The thiol-disulfide balance and the nitric oxide system in the brain tissue of rats subjected to experimental acute impairment of cerebral blood flow: The therapeutic effects of nootropic drugs

Chuanxiong Rhizoma and Cyperi Rhizoma (CRCR), an ancient and classic formula comprised of Chuanxiong Rhizoma and Cyperi Rhizoma in a weight ratio of 1:2, has long been used for curing migraine. This study aimed to explore their anti-migraine effect and active constituents. A nitroglycerin (NTG)-induced migraine model in rats was established to evaluate pharmacological effects. Cerebral blood flow was detected by a laser Doppler perfusion monitor. The levels of endothelin-1 (ET-1), γ-aminobutyric acid (GABA), nitric oxide synthase (NOS), nitric oxide (NO), 5-hydroxytryptamine (5-HT), 5-hydoxyindoleacetic acid (5-HIAA), calcitonin gene-related peptide (CGRP) and β-endorphin (β-EP) were quantified with enzyme-linked immunosorbent assay. CGRP and c-Fos mRNA expression were quantified with quantitative real-time polymerase chain reaction. A UPLC-MS/MS method was developed and validated for the simultaneous quantification of active constituents in rat serum and cerebral cortex. CRCR significantly increased cerebral blood flow, decreased the levels of ET-1, GABA and NOS, and increased the levels of 5-HT, 5-HIAA and β-EP in NTG-induced migraine rats. CGRP levels and CGRP mRNA expression, as well as c-Fos mRNA expression in the brainstem were markedly down-regulated with the treatment of CRCR. After oral administration of CRCR, ferulic acid (FA), senkyunolide A (SA), 3-n-butylphthalide (NBP), Z-ligustilide (LIG), Z-3-butylidenephthalide (BDPH), cyperotundone (CYT), nookatone (NKT) and α-cyperone (CYP) were qualified in rat serum and cerebral cortex. The above results suggested that CRCR showed powerfully therapeutic effects on migraine via increasing the cerebral blood flow, decreasing the expression of CGRP and c-Fos mRNA, and regulating the releasing of ET-1, GABA, NOS, 5-HT, 5-HIAA, CGRP and β-EP in the serum and brainstem, consequently relieving neurogenic inflammation. The active constituents in CRCR for treating migraine were FA, SA, NBP, LIG, BDPH, CYT, NKT and CYP. These findings contributed for the further use of CRCR as a combinational and complementary phytomedicine for migraine treatment.

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Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16649194 ◽

2016 ◽

Vol 37 (3) ◽

pp. 994-1005 ◽

Cited By ~ 15

Author(s):

Lindsay S Cahill ◽

Lisa M Gazdzinski ◽

Albert KY Tsui ◽

Yu-Qing Zhou ◽

Sharon Portnoy ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Brain Tissue ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Cell Model ◽

Ex Vivo ◽

Tissue Hypoxia ◽

Brain Physiology ◽

The Brain

Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.

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Evidence That Acetylcholine Mediates Increased Cerebral Blood Flow Velocity in Crucian Carp through a Nitric Oxide—Dependent Mechanism

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1995.64 ◽

1995 ◽

Vol 15 (3) ◽

pp. 519-524 ◽

Cited By ~ 47

Author(s):

Patrick Hylland ◽

Göran E. Nilsson

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Flow Velocity ◽

Blood Flow Velocity ◽

Crucian Carp ◽

Cerebral Blood Flow Velocity ◽

Early Event ◽

Brain Blood Flow ◽

The Brain

Nitric oxide (NO)–dependent regulation of brain blood flow has not been proven to exist in fish or other ectothermic vertebrates. Using epi-illumination microscopy on the brain surface (optic lobes) of crucian carp ( Carassius carassius), we show that superfusing the brain with acetylcholine (ACh) induces an increase in cerebral blood flow velocity that can be completely blocked by the NO synthase inhibitors NG-nitro-l-arginine methylester (L-NAME) and NG-nitro-l-arginine. Also, sodium nitroprusside, which decomposes to liberate NO, causes an increase in cerebral blood flow velocity. By contrast, L-NAME does not block the increase in blood flow velocity caused by anoxia. The results suggest that NO is an endogenous vasodilator in crucian carp brain that mediates the effects of ACh. Because teleost fish deviated from other vertebrates 400 million years ago, these results suggest that NO-dependent brain blood flow regulation was an early event in vertebrate evolution.

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The Effects of Traumatic Brain Injury on Cerebral Blood Flow and Brain Tissue Nitric Oxide Levels and Cytokine Expression

Journal of Neurotrauma ◽

10.1089/neu.2004.21.1431 ◽

2004 ◽

Vol 21 (10) ◽

pp. 1431-1442 ◽

Cited By ~ 52

Author(s):

Myung-Ja Ahn ◽

Edward R. Sherwood ◽

Donald S. Prough ◽

Cheng Yie Lin ◽

Douglas S. DeWitt

Keyword(s):

Nitric Oxide ◽

Traumatic Brain Injury ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Brain Injury ◽

Brain Tissue ◽

Cytokine Expression

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Cerebral Metabolism of Nitric Oxide during Retrograde Cerebral Perfusion

Asian Cardiovascular and Thoracic Annals ◽

10.1177/021849230201000307 ◽

2002 ◽

Vol 10 (3) ◽

pp. 223-227 ◽

Cited By ~ 1

Author(s):

Katsuhito Ueno ◽

Shinichi Takamoto ◽

Takeshi Miyairi ◽

Tetsuro Morota ◽

Ko Shibata ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Cardiopulmonary Bypass ◽

Cerebral Perfusion ◽

Cerebral Metabolism ◽

Oxidation Products ◽

Retrograde Cerebral Perfusion ◽

Ph Stat ◽

The Brain

The aim of this study was to determine whether alpha- or pH-stat protects the brain during deep hypothermic retrograde cerebral perfusion. Fifteen anesthetized dogs on cardiopulmonary bypass were cooled to 18°C under alpha-stat and underwent retrograde cerebral perfusion for 90 minutes under alpha-stat or pH-stat, or underwent antegrade cardiopulmonary bypass under alpha-stat as the control. Cerebral blood flow of the cortex was monitored and serial analyses of blood gases and total nitric oxide oxidation products made. Cerebral blood flow and cerebral metabolic rate for oxygen were significantly higher and plasma levels of nitric oxide oxidation products in the outflow from the brain were significantly lower in retrograde cerebral perfusion under pH-stat than under alpha-stat. This study shows that reduced levels of nitric oxide oxidation products may protect against neuronal damage induced by nitric oxide and that increased cerebral blood flow under pH-stat may lead to a reduction of nitric oxide oxidation products. Under retrograde cerebral perfusion, pH-stat is thus better than alpha-stat for protecting the brain.

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Compartmental analysis of regional cerebral blood flow in patients with acute severe head injuries

Journal of Neurosurgery ◽

10.3171/jns.1977.47.5.0699 ◽

1977 ◽

Vol 47 (5) ◽

pp. 699-712 ◽

Cited By ~ 27

Author(s):

Erna M. Enevoldsen ◽

Finn Taagehøj Jensen

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Brain Tissue ◽

Regional Cerebral Blood Flow ◽

Head Injuries ◽

Initial Slope ◽

Flow Index ◽

Normal Brain ◽

Regional Cerebral Blood ◽

The Brain

✓ Bicompartmental analysis for the calculation of regional cerebral blood flow (rCBF) from 133Xe clearance in brain tissue has not been thoroughly explored in clinical studies. Most authors rely either on the average rCBF obtained by height/area analysis of the clearance curves or on the initial-slope flow index. Possibly the reason is that the validity of the bimodal flow distribution in abnormal brain tissue is considered questionable. In the present study, bicompartmental analysis, performed by a least-square computerized iterative approach, was used in the calculation of the flow and weight of the tissue of the brain of patients with severe head injuries. The analysis was found to give important information of the nature and course of the brain lesions even if the clearance curves did not have the normal bi-exponential shape, provided the results obtained were properly interpreted. In such cases, the values of the flow and relative weight could not be taken as flow and weight values of gray and white matter, but rather as indices of fast and slower flow components. The interpretation of the results was based on the identification of three types of 13-minute clearance curves, each being characteristic of a type of brain lesion. The clearance curves from fairly normal brain tissue appeared to be bi-exponential; curves from areas of severe cortical contusion had, in addition, an initial and rapid “third” component, a tissue peak, whereas curves from severely edematous brain tissue approached the monoexponential shape.

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Nitric Oxide Pathways in Neurovascular Coupling Under Normal and Stress Conditions in the Brain: Strategies to Rescue Aberrant Coupling and Improve Cerebral Blood Flow

Frontiers in Physiology ◽

10.3389/fphys.2021.729201 ◽

2021 ◽

Vol 12 ◽

Author(s):

Cátia F. Lourenço ◽

João Laranjinha

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Nmda Receptor ◽

Neuronal Activity ◽

Energy Requirements ◽

Neuronal Dysfunction ◽

No Bioavailability ◽

The Brain

The brain has impressive energy requirements and paradoxically, very limited energy reserves, implying its huge dependency on continuous blood supply. Aditionally, cerebral blood flow must be dynamically regulated to the areas of increased neuronal activity and thus, of increased metabolic demands. The coupling between neuronal activity and cerebral blood flow (CBF) is supported by a mechanism called neurovascular coupling (NVC). Among the several vasoactive molecules released by glutamatergic activation, nitric oxide (•NO) is recognized to be a key player in the process and essential for the development of the neurovascular response. Classically, •NO is produced in neurons upon the activation of the glutamatergic N-methyl-D-aspartate (NMDA) receptor by the neuronal isoform of nitric oxide synthase and promotes vasodilation by activating soluble guanylate cyclase in the smooth muscle cells of the adjacent arterioles. This pathway is part of a more complex network in which other molecular and cellular intervenients, as well as other sources of •NO, are involved. The elucidation of these interacting mechanisms is fundamental in understanding how the brain manages its energy requirements and how the failure of this process translates into neuronal dysfunction. Here, we aimed to provide an integrated and updated perspective of the role of •NO in the NVC, incorporating the most recent evidence that reinforces its central role in the process from both viewpoints, as a physiological mediator and a pathological stressor. First, we described the glutamate-NMDA receptor-nNOS axis as a central pathway in NVC, then we reviewed the link between the derailment of the NVC and neuronal dysfunction associated with neurodegeneration (with a focus on Alzheimer’s disease). We further discussed the role of oxidative stress in the NVC dysfunction, specifically by decreasing the •NO bioavailability and diverting its bioactivity toward cytotoxicity. Finally, we highlighted some strategies targeting the rescue or maintenance of •NO bioavailability that could be explored to mitigate the NVC dysfunction associated with neurodegenerative conditions. In line with this, the potential modulatory effects of dietary nitrate and polyphenols on •NO-dependent NVC, in association with physical exercise, may be used as effective non-pharmacological strategies to promote the •NO bioavailability and to manage NVC dysfunction in neuropathological conditions.

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A prospective, randomized clinical trial to compare the effect of hyperbaric to normobaric hyperoxia on cerebral metabolism, intracranial pressure, and oxygen toxicity in severe traumatic brain injury

Journal of Neurosurgery ◽

10.3171/2009.7.jns09363 ◽

2010 ◽

Vol 112 (5) ◽

pp. 1080-1094 ◽

Cited By ~ 119

Author(s):

Sarah B. Rockswold ◽

Gaylan L. Rockswold ◽

David A. Zaun ◽

Xuewei Zhang ◽

Carla E. Cerra ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Intracranial Pressure ◽

Brain Tissue ◽

Cerebral Metabolism ◽

Treatment Session ◽

Control Group ◽

Normobaric Hyperoxia ◽

The Brain

Object Oxygen delivered in supraphysiological amounts is currently under investigation as a therapy for severe traumatic brain injury (TBI). Hyperoxia can be delivered to the brain under normobaric as well as hyperbaric conditions. In this study the authors directly compare hyperbaric oxygen (HBO2) and normobaric hyperoxia (NBH) treatment effects. Methods Sixty-nine patients who had sustained severe TBIs (mean Glasgow Coma Scale Score 5.8) were prospectively randomized to 1 of 3 groups within 24 hours of injury: 1) HBO2, 60 minutes of HBO2 at 1.5 ATA; 2) NBH, 3 hours of 100% fraction of inspired oxygen at 1 ATA; and 3) control, standard care. Treatments occurred once every 24 hours for 3 consecutive days. Brain tissue PO2, microdialysis, and intracranial pressure were continuously monitored. Cerebral blood flow (CBF), arteriovenous differences in oxygen, cerebral metabolic rate of oxygen (CMRO2), CSF lactate and F2-isoprostane concentrations, and bronchial alveolar lavage (BAL) fluid interleukin (IL)–8 and IL-6 assays were obtained pretreatment and 1 and 6 hours posttreatment. Mixed-effects linear modeling was used to statistically test differences among the treatment arms as well as changes from pretreatment to posttreatment. Results In comparison with values in the control group, the brain tissue PO2 levels were significantly increased during treatment in both the HBO2 (mean ± SEM, 223 ± 29 mm Hg) and NBH (86 ± 12 mm Hg) groups (p < 0.0001) and following HBO2 until the next treatment session (p = 0.003). Hyperbaric O2 significantly increased CBF and CMRO2 for 6 hours (p ≤ 0.01). Cerebrospinal fluid lactate concentrations decreased posttreatment in both the HBO2 and NBH groups (p < 0.05). The dialysate lactate levels in patients who had received HBO2 decreased for 5 hours posttreatment (p = 0.017). Microdialysis lactate/pyruvate (L/P) ratios were significantly decreased posttreatment in both HBO2 and NBH groups (p < 0.05). Cerebral blood flow, CMRO2, microdialysate lactate, and the L/P ratio had significantly greater improvement when a brain tissue PO2 ≥ 200 mm Hg was achieved during treatment (p < 0.01). Intracranial pressure was significantly lower after HBO2 until the next treatment session (p < 0.001) in comparison with levels in the control group. The treatment effect persisted over all 3 days. No increase was seen in the CSF F2-isoprostane levels, microdialysate glycerol, and BAL inflammatory markers, which were used to monitor potential O2 toxicity. Conclusions Hyperbaric O2 has a more robust posttreatment effect than NBH on oxidative cerebral metabolism related to its ability to produce a brain tissue PO2 ≥ 200 mm Hg. However, it appears that O2 treatment for severe TBI is not an all or nothing phenomenon but represents a graduated effect. No signs of pulmonary or cerebral O2 toxicity were present.

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Inhibition of Neuronal Nitric Oxide Synthase by 7-Nitroindazole: Effects upon Local Cerebral Blood Flow and Glucose Use in the Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1995.96 ◽

1995 ◽

Vol 15 (5) ◽

pp. 766-773 ◽

Cited By ~ 75

Author(s):

Paul A. T. Kelly ◽

Isobel M. Ritchie ◽

Gordon W. Arbuthnott

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Nitric Oxide Synthase ◽

Physiological Role ◽

Neuronal Nitric Oxide Synthase ◽

Conscious Rat ◽

Arterial Blood ◽

Oxide Synthase ◽

The Brain

The novel nitric oxide synthase inhibitor 7-nitroindazole (7-NI) is relatively specific for the neuronal isoform of the enzyme and in this study we have used this compound to investigate the physiological role of perivascular nitric oxide-containing nerves in the cerebrovascular bed. Following injection of 7-NI (25 or 50 mg/kg, i.p.), cerebral blood flow and glucose utilization were measured in the conscious rat using the fully quantitative [14C]iodoantipyrine and 2-[14C]deoxyglucose techniques, respectively. Neither dose of the drug produced any change in arterial blood pressure, confirming a lack of effect upon the endothelial isoform of the enzyme, although there was a pronounced decrease in heart rate (−28% by 10 min postinjection). Throughout the brain 25 mg/kg 7-NI i.p. resulted in decreases in blood flow of between −20% in the hippocampus and −58% in the substantia nigra. Increasing the dose to 50 mg/kg resulted in a further generalized decrease, to almost −60% in parts of the thalamus and hippocampus, but in every animal this higher dose of 7-NI also produced randomly distributed areas of relative hyperaemia, which were most commonly found in those areas where the most intense hypoperfusion was otherwise in evidence. Despite these changes in blood flow, in all but a very few areas of the brain no significant decrease in glucose use was measured at either of the two doses of 7-NI. Thus despite the greater specificity of 7-NI for neuronal nitric oxide synthase, the cerebrovascular effects of the drug in vivo are very similar to that reported for the arginine analogues. However, these data do suggest that nitric oxide-releasing neurones in the brain may have an important role to play in the regulation of cerebral blood flow.

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