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.     

The anticonvulsant effect of citalopram on El mice,and the levels of tryptophan and tyrosine and their metabolites in the brain

Serotonin (5-HT) plays an important role in the seizures of El mice since the seizure threshold of El mice correlates with the 5-HT concentration in the central nervous system. In this study, the anticonvulsant effect of a 5-HT reuptake blocker, citalopram, was evaluated behaviorally and biochemically. El mouse convulsions were inhibited by oral administration of citalopram for 2 weeks. Citalopram increased tryptophan and tyrosine amounts, and decreased the 5-HT, 5-hydroxy-indoleacetic acid, kynurenine, and dopamine amounts in the brain. These findings show that citalopram depresses monoaminergic metabolism. Given the known convulsant effect of kynurenine, it is suggested that its decrease by citalopram may involve attenuation of El mice seizures.     

Enhancing effect of phenobarbital sodium on Tyzzer's disease in mice

Tyzzer's disease in mice was aggravated by phenobarbital sodium (PB) given consecutively after bacterial inoculation. In PB-treated mice, mortality rate and severity of liver lesions were higher with more prominent bacterial propagation in hepatocytes as compared with non-treated ones, suggesting that PB had an enhancing effect on metabolic activities of host hepatocytes resulting in increased intracellular growth of bacteria.     

Possible mechanism of anticonvulsant effect of ketamine in mice

The study was designed to investigate the effect of ketamine on convulsive behaviour using maximal electroshock (MES) test. An attempt was also made to study the possible receptor mechanisms involved. MES seizures were induced in mice via transauricular electrodes (60 mA, 0.2sec). Seizure severity was assessed by the duration of tonic hindlimb extensor phase and mortality due to convulsions. Intraperitoneal administration of ketamine produced a dose-dependent (5-50 mg/kg) protection against hindlimb extensor phase. The anticonvulsant effect of ketamine was antagonized neither by naloxone (low as well as high doses) nor sulpiride, but was attenuated by haloperidol, a dopamine (D2)/sigma receptor antagonist. Co-administration of gamma-aminobutyric acid (GABA)-ergic drugs (GABA, muscimol, diazepam and baclofen) and N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801) with ketamine facilitated the anticonvulsant action of the latter drug. In contrast, flumazenil, a benzodiazepine (BZD)-GABAA receptor antagonist, reversed the facilitatory effect of diazepam on the anti-MES effect of ketamine. Similarly, delta-aminovaleric acid (DAVA), antagonized the facilitatory effect of baclofen on anti-MES action of ketamine. These BZD-GABAergic antagonists, flumazenil or DAVA per se also attenuated the anti-MES effect of ketamine given alone. The results suggest that besides its known antagonistic effect on NMDA channel, other neurotransmitter systems i.e. sigma, GABAA-BZD-chloride channel complex and GABAB receptors may also be involved in the anti-MES action of ketamine.     

Effect of phenobarbital on in vitro aromatization of testosterone to estradiol by adult male mice brain

Adult male mice were given phenobarbital (PB) through their food containing 3.5 g/kg for 5 consecutive days. On days 3 and 5 of treatment and 5 days following termination of PB treatment the animals were sacrificed and the in vitro conversion of (1,2-3H)-testosterone to estradiol in the brains was measured. During PB treatment brain aromatization of testosterone was reduced by approximately 50% as compared to the untreated group. Five days after termination of PB administration, brain aromatase activity was as in the control group. Direct addition of PB to brain homogenates (200 micrograms/ml) reduced the conversion of testosterone to estradiol by approximately 30%. These results demonstrate that PB can act directly upon brain tissue to inhibit aromatase activity. It is assumed that this effect of PB is one of the mechanisms by which this drug inhibits testosterone action.     

The effect of recipient age on the success of embryo transfer in mice

Eight-hundred-sixteen morulae and blastocysts were transferred to the uteri of 102 recipients of various ages on Day 3 or 4 of pseudopregnancy (Day 1 is the day of the vaginal plug). Day 3 recipients had significantly higher pregnancy rates and embryo survival rates than Day 4 recipients. Recipient age had little effect on pregnancy rates, but had a significant effect on embryo survival in Day 3 recipients. Day 3 recipients of 11-13 weeks of age had the highest pregnancy rate (100%) and embryo survival (75%). The results suggest that recipient age should be considered an important factor in embryo transfer experiments.     

Neuropeptide thyroliberin--an endogenous anticonvulsant in the brain

Thyroliberin (TRH) promoting endogenous antidepressive effect is the most general regulator of the central mechanisms and visceral functions (especially respiration). Our group pioneered in applying the anticonvulsant action of TRH after local intranasal application. This application TRH in ultra-low doses contrast the method of systemic TRH administration (i.v., i.m. or oral in the large doses--mg). In our experiments intranasal application of 10(-9) M, 10(-10) M and 10(-12) M TRH significantly inhibited the severe epileptic motor fits in rats induced by pentylenetetrazole (PTZ). Beneficent effect of TRH is also confirmed by EEG (TRH suppressed SWD in cortex, amygdala and hippocamp). In the experiment that follows compared effects of TRH (pyroGlu-His-Pro-NH2) and its metabolite dipeptide cHis-Pro-NH2 (10(-10) M, 10(-5) M). The experiments make more precise that only TRH but not His-Pro posses the anticonvulsant properties. There is a good believe that medical potentialities of TRH have not been exhausted and its new possibilities of its usage will be revealed in epileptology.     

Diurnal variation in the dopamine level of rat brain areas: effect of sodium phenobarbital

The levels of dopamine in the caudate nucleus, cerebellum, cortex and midbrain were determined every three hours in control rats nd in rats pretreated with sodium phenobarbital over a twenty-four hour period. All animals were adapted for a minimum period of three weeks to an environmental room equipped with a programmed 12 hour dark — 12 hour light illumination cycle. The level of dopamine was highest during the dark phase and lowest during the light phase of the photoperiod in all the brain areas studied. Sodium phenobarbital pretreatment increased dopamine level in all the brain areas studied at most times, particularly during the dark phase and enhanced the circadian rhythmicity of dopamine levels in the cortex, cerebellum and midbrain.     

The effect of age on lung structure in male BALB/cNNia inbred mice

Morphometric examination using light, scanning electron, and transmission electron microscopy was performed on the lungs from 32 inbred male BALB/ cNNia mice between 38 days and 28 months of age. Between 38 days and 9 months of age the changes were primarily those of growth. Alveolar multiplication and total elastic-fiber length appeared complete by 38 days of age. The major increase in the number of interalveolar pores occurred by 68 days, but there was a significant further increase from 68 days to 9 months of age. At 9 months, approximately 10% of the alveolar wall was formed by pores. Alveolar ducts, the cylindrical core of air central to alveolar mouths, increased more in diameter than length. Between 9 and 28 months the changes were attributed to aging and were different from those reported in humans and other species. Lung volume, alveolar surface area, and total volume of alveolar wall increased with age; there was no change in mean linear intercept and volume proportion of alveolar and alveolar duct air. Total area of pores increased with age, but their number and area fraction of the alveolar wall did not change. No transmission electron microscopic changes were seen in the alveolar walls. We speculate that the morphometric differences between our animals and those studied in other reports may reflect the fact that our animals were specific-pathogen-free animals and kept under protected circumstances.