Age-Dependent Brain Tissue Hydration, Ca Exchange and their Dose- Dependent Ouabain Sensitivity

Maturational differences in the effects and mechanisms of action of endothelin 1 (ET-1) on airway contractility were investigated in tracheal smooth muscle (TSM) segments isolated from 2-wk-old and adult rabbits. In TSM under passive tension, ET-1 elicited dose-dependent contractions, with a potency of action that was significantly greater (P less than 0.001) in the 2-wk-old vs. adult tissues (i.e., mean +/- SE - log 50% of maximal response values: 8.59 +/- 0.17 vs. 7.79 +/- 0.15 - log M, respectively). In TSM half-maximally contracted with acetylcholine (ACh), however, ET-1 elicited dual and opposing dose-dependent effects. At lower doses (less than or equal to 10(-9) M), ET-1 induced TSM relaxation that was significantly greater in the adult vs. 2-wk-old TSM segments (i.e., approximately 100 vs. 26.5% decrease in active tension, respectively). The relaxant responses were associated with significantly enhanced (P less than 0.001) ET-1-induced release of prostaglandins E2 and I2 in the adult tissues. At higher doses (greater than 10(-9) M), ET-1 induced TSM contractions that were 1) attenuated to a relatively greater extent by the Ca2+ channel blocker, nifedipine (10(-5) M) in the 2-wk-old tissues and 2) associated with significantly (P less than 0.001) enhanced ET-1-stimulated accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] in the immature TSM. Moreover, the TSM contractions were inhibited by the protein kinase C (PKC) antagonist, H-7, and the latter effect was more potent in the immature TSM. Collectively, these findings demonstrate that ET-1 exerts a potent duality of action in rabbit TSM which varies significantly with maturation, wherein 1) age-dependent differences in airway relaxation are associated with changes in the evoked release of bronchodilatory prostaglandins and 2) maturational differences in airway contraction are associated with changes in Ins(1,4,5)P3 accumulation and extracellular Ca2+ mobilization, coupled to differences in PKC activation.

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4Hz mechanical vibration relieves pain through Na+/K+-ATPase α3 isoform-dependent brain tissue dehydration

International Journal of Basic and Applied Sciences ◽

10.14419/ijbas.v6i2.7365 ◽

2017 ◽

Vol 6 (2) ◽

pp. 29

Author(s):

Gohar Musheghyan ◽

Arevik Minasyan ◽

Gohar Arajyan ◽

Sinerik Ayrapetyan

Keyword(s):

Brain Tissue ◽

Muscle Tissue ◽

Heart Muscle ◽

Pain Threshold ◽

Mechanical Vibration ◽

Membrane Receptors ◽

Tissue Hydration ◽

Thermal Pain ◽

Muscle Tissues

In this work the effect of 4Hz 30dB horizontal mechanical vibration (MV) on thermal pain threshold, hydration and [3H]-ouabain binding in brain and heart muscle tissues of rats was studied. It was revealed that 4Hz MV treatment for 10 minutes increased pain threshold, which was accompanied by brain and heart muscle tissue dehydration. In vitro state, hydration of brain and heart muscle tissues of sham animals was increased, while in 4Hz MV-treated animals the increase of brain tissue hydration was more pronounced and heart muscle tissues were dehydrated. The fact that 4Hz MV treatment also impacted heart muscle tissue hydration indicates that 4Hz MV effect on brain and heart muscle tissues is realized through a common messenger circulating in blood. The incubation of brain and heart muscle tissues in PS containing 10-4M and 10-9M ouabain led to tissue hydration in sham and 4Hz MV-treated animals. However, tissues of 4Hz MV-treated animals were less hydrated, and this hydration was accompanied by the decrease and increase of membrane receptors’ affinity at 10-4M and 10-9M ouabain concentrations, respectively. Based on the obtained data, it is suggested that pain-relieving effect of 4Hz MV is due to α3 isoform-dependent brain tissue dehydration.

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Serotonergic modulation of respiratory motor output during tadpole development

Journal of Applied Physiology ◽

10.1152/japplphysiol.00104.2002 ◽

2002 ◽

Vol 93 (3) ◽

pp. 936-946 ◽

Cited By ~ 21

Author(s):

Richard Kinkead ◽

Olivier Belzile ◽

Roumiana Gulemetova

Keyword(s):

Brain Stem ◽

Lung Ventilation ◽

Receptor Activation ◽

Motor Output ◽

Burst Frequency ◽

Bath Application ◽

Age Dependent ◽

Dose Dependent ◽

Serotonergic Modulation

To test the hypothesis that serotonin (5-hydroxytryptamine; 5-HT)-receptor activation elicits age-dependent changes in respiratory motor output, we compared the effects of 5-HT bath application (5-HT concentration = 0.5–25 μM) onto in vitro brain stem preparations from pre- and postmetamorphic bullfrog tadpoles. Recording of motor output related to gill and lung ventilation showed that 5-HT elicits a dose-dependent depression of gill burst frequency in both groups. In contrast, the lung burst frequency response was stage dependent; an increase in lung burst frequency at low 5-HT concentration (≤0.5 μM) was observed only in the postmetamorphic group. Higher 5-HT concentrations decreased lung burst frequency in all preparations. Gill burst frequency attenuation is mediated (at least in part) by 5-HT1A-receptor activation in an age-dependent fashion. We conclude that serotonergic modulation of respiratory motor output 1) changes during tadpole development and 2) is distinct for gill and lung ventilation.

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Antifungal Therapy of Experimental Cerebral Phaeohyphomycosis Due to Cladophialophora bantiana

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.5.1701-1707.2005 ◽

2005 ◽

Vol 49 (5) ◽

pp. 1701-1707 ◽

Cited By ~ 30

Author(s):

Hail M. Al-Abdely ◽

Laura K. Najvar ◽

Rosie Bocanegra ◽

John R. Graybill

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Brain Tissue ◽

Amphotericin B ◽

Antifungal Therapy ◽

Central Nervous System Infection ◽

Continuous Therapy ◽

Prolonged Therapy ◽

Improvement In Survival ◽

Dose Dependent

ABSTRACT Cladophialophora bantiana is associated with central nervous system infection and a poor outcome. C. bantiana tends to be resistant to amphotericin B. Accordingly, we evaluated amphotericin B and three triazoles—posaconazole, itraconazole, and fluconazole—for treatment of C. bantiana infection in mice. In immunosuppressed ICR mice infected intravenously, posaconazole, itraconazole, and amphotericin B prolonged survival. This improvement in survival corresponded with a reduction in brain fungal concentrations for mice which were given itraconazole and posaconazole, but not amphotericin B. In nonimmunosuppressed BALB/c mice infected intracerebrally, posaconazole showed dose-dependent responses in survival and reduction of brain tissue counts. These responses were observed for short, delayed, and prolonged therapy. Although posaconazole prolonged the survival of mice with reductions in brain fungal counts, it did not sterilize brain tissue with continuous therapy for 8 weeks. We concluded that posaconazole shows promise for the treatment of C. bantiana brain infections.

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Molecular Analyses Of The Effects Induced By Orally Administered Bortezomib In Drosophila Flies: A Novel In Vivo Experimental Platform To Screen For The Tissue- and Age-Dependent Effects Of Proteasome Inhibitors

Blood ◽

10.1182/blood.v122.21.2910.2910 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2910-2910 ◽

Cited By ~ 1

Author(s):

Eleni N. Tsakiri ◽

Evangelos Terpos ◽

Gerasimos P. Sykiotis ◽

Issidora S. Papassideri ◽

Vassilis G. Gorgoulis ◽

...

Keyword(s):

Signaling Pathway ◽

Proteasome Inhibitors ◽

Proteasome Inhibition ◽

Molecular Analyses ◽

Regulatory Circuit ◽

Somatic Tissues ◽

Age Dependent ◽

The Impact ◽

Dose Dependent

Abstract Organisms require efficient surveillance of proteome quality to prevent disruption of proteostasis (homeostasis of the proteome). Central to the proteostasis ensuring mechanisms is the proteasome, which is involved in the degradation of both normal short-lived ubiquitinated proteins and mutated or damaged proteins. Proteome quality control also depends on the activity of the Nrf2/Keap1 signaling pathway which upon increased oxidative stress stimulates the expression of phase II and antioxidant enzymes. Recent findings indicate that over-activation of the proteostasis ensuring mechanisms (e.g. the proteasome) represents a hallmark of advanced tumors, and thus their inhibition provides a strategy for the development of novel anti-tumor therapies. This approach is effectively applied in multiple myeloma (MM) that represents the second most common hematological malignancy. Bortezomib is the first-in-class proteasome inhibitor that is used in the clinic for the treatment of MM, both as a single agent and as part of combination regimens. Nevertheless, the impact of the in vivo impaired proteasome functionality in tissues of higher metazoans (which maybe related to adverse effects in the clinic) remains poorly understood. To address this issue we harnessed the power of Drosophila genetics and developed a novel in vivo model of specific dose-dependent pharmacological inhibition of proteasome in adult flies. Drosophila is well-suited to this line of investigation, due to its powerful genetics and its similarities in key metabolic and aging pathways with mammals; the fact that its proteasome resemble those from mammals and finally, because it comprises a soma-germ line demarcation composed of both post-mitotic and mitotic cell lineages. We have found that feeding of bortezomib to young flies causes dose-dependent decrease of proteasome activities in the hemolymph and the somatic tissues, disruption of proteostasis, reduced motor function (a phenotype that recapitulates peripheral neuropathy of bortezomib treatment in the clinic) and a marked reduction of flies’ lifespan. Further molecular analyses showed that proteasome dysfunction is signaled to the proteostasis network of the young (but not the aged) somatic tissues by reactive oxygen species that originated from damaged mitochondria and downstream activated the Nrf2/Keap1 signaling pathway. Nrf2 activation was essential for stimulation of the genomic antioxidant response elements and the upregulation of the proteasome subunits in order to restore normal proteasome proteolysis rates. Interestingly, the reproductive tissues of the flies were more resistant than somatic tissues to proteasome inhibition triggering (in an age-independent manner) a more intense upregulation of proteasome components after bortezomib-mediated proteasome dysfunction. Additional observations indicated that the toxicity of the bortezomib may also relates to the type of diet and that aged flies are extremely sensitive (compared to young organisms) to proteasome inhibition, while even short term exposures of young flies to bortezomib still affected their overall longevity. Finally, our studies showed that the lower threshold of proteasome activities that can support life is ∼30-40% of the physiological basal activities. Taken together, our findings establish that impaired proteasome function triggers the activation of a tissue- and age-dependent regulatory circuit aiming to adjust the actual cellular proteasome activity according to temporal and/or spatial proteolytic demands. Prolonged deregulation of this proteostasis regulatory circuit has significant detrimental effects and accelerates aging. These studies at the in vivo setting of fruit flies add new knowledge on the proteasome inhibitors effects in higher metazoans. Also, as research in this area of high biomedical interest has been developing fast they will, most likely, be of interest to a broader scientific community from distinct disciplines and they have the potential to enter the important, yet challenging, arena of translational medicine. To this end we have started translating findings from our Drosophila model in the clinical setting in order to demonstrate that our Drosophila pharmacological model fit in the spectrum of bench to bedside research. Disclosures: No relevant conflicts of interest to declare.

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Regional, Directional, and Age-Dependent Properties of the Brain Undergoing Large Deformation

Journal of Biomechanical Engineering ◽

10.1115/1.1449907 ◽

2002 ◽

Vol 124 (2) ◽

pp. 244-252 ◽

Cited By ~ 379

Author(s):

Michael T. Prange ◽

Susan S. Margulies

Keyword(s):

White Matter ◽

Brain Tissue ◽

Large Strain ◽

Human Brain Tissue ◽

Tissue Properties ◽

Age Dependent ◽

Autopsy Data ◽

Degree Of Anisotropy ◽

The Brain ◽

Human Autopsy

The large strain mechanical properties of adult porcine gray and white matter brain tissues were measured in shear and confirmed in compression. Consistent with local neuroarchitecture, gray matter showed the least amount of anisotropy, and corpus callosum exhibited the greatest degree of anisotropy. Mean regional properties were significantly distinct, demonstrating that brain tissue is inhomogeneous. Fresh adult human brain tissue properties were slightly stiffer than adult porcine properties but considerably less stiff than the human autopsy data in the literature. Mixed porcine gray/white matter samples were obtained from animals at “infant” and “toddler” stages of neurological development, and shear properties compared to those in the adult. Only the infant properties were significantly different (stiffer) from the adult.

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The protective effect of ligustrazine on rats with cerebral ischemia–reperfusion injury via activating PI3K/Akt pathway

Human & Experimental Toxicology ◽

10.1177/0960327119851260 ◽

2019 ◽

Vol 38 (10) ◽

pp. 1168-1177 ◽

Cited By ~ 5

Author(s):

Y Ding ◽

J Du ◽

F Cui ◽

L Chen ◽

K Li

Keyword(s):

Nitric Oxide ◽

Cerebral Ischemia ◽

Brain Tissue ◽

Ischemia Reperfusion ◽

Pi3k Inhibitor ◽

Akt Pathway ◽

Control Group ◽

Dependent Manner ◽

Cerebral Ischemia Reperfusion ◽

Dose Dependent

The study was to investigate the effects of ligustrazine on rats with cerebral ischemia–reperfusion (I/R) injury and to explore the potential mechanism. Transient focal cerebral ischemia Wistar rat model was established through middle cerebral artery occlusion. The cerebral I/R injury rats were treated with intraperitoneal injection of ligustrazine (1, 3, and 10 mg/kg). Human amniotic epithelial cells (HAECs) were treated with ligustrazine (1, 10, 100 μM) and PI3K inhibitor wortmannin (100 μM), following oxygen–glucose deprivation (OGD) treatment. The expression levels of protein kinase B (PKB or AKT), phospho-Akt (p-Akt), endothelial nitric oxide synthase (eNOS), and phosphor-eNOS (p-eNOS) in HAECs and brains of rats were measured by Western blot. The levels of nitric oxide (NO) in HAECs were measured by Griess method using NO2−/NO3− Assay Kit. Infarct volume and neurological deficits were evaluated 24 h after reperfusion. The levels of NO, p-Akt/Akt, and p-eNOS/eNOS in HAECs were significantly reduced after OGD, but ligustrazine treatment increased the levels of those factors in a dose-dependent manner, while those increases were reversed by PI3K inhibitor wortmannin. Similarly, p-Akt/Akt and p-eNOS/eNOS in brain tissue of rats with I/R were significantly reduced compared with control group ( p < 0.05), but ligustrazine treatment increased the levels of p-Akt and p-eNOS in a dose-dependent manner ( p < 0.05), while those increases were also reversed by using wortmannin. Ligustrazine also improved the damage of rat brain tissue caused by I/R, but wortmannin reversed the improvement. Ligustrazine plays a neuroprotective role in rats with cerebral I/R injury through the activation of PI3K/Akt pathway.

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Competition among oxidizable substrates in brains of young and adult rats. Whole homogenates

Biochemical Journal ◽

10.1042/bj2190125 ◽

1984 ◽

Vol 219 (1) ◽

pp. 125-130 ◽

Cited By ~ 20

Author(s):

L M Roeder ◽

J T Tildon ◽

J H Stevenson

Keyword(s):

Brain Tissue ◽

Ketone Bodies ◽

Adult Brain ◽

Adult Rats ◽

Young Rats ◽

Age Dependent ◽

14Co2 Production ◽

Presence And Absence

The rates of conversion into 14CO2 of D-(-)-3-hydroxy[3-14C]butyrate, [3-14C]acetoacetate, [6-14C]glucose and [U-14C]glutamine were measured in the presence and absence of unlabelled alternative oxidizable substrates in whole homogenates from the brains of young and adult rats. The addition of unlabelled glutamine resulted in decreased 14CO2 production from [6-14C]glucose in brain homogenates from both young and adult rats. In contrast, glucose had no effect on [U-14C]glutamine oxidation. In suckling animals, both 3-hydroxybutyrate and acetoacetate decreased the rate of oxidation of [6-14C]glucose, but in adults only 3-hydroxybutyrate had an effect, and to a lesser degree. The addition of unlabelled glucose markedly enhanced the rates of oxidation of both ketone bodies in adult brain tissue and had little or no effect in the young. The rate of production of 14CO2 from [U-14C]glutamine was increased by the addition of unlabelled ketone bodies in brain homogenates from young, but not from adult rats. In the converse situation, unlabelled glutamine added to 14C-labelled ketone bodies diminished 14CO2 production in young rats, but had no effect in adult animals. These results revealed a complex age-dependent pattern of interaction in which certain substrates apparently competed with each other, whereas an enhanced rate of 14CO2 production was found with others.

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Developmental changes in alpha 1-adrenergic receptors, IP3 responses, and NE-induced contraction in cerebral arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.271.6.h2313 ◽

1996 ◽

Vol 271 (6) ◽

pp. H2313-H2319 ◽

Cited By ~ 13

Author(s):

L. D. Longo ◽

N. Ueno ◽

Y. Zhao ◽

W. J. Pearce ◽

L. Zhang

Keyword(s):

Cerebral Artery ◽

Adrenergic Receptors ◽

Cerebral Arteries ◽

Developmental Changes ◽

Developmental Age ◽

Age Dependent ◽

Density Values ◽

The Common ◽

Pharmacomechanical Coupling ◽

Dose Dependent

Cerebral arteries show significant developmental and artery-specific changes in noradrenergic-mediated contraction. To test the hypothesis that these changes result from differences in the density of alpha 1-adrenergic receptors (alpha 1-ARs) and/or norepinephrine (NE)-induced inositol 1,4,5-trisphosphate [Ins(1,4,5)P3,IP3] synthesis, we quantified these variables and the NE-induced contraction in the common carotid artery (Com) and main branch cerebral arteries (MBC) from term fetal (approximately 140 gestational day) and newborn (2- to 5-day) sheep and compared them with adult values. In fetal and newborn Com, maximal contractions to NE (percent K+ maximum response) were 132 +/- 14 and 118 +/- 9%, respectively (adult = 92 +/- 7%). For fetal and newborn middle cerebral artery, these values were 34 +/- 10 and 43 +/- 7%, respectively (adult = 24 +/- 7%). alpha 1-AR density values in Com of fetal and newborn sheep were 113 +/- 18 and 106 +/- 4 fmol/mg protein, respectively (adult = 54 +/- 3 fmol/mg protein). For the MBC, density values were 47 +/- 2 and 24 +/- 3 fmol/mg protein, respectively (adult = 23 +/- 3 fmol/protein). In term fetal and newborn MBC, NE produced dose-dependent increases in Ins(1,4,5)P3, the maximal increases above basal values being 245 +/- 40 and 189 +/- 16%, respectively (adult = 254 +/- 35%). Neither fetus nor newborn Com showed significant Ins(1,4,5)P3 responses to NE. We concluded that in fetal and newborn Com and MBC, alpha 1-AR density and NE-induced Ins(1,4,5)P3 response varied as a function of developmental age and specific vessel. However, these variations did not correlate with NE-induced maximum contraction. Thus we reject the hypothesis that age-dependent and vessel-specific differences of cerebral artery adrenergic-mediated contraction are a function of alpha 1-AR density or Ins(1,4,5)P3 response. Rather, the differences would appear to result from other factors such as non-Ins(1,4,5)P3-mediated calcium activation and/or sensitivity to Ins(1,4,5)P3. The studies also suggest considerable potential for maturational modulation of pharmacomechanical coupling and homeostatic regulation of cerebrovascular tone.

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