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M Nokubo

Publications and source records attributed to M Nokubo.

At least 37 records · Page 2Linked to original sources
PubMed1988

Age-dependent decrease in the lethal threshold of pentylenetetrazole in mice.

We previously reported that the minimal effective concentrations in plasma and brain for inducing the maximal seizure after intraperitoneal injection of pentylenetetrazole (PTZ) significantly increased with age in mice. We also observed that some old mice died without the maximal seizure during the observation period of 15 min. To examine how the lethal dose changes with age in the mouse, in the present study we employed a continuous intravenous infusion of PTZ that enabled us to control the dose, either stopping the infusion after the maximal seizure or continuing it until the lethal dose was reached. This study has demonstrated that the lethal threshold of PTZ in the oldest mice (27 months for males and 30 months for females) was significantly lower than that for the respective younger groups. We conclude that our observation in old mice of death occurring before the appearance of maximal seizure is due to a decrease in the lethal threshold combined with an increase in the threshold for maximal seizure.

Aging↗
PubMed1988

The neurotoxicity of phenobarbital and its effect in preventing pentylenetetrazole-induced maximal seizure in aging mice.

The effects of age on the neurotoxicity of phenobarbital and its anticonvulsant effect were examined in female BDF1 mice of different ages by means of a rotorod test and the pentylenetetrazole (PTZ)-induced maximal seizure, respectively. The minimal neurotoxic concentrations (MTCs) of phenobarbital in both plasma and brain evaluated by a rotorod test were 50% lower (p less than 0.05) in old (24-months-old) mice compared with the respective values in young (6-months-old) mice, while 12-months values were the highest of the three groups. Mice given some dosages of phenobarbital, particularly old (24-months-old) mice, died within the 15-min observation period after an i.p. injection of PTZ (150 mg/kg) without demonstrating a hindlimb extensor component (HLE) of maximal seizure. When these animals were classified as responders with regard to the anticonvulsant effect of phenobarbital, the minimal effective concentrations (MECs) in plasma and brain required for abolishing the PTZ-induced maximal seizure in old mice were only 10-20% those of young mice. Present results coupled with our past studies using electroshock seizure suggest that both the neurotoxicity and the efficacy of phenobarbital increase with age in mice.

Administration, Oral↗
PubMed1988

The age-dependent decline in the biliary transport maximum of conjugated sulfobromophthalein in the rat.

In order to elucidate the effect of aging on the biliary transport of organic anions, we examined the biliary transport maximum (Tm) for sulfobromophthalein (BSP) conjugated with glutathione in male and female Fischer-344 rats of various ages (3, 6, 24 and 30 months) during the constant intravenous infusion of conjugated BSP. For young rats the Tm values for conjugated BSP were higher in females than in males in contrast to the reported higher Tm value in males infused with free (unconjugated) BSP. In both sexes, Tm values progressively decreased with age up to 30 months. The results suggest that the previously reported higher Tm value for young male rats compared to young females during free BSP infusion is due to the lower conjugation capacity in females, and that the biliary transport process per se is more efficient in females at least for organic anions like conjugated BSP. Furthermore, the results support the previously proposed hypothesis that the biliary transport mechanism per se is steadily affected by aging in rats of both sexes.

Aging↗
PubMed1987

Increasing anticonvulsant effect of AD-810 (zonisamide) in aging BDF1 mice.

The anticonvulsant efficacy of a newly developed anticonvulsant, AD-810 (zonisamide, 3-sulfamoylmethyl-1,2-benzisoxazole) was examined in relation to mouse age in three different age groups of female BDF1 mice (7-, 25- and 29-month-old). The minimal effective concentration (MEC) of AD-810 in both plasma and brain for abolishing the electroshock-induced maximal seizure steadily decreased with age, the 25- and 29-month values being 50 and 30% of respective 7-month values. The observation in the present study was almost identical to previous observations by the authors on phenytoin, phenobarbital and oxazepam. The present results support our previous contention that the dose and plasma concentration of anticonvulsants can (and probably should) be reduced in the elderly regardless of the drug. Since the anticonvulsant mechanism of AD-810 has been reported to differ from those of previously examined drugs (phenobarbital and oxazepam), the results also suggest that the apparent increase in the pharmacological effect of these anticonvulsants may be due to old animals' lowered response capability for seizures rather than a specific age effect on the pharmacological reaction sites for individual anticonvulsants.

Aging↗
PubMed1987

Effect of lecithin on the release of 5'-nucleotidase from liver plasma membrane of rat by bile acids.

Bile acids solubilize proteins from liver plasma membrane both in vivo and in vitro. The ability to solubilize the proteins is dependent on the species of bile acid. In this paper, the effect of phospholipid on the solubilization of a membrane-bound enzyme by bile acids was investigated in vitro. Taurocholate (TC) and tauroursodeoxycholate (TUDC) solubilized the enzyme, 5'-nucleotidase, from the liver plasma membrane of the rat in a concentration-dependent manner, although there was a great difference in their effect; at 40 mM, TC solubilized 55.4% of the original 5'-nucleotidase activity of the membrane, but TUDC only 5.7%. While lecithin alone had no solubilizing effect, its addition to the bile acids provoked a 10-fold increase in the solubilizing effect of TUDC, but virtually no change for TC, essentially equalizing the solubilizing effect of the two. Both TC-rich and TUDC-rich bile were obtained from rats infused with the respective bile acids via the jugular vein after their endogenous bile acid pool had been depleted. The solubilization effect of these biles was quite similar to the bile acid-lecithin mixtures. These findings demonstrate that lecithin enhances the ability of the bile acids to solubilize the membrane protein and eliminates the difference in the two bile acid species in their solubilizing ability.

5'-Nucleotidase↗
PubMed1986

The effect of age on the adaptation of the brain to the anticonvulsant effect of phenobarbital in mice.

The anticonvulsant effect of phenobarbital was examined in young (6 month old) and old (24 month old) BDF1 female mice consisting of three groups each (one control and two chronically dosed phenobarbital groups), using the abolition of the tonic hindlimb extensor component of maximal electroshock seizure as the index. The minimal effective concentrations (MEC) of phenobarbital in plasma and brain in old control mice that were given a vehicle (tragacanth) for one week were significantly lower in comparison to the respective values in young adult control mice with the same treatment, confirming our previous findings. In young mice chronically treated with phenobarbital for one week (20 mg/kg daily for two days followed by daily dose of 50 mg/kg for 5 days), the MECs in both plasma and brain were significantly higher compared with respective control values. The 3 week treatment also produced an increase in MEc comparable to the one-week treatment. The same one-week treatment with phenobarbital in old mice similarly caused significantly higher plasma and brain MEC values but 3-week-treatment values were not significantly different from corresponding control values. It is concluded that the development of brain adaptation to phenobarbital is almost equal for young and old mice, so that the reduction in MEC with age indicates the need for lowered dosages for the aged, even when the age effect on brain adaptation developed to chronic dosing is taken into consideration.

Adaptation, Physiological↗
PubMed1986

Age-dependent increase in the threshold for pentylenetetrazole induced maximal seizure in mice.

The thresholds for inducing the maximal seizure by pentylenetetrazole (PTZ) were compared for BDF1 mice of both sexes with varying ages after intraperitoneal administration of various doses of PTZ. The minimal effective PTZ concentrations (MECs) in the brain for inducing the maximal seizure were significantly higher in 24-month or older mice than in 6-month-old animals of both sexes. Some mice of 30 months did not demonstrate the maximal seizure but died within the 15-min observation period, a phenomenon never observed in mice of 24 months or younger. The relationship between plasma and brain concentrations of PTZ changed little during aging. It was concluded that the brain becomes less sensitive to PTZ with age in regard to its convulsant activity, as was previously shown for electroshock by the authors. This observation, coupled with our earlier observations on anticonvulsants, appears to support the classical hypothesis that age has a dual effect on drug sensitivity i.e. a decrease for stimulants but an increase for sedative (or depressant) drugs.

Aging↗
PubMed1985

Increased anticonvulsant effect of phenobarbital with age in mice--a possible pharmacological index for brain aging.

We have recently reported that the anticonvulsant effect of phenytoin increases with age in mice (1). Since some of the mechanisms of anticonvulsant action of phenytoin and phenobarbital may be different, the present study sought to determine whether a similar increase with age in the anticonvulsant effect of phenobarbital could also be observed. The anticonvulsant effect of phenobarbital was examined in BDF1 female mice of different ages (6, 12, 24 and 30 months old) using the abolition of the tonic hindlimb extensor component of maximal electro-shock seizure as the index. The minimal effective concentration (MEC) values of phenobarbital in plasma and brain were significantly lower in aged (24 and 30 month old) mice compared with the respective values in the youngest animal group (6 month old). Series using nearly two-fold different intensities of electroshock (30 and 55 mA) showed almost identical MEC values in 24 month-old mice. It was concluded that the brain of aged mice is more sensitive to phenobarbital, as it is to phenytoin.

Aging↗
PubMed1985

Age related increased threshold for electroshock seizure in BDF1 mice.

The thresholds for inducing the minimal and maximal electroshock seizures were examined in relation to age in BDF1 mice of both sexes. The 50 percent effective intensities for the maximal electroshock seizure (tonic hindlimb extensor component) were lowest in the youngest age groups (6-month-old) for both male (10.68 mA) and female (9.18 mA) animals. The threshold increased with age and became significantly higher at 24 months (14.00 mA, 12.70 mA for male and female mice respectively). There was also a further increase in threshold at 30 months for both sexes. Similarly, the threshold for inducing the minimal seizure also increased with age but the differences in mean threshold levels between the youngest and oldest groups were much smaller in comparison to the maximal seizure. It was concluded that the threshold for inducing electroshock seizures significantly increases with age in mice of both sexes.

Age Factors↗
PubMed1985

Physical-chemical and biochemical differences in liver plasma membranes in aging F-344 rats.

Age-associated differences in the microviscosity and the activities of enzymes (Mg++-ATPase, Na+,K+-ATPase and 5'-nucleotidase) in the liver plasma membrane were investigated in male and female rats of various ages ranging from 2 to 30 months. The membrane microviscosity, as determined by fluorescence polarization using 1,6-diphenyl-1,3,5,-hexatriene (DPH) as a probe, increased progressively with age after 2 months in male rats, whereas in female rats the microviscosity began to increase only after 24 months. On the other hand, age-associated differences in the activities of membrane-bound enzymes were generally minimal or not significant with the exception of the 5'-nucleotidase activity determined at the pH 9.1, which progressively decreased with age in male rats. The Na+, K+-ATPase activity tended to decrease in both sexes. These decrements in activity did not appear to be large enough, however, to be of definitive physiological significance. These results suggest that age may change the physical-chemical and biochemical qualities of the rat's hepatocyte plasma membrane, but the relationship between the membrane microviscosity and the activities of membrane bound enzymes is not a simple parallelism.

5'-Nucleotidase↗
PubMed1984

Increased anticonvulsant effect of phenytoin in aging BDF1 mice.

The anticonvulsant effect of phenytoin was examined in BDF1 mice of both sexes and various ages (6, 12, 24 and 30 months old) using the abolition of the tonic hindlimb extensor component of maximal electroshock seizure as the index. The minimal effective plasma concentration of phenytoin was significantly lower in 24- and 30-month-old mice compared with young adult (6 month old) mice. Similarly, all older groups (24 and 30 month old, both sexes) showed significantly lower minimal effective brain concentrations compared with respective younger (6 and 12 month old) animal groups. Studies using nearly 2-fold different intensities of electroshock (30 and 55 mA) showed almost identical results. The results provide evidence that, in adult mice, the brain becomes more sensitive with age to phenytoin with regard to its anticonvulsant effect.

Aging↗
PubMed1982

Biliary excretion of digitoxin and its metabolites in young and old male Wistar rats.

The biliary excretion of digitoxin (Dt3) and its metabolites were compared between young (3-month-old) and old (25-month-old) male Wistar rats after an iv injection of [3H]Dt3 (0.03 mg/100g body weight) for 2 hrs. The 2-hr. total biliary recovery of iv injected radioactivity (percent of the dose) was two times lower in old rats (7.40 +/- 1.36% mean +/- SD) compared with young rats (14.74 +/- 4.10%). This difference was primarily due to the decrease in the excretion of Dt3 metabolites in the bile, while the excretion of the parent drug, Dt3 was 1.3 times higher in old rats. Among various Dt3 metabolites in the bile, digitoxigenin bis-digitoxoside (Dt2), digoxigen bis-digitoxoside (Dg2), and polar (conjugated) metabolites were major components, which all decreased with age. In accord with the decreased excretion of the radioactivity in the bile of old rats, the plasma disappearance of radioactivity was generally slower in old animals compared with young ones, yielding significantly higher plasma levels at different times of observation. Despite the increase in plasma radioactivity, the radioactivity concentration in the liver 2 hrs. after the injection was almost equal between the two age groups. It is suggested that at least in this rat strain and sex the biliary excretion of Dt3 metabolites was markedly age-dependent, presumably due to the decreased capacity of the liver to biotransform Dt3 with age. Furthermore, the lower liver plasma radioactivity ratio in old animals suggested the possibility that the distribution of Dt3 in the liver may also decrease with age.

Aging↗
PubMed1981

The effect of bucolome on the biliary excretion of colchicine in the rat.

The biliary excretion of intravenously administered [14C]-colchicine was compared for 2 hr between control rats and rats treated with bucolome (5-n-butyl-1-cyclohexyl-2,4,6-trioxoperhydropyrimidine, 200 mg/kg, i.p.). In the first 10-min period after colchicine injection, the bile flow rate was 70 percent higher (p less than 0.01) in bucolome treated rats than in control rats. The bile flow rate in bucolome treated rats gradually decreased and 1 hr later, the difference between control and bucolome treated rats was no longer significant (p greater than 0.05). The percent of the administered colchicine dose recovered in the first 2 hr in bucolome treated rats given an i.v. injection of 70 or 700 micrograms/kg colchicine was significantly higher than in control rats. The difference was primarily due to the higher excretion rate in the former group in the first 10-min period. When the biliary radioactivity was examined by thin layer chromatography, it was found that the excretion of free colchicine was significantly increased in bucolome treated rats which accounted for the observed increase in the biliary excretion of radioactivity in bucolome treated rats. It was concluded that bucolome is effective in increasing the biliary excretion of free colchicine.

Animals↗