L. Ciesielski

Effect of sodium n-dipropylacetate on audiogenic seizures and brain γ-aminobutyric acid level

A brain γ-aminobutyric acid (GABA) level increase has been observed after n-dipropylacetate (nDPA) treatment. A relation between brain GABA level increase and protection against seizures has been pointed out; in fact, as long as the GABA rate is higher than 1.7 μmoles/g, mice are protected against audiogenic fits. Enzymatic studies have shown that nDPA inhibits competitively GABA-transaminase (GABA-T) in regard to GABA. Dreiding models show that there is a close structural relationship between GABA and nDPA, explaining the competitive inhibition.

Protective effect of adenosine and nicotinamide against audiogenic seizure

Abstract Intraperitoneal injection of adenosine into Swiss albino mice, RB strain, sensitive to audiogenic convulsions, rapidly produces, in proportion to the dose administered: sedation, modification of the EEG, lowering of arterial pressure and protection against audiogenic seizures. Simultaneous injection of adenosine and nicotinamide, produces the most striking protection, the effect being independent of all the others. During the protective period to convulsions, there is an elevation in the energy rich compounds, ATP and phosphocreatine, which is attributable to a reduction in their rate of degradation. During the same period, a diminution in the cerebral level of noradrenaline takes place. The pharmacological effects of adenosine appear to oppose those of its structural analogue, caffeine, with regard to mobility, arterial pressure, basal metabolic rate and body temperature.

Inhibition of mouse killing behavior by serotonin-mimetic drugs: Effects of partial alterations of serotonin neurotransmission

Rats which do not kill mice and which acquire mouse killing behavior after partial lesion of the serotonin neurotransmission, either by p-chlorophenylalanine treatment or by electrolytical lesions of dorsal and median raphe nucleus, were treated by IP injection of serotonin-mimetics. The following drugs were used: 5-methoxy-N-N-dimethyl-tryptamine and 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide, serotonin-agonists, fluoxetine and citalopram, inhibitors of serotonin uptake. All these serotonin-mimetics inhibit mouse killing behavior without apparent secondary effects. When these compounds were tested on killer rats, a stronger antimuricidal effect was observed in rats having altered serotonin neurotransmission. These results support a role for the serotoninergic supersensitivity in a model of aggressive behavior.

Age-dependent changes of brain GABA levels, turnover rates and shock-induced aggressive behavior in inbred strains of mice

Shock-induced aggressive behavior (SIAB) is absent or very weak in C57BL/6 (C57) mice at the age of 12 weeks while it reaches high levels at the age of 20 weeks. This age-dependent increase of aggressive responses is absent in DBA/2 (DBA) mice. Aggressive C57 mice (20 week old) are characterized by lower GABA levels in amygdala, striatum and substantia nigra than both non-aggressive C57 (12 week old) and DBA mice (12-20 week old). Concerning turnover rate, C57 mice at the age of 20 weeks show lower turnover rate values in cerebellum and raphe and higher values in septum in comparison with 12 week old mice of the same strain. These results are discussed in terms of the role of GABA function in brain areas which are involved in the control of emotionality and aggressive behavior.

Influence of castration and brain GABA levels in three strains of mice on aggression towards lactating intruders

This study examined the relationship among aggression towards lactating intruders, castration and brain GABA levels in three strains of mice (C57, C3H and CBA). Both C57 and C3H (but not CBA) animals showed reduced attack latencies following castration. C57 mice showed the highest intensity of this behavior and the response was almost absent in the CBA strain. Considerable strain differences in brain GABA levels were observed. In particular the most aggressive C57 castrates had significantly higher levels of GABA in the hypothalamus, the olfactory bulbs and the amygdala. Such changes are not recorded in C3H or CBA strains of mice, which are both characterized by low levels of baseline aggression towards lactating intruders.

Sodium valproate: kinetic profile and effects on GABA levels in various brain areas of the rat.

1. The kinetic profile of sodium valproate (VPA) and the GABA levels were studied in discrete brain areas of the rat after an i.p. injection of 200 mg/kg. The results were discussed comparatively with GABA-T and GAD activities reported in the literature. 2. VPA was rapidly distributed in brain areas; its concentrations, its kinetic parameters and the GABA levels after the drug administration were not uniform in the different brain areas studied. 3. The results showed a particular relation of the VPA to the olfactory bulbs; in this specific area the VPA effect on GABA level was stronger; the VPA apparent half life of elimination was longest; the VPA apparent disappearance rate constant was smallest; the initial GABA level was higher; the activities of GABA-T and GAD were higher than in other brain areas studied except the hypothalamus. 4. These data were correlated with the role of the olfactory bulbs in the behaviour of the rodents.

Purification and properties of rat brain succinic semialdehyde dehydrogenase.

Succinic semialdehyde dehydrogenase from rat brain has been purified to electrophoretic homogeneity. It has a molecular weight of about 140, 000 and is composed of two apparently identical subunits. The reaction catalized by the pure protein is entirely dependent on endogenous --SH groups. The Kim (limits) for NAD and succinic semialdehyde are 2 X 10(-5) M and 1 X 10(-4) M respectively at the optimum pH of 8.6. Inhibition studies show that the reaction mechanism is a compulsory ordered on where NAD binds first followed by succinic semialdehyde.

Purification and partial characterisation of 4-aminobutyrate 2-ketoglutarate transaminase from human brain

A parallelism has been shown between the anticonvulsive effect and an increase in the cerebral GABA level after in vivo administration of some branched chain fatty acids such as n-dipropylacetate [ 1,2] . It has also been shown that these compounds improve conditioned behaviour [3] . It was later demonstrated that these compounds are competitive inhibitors of rat and mouse cerebal GABA-T**, thus probably explaining these effects [4]. This has stimulated interest in the search for non toxic compounds, slowly metabolised by the body, yet being powerful inhibitors of cerebral GABA-T. In order to test these compounds with human therapy in mind, it seemed pertinent to use GABA-T from human brain. We thus proceeded to purify this enzyme guided by the methods we employed for purification of GABA-T from rat brain [ 51. This human GABA-T preparation will also enable a comparison to be made with brain GABA-T from other species, in particular that of the mouse [6] and that of the rat [5] .

Effects of the potentiation of the GABAergic neurotransmission in the olfactory bulbs on mouse-killing behavior

Intra olfactory bulb administration of three classes of GABA-mimetics (GABAa agonists, inhibitors of reuptake, inhibitors of GABA degradation) clearly inhibit mouse-killing behavior, without sedation. A linear correlation is observed between GABA levels increase in the olfactory bulbs and muricidal inhibition following local injection of valproic acid and gamma-vinyl GABA, two GABA-T inhibitors; the differences observed between these two compounds may be due to the differences in their mechanism of action on GABA-T activity and to the different pool of GABA on which they act. No diffusion to extra bulbar sites were observed after local administration of gamma-vinyl GABA. This evidence suggests an inhibitory role of GABA from olfactory bulbs in the modulation of mouse-killing behavior.

Age-associated changes of rat brain neuronal and astroglial poly(ADP-ribose) polymerase activity.

Abstract: Nuclear poly(ADP‐ribose) polymerase levels as well as the DNA strand break levels of whole‐brain neuronal and astroglial cells were investigated. Three‐ and 30‐month‐old rats were used. Low‐molecular‐weight neurofilaments and glutamine synthetase served as neuronal and astroglial markers, respectively. A large increase in the poly(ADP‐ribose) polymerase activity was observed in the neurons (threefold) and astrocytes (3.7‐fold) derived from 30‐month‐old rats. Similarly, the amount of poly(ADP‐ribose) polymerase, evaluated per milligram of DNA, increased ∼3.5‐fold in neurons and 3.9‐fold in astrocytes prepared from 30‐month‐old rats. Whether the increase in the poly(ADP‐ribose) polymerase activity was due to an enhanced rate of DNA strand break was investigated by determining the rate of DNA unwinding. A significant increase in DNA unwinding rate was detected in the neurons (2.7‐fold), although a lower increase was observed in the astroglia (1.3‐fold) of aged animals.