia (HH) and carbon monoxide hypoxia (COH), were examined in seven unanesthetized adult sheep by the radiolabeled microsphere technique. Comparisons were made with newborn lambs (5–12 days old) previously studied under similar conditions. The arterial O2 content (Cao2) was reduced in a graded manner to 50–60% of the control value. During HH, CBF increased to maintain cerebral O2 delivery (Cao2 x CBF) in both adults and newborns; however, cerebral O2 uptake (CMRO2) did not change. Although CMRO2 was higher in newborns, the responses of CBF/CMRO2 to HH did not differ significantly in newborns and adults. In newborns, regional CBF showed that brainstem areas were particularly responsive to HH. In both age groups, CBF increased to a greater extent with COH than with HH for similar reductions in Cao2. This resulted in an increase in cerebral O2 delivery with COH. The degree to which COH differed from HH correlated with the magnitude of the leftward shift of the oxyhemoglobin dissociation curve that accompanies COH. In adults, CMRO2 fell by 16% with COH but was maintained in newborns. We conclude that maintenance of cerebral O2 delivery during acute, isocapnic HH is a property of CBF regulation common to both newborn and adult sheep. During COH, the position of the oxyhemoglobin dissociation curve is an additional factor that sets the level of O2 delivery. The fetal conditions of low Cao2 and a left-shifted oxyhemoglobin dissociation curve may have provided the newborn with a microcirculation better suited for maintaining CMRO2 during COH.

scholarly journals Arachidonic acid- and prostaglandin E2-induced cerebral vasodilation is mediated by carbon monoxide, independent of reactive oxygen species in piglets

2011 ◽  
Vol 301 (6) ◽  
pp. H2482-H2487 ◽  
Author(s):  
Alie Kanu ◽  
Charles W. Leffler
Keyword(s):  
Reactive Oxygen Species ◽  
Carbon Monoxide ◽  
Arachidonic Acid ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Artificial Cerebrospinal Fluid ◽  
Newborn Pigs ◽  
Cerebral Vasodilation ◽  
Prostacyclin Analog ◽  
Cerebral Vascular

Arachidonic acid (AA) and prostaglandin (PG) E2 stimulate carbon monoxide (CO) production, and AA metabolism is known to be associated with the generation of reactive oxygen species (ROS). This study was conducted to address the hypothesis that CO and/or ROS mediate cerebrovascular dilation in newborn pigs. Experiments were performed on anesthetized newborn pigs with closed cranial windows. Different concentrations of AA (10−8-10−6 M), PGE2 (10−8-10−6 M), iloprost (10−8-10−6 M), and their vehicle (artificial cerebrospinal fluid) were given. Piglets with PGE2 and iloprost received indomethacin (5 mg/kg iv) to inhibit cyclooxygenase. AA, PGE2, and iloprost caused concentration-dependent increases in pial arteriolar diameter. The effects of both AA and PGE2 in producing cerebral vascular dilation and associated CO production were blocked by the heme oxygenase inhibitor chromium mesoporphyrin (2 × 10−5 M), but not by the prostacyclin analog, iloprost. ROS inhibitor tempol (SOD mimetic) (1 × 10−5 M) and the H2O2 scavenger catalase (1,000 U/ml) also do not block these vasodilator effects of AA and PGE2. Heme-l-lysinate-induced cerebrovascular dilation and CO production was blocked by chromium mesoporphyrin. Hypoxanthine plus xanthine oxidase, a combination that is known to generate ROS, caused pial arteriolar dilation and CO production that was inhibited by tempol and catalase. These data suggest that AA- and PGE2-induced cerebral vascular dilation is mediated by CO, independent of ROS.

Abstract P531: Cerebral Blood Flow Analysis Using Flow Wire Measurements and CFD Analysis

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Aichi Chien ◽  
Huy Dinh ◽  
Viktor Szeder ◽  
Fernando Vinuela
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Flow Velocity ◽  
Cfd Simulation ◽  
Cfd Analysis ◽  
Flow Data ◽  
Velocity Data ◽  
Mean Flow ◽  
Good Agreement ◽  
Cerebral Vascular

Introduction: Clinical reports show that cerebral blood flow conditions are indicative of cerebral vascular disease. While methods for characterizing cerebral vascular flow have been extensively reported in the past, comparative analyses between direct flow measurements (DM) and computational flow dynamic (CFD) analysis remain limited. We hypothesize that flow data can be reliably measured both directly and through CFD in normal vessels. Methods: A left heart replicator was used as a realistic cardiac pump which maintained systolic pressure at 120 mmHg and diastolic pressure at 80 mmHg. A stenotic model with 50% stenosis for the ICA was connected to the replicator. A ComboWire was used for DM and recorded flow pressure and velocity. CFD was used to study flow. Results: In areas at the proximal end of the stenosis, the pressure and flow velocity derived from DM and CFD were in good agreement. At the end of systole and diastole, DM pressure were 145.42 mmHg and 73.53 mmHg, respectively. CFD simulation for the same system obtained the pressure at the end of systole and diastole of 147.16 mmHg and 74.64 mmHg, respectively. The velocity data collected from DM was at 15.40 cm/s and 7.74 cm/s for systolic flow and mean flow velocity. CFD measured flow was 17.85 cm/s and 11.37 cm/s, respectively. In areas at the distal end of the stenosis, pressure data showed good agreement between DM and CFD analysis. The DM were 138 and 70.81 mmHg at the end of systole and diastole, respectively; CFD simulation yielded 145.95 and 74.51 mmHg, respectively. Variations in the velocity data were observed at this location (Fig, pink arrows). Conclusion: DM of pressure showed good agreement with CFD simulation in all areas of the vessel. DM of velocity using the flow wire were highly affected by location of the measurement. CFD analysis can provide more consistent flow data for flow information collection along the vasculature.

scholarly journals Repetitive mTBI is associated with age-related reductions in cerebral blood flow but not cortical thickness

2020 ◽  
pp. 0271678X1989744 ◽  
Author(s):  
Alexandra L Clark ◽  
Alexandra J Weigand ◽  
Katherine J Bangen ◽  
Victoria C Merritt ◽  
Mark W Bondi ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Blood Flow ◽  
Risk Factor ◽  
Cerebral Blood Flow ◽  
Cortical Thickness ◽  
Regression Analyses ◽  
Brain Scans ◽  
Age Related ◽  
Cerebrovascular Dysfunction ◽  
Parietal Cortices

Mild traumatic brain injury (mTBI) is a risk factor for Alzheimer’s disease (AD), and evidence suggests cerebrovascular dysregulation initiates deleterious neurodegenerative cascades. We examined whether mTBI history alters cerebral blood flow (CBF) and cortical thickness in regions vulnerable to early AD-related changes. Seventy-four young to middle-aged Veterans (mean age = 34, range = 23–48) underwent brain scans. Participants were divided into: (1) Veteran Controls ( n =  27), (2) 1–2 mTBIs ( n =  26), and (2) 3+ mTBIs ( n =  21) groups. Resting CBF was measured using MP-PCASL. T1 structural scans were processed with FreeSurfer. CBF and cortical thickness estimates were extracted from nine AD-vulnerable regions. Regression analyses examined whether mTBI moderated the association between age, CBF, and cortical thickness. Regressions adjusting for sex and posttraumatic stress revealed mTBI moderated the association between age and CBF of the precuneus as well as superior and inferior parietal cortices ( p’s < .05); increasing age was associated with lower CBF in the 3+ mTBIs group, but not in the VCs or 1–2 mTBIs groups. mTBI did not moderate associations between age and cortical thickness ( p’s >.05). Repetitive mTBI is associated with cerebrovascular dysfunction in AD-vulnerable regions and may accelerate pathological aging trajectories.

The Renin-Angiotensin System and the Cerebrovascular Diseases: Experimental and Clinical Evidence

2020 ◽  
Vol 27 (6) ◽  
pp. 463-475 ◽  
Author(s):  
Lucas M. Kangussu ◽  
Lucas Alexandre Santos Marzano ◽  
Cássio Ferraz Souza ◽  
Carolina Couy Dantas ◽  
Aline Silva Miranda ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Renin Angiotensin System ◽  
Cerebrovascular Diseases ◽  
Therapeutic Effects ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Mas Receptor

Cerebrovascular Diseases (CVD) comprise a wide spectrum of disorders, all sharing an acquired or inherited alteration of the cerebral vasculature. CVD have been associated with important changes in systemic and tissue Renin-Angiotensin System (RAS). The aim of this review was to summarize and to discuss recent findings related to the modulation of RAS components in CVD. The role of RAS axes is more extensively studied in experimentally induced stroke. By means of AT1 receptors in the brain, Ang II hampers cerebral blood flow and causes tissue ischemia, inflammation, oxidative stress, cell damage and apoptosis. On the other hand, Ang-(1-7) by stimulating Mas receptor promotes angiogenesis in brain tissue, decreases oxidative stress, neuroinflammation, and improves cognition, cerebral blood flow, neuronal survival, learning and memory. In regard to clinical studies, treatment with Angiotensin Converting Enzyme (ACE) inhibitors and AT1 receptor antagonists exerts preventive and therapeutic effects on stroke. Besides stroke, studies support a similar role of RAS molecules also in traumatic brain injury and cerebral aneurysm. The literature supports a beneficial role for the alternative RAS axis in CVD. Further studies are necessary to investigate the therapeutic potential of ACE2 activators and/or Mas receptor agonists in patients with CVD.

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