Kanamycin Inhibits Cochlear-Renal ODC in Neonatal Rats

1992 ◽  
Vol 107 (4) ◽  
pp. 501-510 ◽  
Author(s):  
Andrew T. Lyos ◽  
William E. Winter ◽  
Charles M. Henley
Keyword(s):  
Organ Of Corti ◽  
Lateral Wall ◽  
Inhibitory Effect ◽  
Polyamine Biosynthesis ◽  
Key Enzyme ◽  
Old Rats ◽  
In Vivo Effects ◽  
The Brain

Ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, is important in development and regeneration. We hypothesize that aminoglycoside inhibition of ODC mediates developmental hypersensitivity to aminoglycoside ototoxicity. Kanamycin effects on ODC activity (decarboxylation of ornithine) in vitro were determined in the postmitochondriai fraction of cochlear and renal homogenates from 11-day-old rats. Kanamycin inhibited cochlear and renal ODC by an uncompetitive mechanism. For the cochlear enzyme, the inhibitor constant (Ki) for kanamycin was 99 ± 25 (μmol/L; for the renal enzyme, the Ki = 1.5 ± 0.1 mmol/L. In vivo effects of kanamycin on cochlear, renal, brain ODC activity were determined in rats treated with kanamycin (400 mg/kg/day, intramuscularly) or saline during postnatal days 11 through 20, the hypersensitive period for ototoxicity. Rats were killed on postnatal days 12,14,16, and 20 and ODC was assayed. Kanamycin significantly inhibited ODC in the lateral wall-organ of Corti and kidney (ANOVA α = 0.05), but had no effect on cochlear nerve and no consistent inhibitory effect in the brain. These results suggest that ODC is a potential target of kanamycin in susceptible tissues and may be a contributing factor in developmental sensitivity to the drug by inhibiting repair and developmental processes mediated by ODC.

Estrogens and progestins: molecular effects on brain cells

2010 ◽  
Vol 4 (3) ◽  
Author(s):  
Paolo Mannella ◽  
Tommaso Simoncini ◽  
Andrea Riccardo Genazzani
Keyword(s):  
Sex Steroids ◽  
Molecular Mechanisms ◽  
Neural Cells ◽  
Protective Effects ◽  
Complete Knowledge ◽  
Molecular Effects ◽  
In Vivo Effects ◽  
The Brain

AbstractSex steroids are known to regulate brain function and their role is so important that several diseases are strictly correlated with the onset of menopause when estrogen-progesterone deficiency makes neural cells much more vulnerable to toxic stimuli. Although in the past years several scientists have focused their studies on in vitro and in vivo effects of sex steroids on the brain, we are still far from complete knowledge. Indeed, contrasting results from large clinical trials have made the entire issue much more complicated. Currently we know that protective effects exerted by sex steroids depend on several factors among which the dose, the health of the cells and the type of molecule being used. In this review, we present an overview of the direct and indirect effects of estrogen and progesterone on the brain with specific focus on the molecular mechanisms by which these molecules act on neural cells.

In Vivo Studies On The Inhibition Of Coagulation By A Heparin Analogue

1981 ◽  
Author(s):  
U Schmitz-Huebner ◽  
F Asbeck ◽  
J van de Loo
Keyword(s):  
Plasma Sample ◽  
Anticoagulant Activity ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
At Iii ◽  
In Vivo Effects ◽  
Higher Doses ◽  
Free Plasma

SSHA, a semi-synthetic heparin analogue belonging to the chondroitin family, was reported to induce considerable anti-Xa activity in vivo being practically inactive in vitro. In a study designed to elucidate further the in vivo effects of this drug, SSHA and sodium heparin from porcine intestinal mucosa were injected subcutaneously into six volunteers on separate occasions over a period of three days in a cross-over trial. Before injection and 2,4,6,8 hours afterwards, the heparin-like activity was measured by means of the APTT, the anti -Xa clotting test and two chromogenic substrate assays. The results show that SSHA mediates both anti-Xa and antithrombin activities in vivo. A comparison between the effects of SSHA and heparin is problematical, due to the heterogeneity of different heparin preparations. Low doses of the analogue (45 mg s.c.) induce proportionally higher and longer lasting anti-Xa activities than higher doses (90 mg s.c.). In an attempt to identify the mediator involved in the anticoagulant activity induced by SSHA in vivo, antithrombin III AT III) was removed from a plasma sample of one the subjects obtaining SSHA injections by immunosorption using Sepharose IVb coupled with antibodies against AT III. The AT III free plasma obtained was found to be devoid of heparin-like activity in the anti-Xa clotting test but it maintained its anticoagulant activity in the APTT assay. When purified AT III was added to this plasma its anti-Xa activity was largely restored. In conclusion, the inhibitory effect of SSHA on coagulation seems to involve at least two mechanisms: a direct one which does not depend on AT III and an indirect one, induced in vivo and mediated by AT III.

High Antiurolithiatic Capacities of Isolated Fractions of the Hydromethanolic Extract from Pituranthos scoparius Roots

2019 ◽  
Author(s):  
H. Benalia ◽  
R. Mahfoudi ◽  
A. Djeridane ◽  
M. Yousfi
Keyword(s):  
Preparative Thin Layer Chromatography ◽  
Renal Calculi ◽  
Inhibitory Effect ◽  
Biologically Active ◽  
Urinary Lithiasis ◽  
Treatment And Prevention ◽  
Turbidimetric Assay ◽  
In Vivo Effects

Natural products, such as plant extracts, open a new horizon for the discovery of new antiurolithiatic agents. In Algeria Pituranthos scoparius commonly known as “guezzah”, one of the most important plants medicinal Saharan is used for the treatment and prevention of urinary lithiasis. The present study deals with the in vitro evaluation of the inhibitory effect on the formation of calcium oxalate kidney stones of isolated fractions from Pituranthos scoparius roots hydromethanolic extract. First, the study led to the isolation of four fractions (F1 = 107 mg, F2 = 19 mg, F3 = 7 mg, F4 = 18 mg) by combining two chromatographic techniques: open column chromatography and preparative thin layer chromatography (TLC). The in vitro antiurolithiatic activity of different isolated fractions has been carried out by two different models. In the turbidimetric assay, we have determined spectrophotometrically the effect of the isolated fractions (1g/l) on the oxalocalcic crystallization, induced by the addition of oxalate in urines from four subjects, whereas the gravimetric assay is used to measure the variation of uric acid and calcium urate renal calculi weight, after putting them in contact with 3 ml of the isolated fractions (1 g/l) during 30 days. In the two assays, the antiurolithiatic activity was compared with that of six antiurolithogenesis inhibitory standards: sodium citrate, succinimide pharbiol, foncitril, alcaphor, allopurinol, and phosphoneuros. The achieved results measured by the two tests show clearly that the fraction 1 (F1) has provided very important antiurolithiatic power (> 50% of inhibition) compared to the standard inhibitors. The in vitro obtained experimental results in this study show that the Pituranthos scoparius roots are a biologically active natural source for the treatment of oxalocalcic lithiasis. Therefore, further experiments will be required to identify the molecules involved in the antiurolithiatic effect and to study their in vivo effects, which can be used therapeutically.

scholarly journals Structural elements of ornithine decarboxylase required for intracellular degradation and polyamine-dependent regulation.

1992 ◽  
Vol 12 (5) ◽  
pp. 2178-2185 ◽  
Author(s):  
L Ghoda ◽  
D Sidney ◽  
M Macrae ◽  
P Coffino
Keyword(s):  
Amino Acids ◽  
Ornithine Decarboxylase ◽  
Distinct Region ◽  
Carboxy Terminus ◽  
Polyamine Biosynthesis ◽  
Key Enzyme ◽  
Reticulocyte Lysate ◽  
Carboxy Terminal

Mammalian ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, is rapidly degraded in cells, an attribute important to the regulation of its activity. Mutant and chimeric ODCs were created to determine the structural requirements for two modes of proteolysis. Constitutive degradation requires the carboxy terminus and is independent of intracellular polyamines. Truncation of five or more carboxy-terminal amino acids prevents this mode of degradation, as do several internal deletions within the 37 carboxy-most amino acids that spare the last five residues. Polyamine-dependent degradation of ODC requires a distinct region outside the carboxy terminus. The ODC of a parasite, Trypanosoma brucei, is structurally very similar to mouse ODC but lacks the carboxy-terminal domain; it is not a substrate for either pathway. The regulatory properties of enzymatically active chimeric proteins incorporating regions of the two ODCs support the conclusion that distinct domains of mouse ODC confer constitutive degradation and polyamine-mediated regulation. Mouse ODC contains two PEST regions. The first was not required for either form of degradation; major deletions within the second ablated constitutive degradation. When mouse and T. brucei ODC RNAs were translated in vitro in a reticulocyte lysate system, the effects of polyamine concentration on ODC protein production and activity were similar for the two mRNAs, which contradicts claims that this system accurately reflects the in vivo effects of polyamines on responsive ODCs.

scholarly journals In vivo activity of glutaminase in the brain of hyperammonaemic rats measured by 15N nuclear magnetic resonance

1995 ◽  
Vol 305 (1) ◽  
pp. 329-336 ◽  
Author(s):  
K Kanamori ◽  
B D Ross
Keyword(s):  
Brain Homogenate ◽  
Inhibitory Effect ◽  
Intact Brain ◽  
Strong Inhibitory Effect ◽  
Glutamine Synthesis ◽  
Gaba Synthesis ◽  
The Brain

The in vivo activity of phosphate-activated glutaminase (PAG) was measured in the brain of hyperammonaemic rat by 15N n.m.r. Brain glutamine was 15N-enriched by intravenous infusion of 15NH4+ until the concentration of [5-15N]glutamine reached 6.1 mumol/g. Further glutamine synthesis was inhibited by intraperitoneal injection of methionine-DL-sulphoximine, an inhibitor of glutamine synthetase, and the infusate was changed to 14NH4+ during observation of decrease in brain [5-15N]glutamine due to PAG and other glutamine utilization pathways. Progressive decrease in brain [5-15N]glutamine, PAG-catalysed production of 15NH4+ and its subsequent assimilation into glutamate by glutamate dehydrogenase were monitored in vivo by 15N n.m.r. Brain [5-15N]glutamine (15N enrichment of 0.35-0.50) decreased at a rate of 1.2 mumol/h per g of brain. The in vivo PAG activity, determined from the observed rate and the quantity of 15NH4+ produced and subsequently assimilated into glutamate and aspartate, was 0.9-1.3 mumol/h per g. This activity is less than 1.1% of the reported activity in vitro measured in rat brain homogenate at a 10 mM concentration of the activator Pi. Inhibition by ammonia (brain level 1.4 mumol/g) alone does not account for the observed low activity in vivo. The result strongly suggests that, in intact brain, PAG activity is maintained at a low level by a suboptimal in situ concentration of Pi and the strong inhibitory effect of glutamate. The observed PAG activity in vivo is lower than the reported in vivo activity of glutamate decarboxylase which converts glutamate into gamma-aminobutyrate (GABA). The result suggests that PAG-catalysed hydrolysis of glutamine is not the sole provider of glutamate used for GABA synthesis.

Development in rats of the brain-pituitary-adrenal response to hypoglycemia in vivo and in vitro

1989 ◽  
Vol 257 (5) ◽  
pp. E757-E763 ◽  
Author(s):  
E. P. Widmaier
Keyword(s):  
Base Line ◽  
Adult Rats ◽  
Glucose Levels ◽  
Altered Glucose ◽  
Dose Dependent Fashion ◽  
Adrenal Response ◽  
Old Rats ◽  
The Brain

To clarify the nature of the stress hyporesponsive period that occurs in neonatal rats, the development of the response of the brain-pituitary-adrenal axis to hypoglycemia stress in rats was assessed in vivo and in vitro. Hypothalami were removed from the brains of neonatal (9-35 days postnatal) or adult rats and incubated in vitro for sequential 30-min periods in Krebs buffer for determination of corticotropin-releasing factor (CRF) secretion under conditions of altered glucose concentrations. As expected from previous studies, CRF secretion from adult hypothalami was significantly increased in severely hypoglycemic conditions (0.55 mM glucose) by approximately 50% above base-line values (in 5.5 mM glucose). However, lowering glucose did not elicit an increase in CRF release from hypothalami of rats less than 35 days of age. Hypothalami obtained from rats less than or equal to 24 days old also failed to show consistent secretory responses to potassium depolarization. At 35 days postnatal the response to hypoglycemia was significant and similar to the adult response. To determine if the lack of hypothalamic response to hypoglycemia in vitro could be correlated with the in vivo responses to hypoglycemia, rats aged 4 days to adult were injected intraperitoneally with porcine insulin and killed at different times after injection. Insulin injections lowered plasma glucose levels in fasted 4-day-old rats in a dose-dependent fashion, but a nadir in glucose (approximately 40 mg/dl) was not reached until 90 min; the same treatment produced a nadir in glucose within 30 min in fasted rats 10 days old and older, suggesting that the 4-day-old rats are relatively insulin insensitive.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Favipiravir treatment prolongs the survival in a lethal mouse model intracerebrally inoculated with Jamestown Canyon virus

2021 ◽  
Vol 15 (7) ◽  
pp. e0009553
Author(s):  
Hirofumi Kato ◽  
Mutsuyo Takayama-Ito ◽  
Masaaki Satoh ◽  
Madoka Kawahara ◽  
Satoshi Kitaura ◽  
...  
Keyword(s):  
Antiviral Treatment ◽  
Febrile Illness ◽  
Drug Efficacy ◽  
Vero Cells ◽  
Inhibitory Effect ◽  
N2a Cells ◽  
Jamestown Canyon Virus ◽  
The Brain

Background Jamestown Canyon virus (JCV) is a mosquito-borne orthobunyavirus that causes acute febrile illness, meningitis, and meningoencephalitis, primarily in North American adults. Currently, there are no available vaccines or specific treatments against JCV infections. Methodology/Principal findings The antiviral efficacy of favipiravir (FPV) against JCV infection was evaluated in vitro and in vivo in comparison with that of ribavirin (RBV) and 2’-fluoro-2’-deoxycytidine (2’-FdC). The in vitro inhibitory effect of these drugs on JCV replication was evaluated in Vero and Neuro-2a (N2A) cells. The efficacy of FPV in the treatment of JCV infection in vivo was evaluated in C57BL/6J mice inoculated intracerebrally with JCV, as per the survival, viral titers in the brain, and viral RNA load in the blood. The 90% inhibitory concentrations (IC90) of FPV, RBV, and 2’-FdC were 41.0, 61.8, and 13.6 μM in Vero cells and 20.7, 25.8, and 8.8 μM in N2A cells, respectively. All mice infected with 1.0×104 TCID50 died or were sacrificed within 10 days post-infection (dpi) without treatment. However, mice treated with FPV for 5 days [initiated either 2 days prior to infection (−2 dpi–2 dpi) or on the day of infection (0 dpi–4 dpi)] survived significantly longer than control mice, administered with PBS (p = 0.025 and 0.011, respectively). Moreover, at 1 and 3 dpi, the virus titers in the brain were significantly lower in FPV-treated mice (0 dpi–4 dpi) versus PBS-treated mice (p = 0.002 for both 1 and 3 dpi). Conclusions/Significance Although the intracerebral inoculation route is thought to be a challenging way to evaluate drug efficacy, FPV inhibits the in vitro replication of JCV and prolongs the survival of mice intracerebrally inoculated with JCV. These results will enable the development of a specific antiviral treatment against JCV infections and establishment of an effective animal model.

Comparison of the Effects of Some Anorectic Drugs on Platelet and Brain 5-Hydroxy-Tryptamine (5 HT) in Rats

1975 ◽  
Author(s):  
C. Roncaglioni ◽  
W. Buczko ◽  
R. Samanin ◽  
G. de Gaetano ◽  
S. Garattini
Keyword(s):  
Drug Administration ◽  
Inhibitory Activity ◽  
Research Council ◽  
Anorectic Drugs ◽  
5 Ht Uptake ◽  
In Vivo Effects ◽  
The Brain ◽  
Uptake And Release

A number of anorectic drugs have been studied for their effects on the uptake and release of 5 HT in platelets and on the levels of brain 5 HT and 5-hydroxyindolacetic acid (5HIAA) in the rat. Platelet studies have been performed in vitro, whereas brain levels have been measured after drug administration. Phentermine (α-dimethylphenylethylamine), die-thylpropion (2-diethylamino propiophenone) and d-amphetamine sulphate showed no effect on the above parameters. Mazindol (5(p-chlorophenyl)-2-5-dihydro-3H-imidazo-(2-1-α)isoindol-5-01) inhibited 5HT uptake by platelets, but neither induced release of 5HT from platelets nor modified 5HT or 5HIAA levels in the brain. Both d-fenfluramine H-Cl and 4-chloroamphetamine-HCl inhibited 5HT uptake by platelets, induced release of platelet-bound 5HT and lowered brain 5HT and 5HIAA levels. S 922 (trifluoro-methylphenyl(benzoyloxy)ethylamino-2-propane), a congener of fenfluramine, was inactive as an inhibitor of 5 HT uptake, was a weak releaser of 5 HT from platelets but effectively reduced 5HT and 5HIAA levels in the brain. This drug is rapidly metabolized in vivo to form fenfluramine.The in vivo effects of anorectic drugs on brain 5 HT levels seem therefore correlated with the capacity of these drugs to release in vitro 5 HT from platelets rather than with their in vitro inhibitory activity on platelet 5HT uptake.Supported by Grants 1ST. 73-00400-04 and H. 73-00218-31 of the Italian Research Council (C.N.R.).

INHIBITORY EFFECT OF METYRAPONE ON GLUCOSE UTILIZATION BY BRAIN AND MUSCLE AND ON INSULIN RELEASE BY THE PANCREAS

1972 ◽  
Vol 70 (4) ◽  
pp. 710-718 ◽  
Author(s):  
O. D. Bruno ◽  
Patricia Metzger ◽  
W. J. Malaisse
Keyword(s):  
Glucose Uptake ◽  
Inhibitory Effect ◽  
Simultaneous Occurrence ◽  
Cerebral Dysfunction ◽  
Residual Glucose ◽  
Experimental Findings ◽  
The Brain ◽  
Oxidation Of Glucose

ABSTRACT The effect of metyrapone on in vitro glucose metabolism in the rat muscle and brain, and on insulin secretion by the rat pancreas was investigated. In the presence of increasing concentrations of metyrapone ditartrate, there was a significant progressive reduction in glucose uptake by incubated hemidiaphragms and in the glucose uptake and oxidation by incubated brain pieces. The insulin output by incubated pieces of pancreas was also significantly inhibited by metyrapone ditartrate. A clear dose-action relationship is shown between the residual glucose uptake by the muscle and the uptake or oxidation of glucose by the brain on one hand, and the logarithm of the corresponding metyrapone ditartrate concentration on the other. These data may help to explain some clinical and experimental findings, i. e. the simultaneous occurrence of hyperglycaemia, signs of cerebral dysfunction and also of growth hormone release after the administration of metyrapone in vivo.

Sign in / Sign up

Export Citation Format

Share Document