Paavo Pokk

Neuroprotective action of group I metabotropic glutamate receptor agonists against oxygen-glucose deprivation-induced neuronal death.

The metabotropic glutamate receptor (mGluR) non-selective agonist (1S,3R)-1-aminocycloheptane-trans-1,3-dicarboxylic acid [(1S, 3R)ACPD] and group I selective receptor agonist 3, 5-dihydrophenylglycine (DHPG) effectively attenuated oxygen-glucose deprivation (OGD)-induced death of the cultured cerebellar granule cells. Furthermore, (1S,3R)ACPD (100 microM) reduced the number of apoptotic cells. Antiapoptotic action of (1S,3R)ACPD was prevented by the group I selective antagonist (RS)-1-aminoindan-1, 5-dicarboxylic acid (AIDA, 100 microM) and protein kinase C (PKC) inhibitor bisindolylmaleimide (BMI, 1 microM).

The effects of the nitric oxide synthase inhibitors on the behaviour of small-platform-stressed mice in the plus-maze test

Effects of the nitric oxide synthase (NOS) inhibitors 7-nitroindazole (7-NI), N(G)-nitro-L-arginine (L-NOARG) and N(G)-nitro-L-arginine methyl ester (L-NAME) on the behaviour of control and small-platform (SP)-stressed mice in the plus-maze test were studied. SP stress was induced by placing mice on SPs (3.5 cm diameter) surrounded by water for 24 h. This model contains several factors of stress like rapid eye movement (REM) sleep deprivation, isolation, immobilization and falling into the water. The plus-maze test was carried out with control and SP-stressed mice. SP stress induced an anxiolytic-like effect that was evidenced by increased percentage of time spent on the open arms of the plus-maze. The administration of NOS inhibitors 7-NI (20.0-120.0 mg/kg) and L-NOARG (20.0 and 40.0 mg/kg) induced an anxiolytic effect and the administration of L-NAME (20.0 and 40.0 mg/kg)--an anxiogenic effect in control mice. In SP-stressed mice, the effects of NOS inhibitors were changed. Contrary to control mice, 7-NI at a dose of 20.0 mg/kg induced an anxiogenic effect in SP-stressed mice and other doses of 7-NI, with exception of 80.0 mg/kg, as well as L-NOARG and L-NAME were without any effect. On the basis of these data, we can propose that SP stress induced changes in the function of L-arginine-NOS-NO pathways. It is also proposed that the behavioural effects of NOS inhibitors can be changed in stressed animals.

Trans-Resveratrol Alone and Hydroxystilbenes of Rhubarb (Rheum rhaponticum L.) Root Reduce Liver Damage Induced by Chronic Ethanol Administration : a Comparative Study in Mice

The hepatoprotective effects and pharmacokinetics of trans‐resveratrol and hydroxystilbenes of the garden rhubarb (Rheum rhaponticum L., R. rhaponticum) root ethanol extract were studied.

Small platform stress attenuates the anxiogenic effect of diazepam withdrawal in the plus-maze test

The effect of stress on the behavioural changes caused by diazepam withdrawal was studied in mice. Diazepam (2.5 mg/kg) or vehicle was injected intraperitoneally twice a day for 2 weeks. When the last vehicle or diazepam injection had been administered to the mice, 12 h later, the mice were subjected to small platform stress exposure or left in their home cages. Small platform stress was induced by placing mice on small platforms (3.5 cm diameter) surrounded by water for 24 h. This experimental model contains several factors of stress like rapid eye movement (REM) sleep deprivation, isolation, immobilization and falling into the water. The plus-maze test was carried out with stressed mice as well as with mice not subjected to stress. Small platform stress induced an anxiolytic effect and diazepam withdrawal--an anxiogenic effect in the plus-maze test. Small platform stress also attenuated the anxiogenic effect of diazepam withdrawal. On the basis of this data it was proposed that small platform stress counteracts the anxiogenic effect of diazepam withdrawal in the plus-maze test. It was also proposed that the effect of stress on the signs of benzodiazepine withdrawal depends on the characteristics and duration of stress.

Ro 15-4513 potentiates, instead of antagonizes, ethanol-induced sleep in mice exposed to small platform stress

The effects of ethanol and the benzodiazepine receptor ligand ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5a] [1,4] benzodiazepine-3-carboxylate (Ro 15-4513), were examined in NMRI mice exposed to small platform stress. This model contains several factors of stress, like rapid eye movement (REM) sleep deprivation, isolation, immobilization, falling into water and soaking. In control mice, ethanol exerted an anxiolytic effect in the plus-maze, but did not further enhance the anxiolytic-like effects induced by small platform stress. Ro 15-4513 antagonized ethanol-induced sleep in control animals, but enhanced the hypnotic and lethal actions of ethanol in small platform stressed mice. Small platform stress did not alter the characteristics (KD and Bmax) of [3H]Ro 15-4513 binding to cerebellar membranes. Muscimol-stimulated 36Cl- uptake into brain microsacs was significantly reduced in cortex from small platform stressed animals. Ethanol had no effect on 36Cl- uptake into brain microsacs from cortex or cerebellum. It is proposed that small platform stress alters the activity of the gamma-aminobutyric acid (GABA)A receptor-chloride ionophore complex, causing changes in the interaction between ethanol and Ro 15-4513.

Small platform stress increases exploratory activity of mice in staircase test.

Small platform (SP) stress was induced by placing mice on small platforms (3.5 cm diameter) surrounded by water for 24 h. This model contains several factors of stress like rapid eye movement (REM) sleep deprivation, isolation, immobilization and falling into the water. The staircase test consisted of placing a mouse in an enclosed staircase with 5 steps and recording (1) the number of steps and (2) rearings made during 3 min. SP stress increased the exploratory activity of mice in the staircase test as evidenced by an increase in the number of steps and rearings made In control mice diazepam (0.25 and 0.5 mg/kg) induced an anxiolytic effect in the staircase test as evidenced by a decrease in the number of rearings without changes in the number of steps. In SP stressed mice the anxiolytic effect of diazepam was not seen and the sedative effect as evidenced by a decrease in the number of steps was more pronounced. Buspirone at a dose of 1.0 mg/kg did not have effect on the behaviour of control or SP stressed mice in the staircase test. To study possible diurnal variations the staircase test was carried out at 3 different times of a day (08:00, 14:00, 20:00) with control and SP stressed mice. The exploratory activity of control mice in the staircase test gradually increased from 08:00 to 20:00 as evidenced by an increased number of steps and rearings made. SP stress increased the exploratory activity of mice irrespective of the time of testing. In conclusion, on the basis of these data the authors can propose that SP stress increases the exploratory activity of mice in the staircase test and induces a hyposensitivity of mice to the anxiolytic effect of diazepam. The effect of SP stress on the behaviour of mice in the staircase test is not caused by the disruptance of diurnal rhythms.

Effects of nitric oxide synthase inhibitors 7-NI, L-NAME, and L-NOARG in staircase test.

BACKGROUND The objective of the study was to investigate the effects of the nitric oxide synthase (NOS) inhibitors 7-nitroindazole (7-NI), N(G)-nitro-L-arginine (L-NOARG), and N(G)-nitro-L-arginine methyl ester (L-NAME) on the behavior of mice in the staircase test. METHODS NOS inhibitors 7-NI (20-120 mg/kg), L-NOARG (20 and 40 mg/kg), and L-NAME (20 and 40 mg/kg) were administered intraperitoneally (i.p.) 30 min prior to the staircase test. Staircase test consisted of placing a mouse in an enclosed staircase with five steps and recording the number of rearings made and the number of steps climbed during a 3-min period. RESULTS 7-NI and L-NOARG did not have a significant effect on the behavior of mice in the staircase test. L-NAME caused a decrease in the number of rearings without changes in the number of steps taken. CONCLUSIONS NOS inhibitor L-NAME but not 7-NI or L-NAME induced an anxiolytic effect in the staircase test.

The effects of flumazenil, Ro 15-4513 and β-CCM on the behaviour of control and stressed mice in the staircase test

The effects of flumazenil, Ro 15-4513 and β-CCM in the staircase test were studied in control and small platform (SP) stressed mice. SP stress was induced by placing mice on small platforms (3.5 cm in diameter) surrounded by water for 24 h. This model contains several factors of stress, such as rapid eye movement sleep deprivation, isolation, immobilization and falling into the water. The staircase test consisted of placing a mouse in an enclosed staircase with five steps and recording: (i) the number of rearings and (ii) steps made during 3 min. SP stress increased the exploratory activity of mice in the staircase test as demonstrated by an increase in the number of rearings and steps made. In control mice flumazenil (2.0 and 10.0 mg/kg), Ro 15-4513 (1.0 and 3.0 mg/kg) and β-CCM (1.0 and 2.0 mg/kg) exerted an anxiogenic effect that was demonstrated by an increase in the number of rearings without significant changes in the number of steps. Similar to control mice, flumazenil induced an anxiogenic effect in SP stressed mice as demonstrated by an increase in the number of rearings. However, the sedative effect of flumazenil as demonstrated by a decrease in the number of steps made was more pronounced in SP stressed mice. In the SP stressed mice, the anxiogenic effect of Ro 15-4513 and β-CCM was masked by their strong sedative effect and a decrease in both measures of exploratory activity (number of rearings and number of steps). These data suggest that SP stress induces hypersensitivity to the sedative effect of flumazenil, Ro 15-4513 and β-CCM in the staircase test.

Small platform stress increases [3H]Ro 15-4513 binding in the cerebellum of mice

Abstract— Small platform stress was induced in male BALB/c mice by placing them on small platforms (d = 3.5 cm) surrounded by water for 24 or 72 h. This experimental model contains several factors of stress, like rapid eye movement (REM) sleep deprivation, isolation, immobilization and falling into the water. After 24 h small platform stress exposure latency to sleep was measured after the administration of the benzodiazepine receptor agonist diazepam (1.0 and 2.5 mg/kg, i.p.) and the benzodiazepine receptor inverse agonist Ro 15–4513 (1.0 mg/kg, i.p.). As could be expected, diazepam significantly shortened the latency to sleep. Surprisingly the administration of Ro 15–4513 also shortened the latency to sleep. In addition [3H]Ro 15–4513 binding was measured in the cerebellum of control and small platform stressed mice. Small platform stress for 24 h did not alter the maximal number of [3H]Ro 15–4513 binding sites (Bmax) and decreased their affinity (KD). Small platform stress for 72 h significantly increased the number of [3H]Ro 15–4513 binding sites and decreased their affinity. These effects were due to changes in diazepam‐sensitive binding. In conclusion, it could be supposed that exposure of mice to small platform stress causes changes in the function of the [3H]Ro 15–4513 binding sites, probably a shift of binding sites toward agonist conformation, that leads to changes in the effects of Ro 15–4513.

Litter has an effect on the behavioural changes caused by the administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine and ethanol in mice.

The aim of the work was to study the effects of litter and the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine (L-NOARG) on the behaviour of mice after acute and chronic ethanol administration and withdrawal. Male outbred NIH/S mice, from 21 litters, were distributed among experimental groups and subjected to acute and chronic ethanol administration. After acute or chronic ethanol administration, the effects of L-NOARG on the behaviour of mice in the plus-maze test were studied. Acute ethanol (1 g/kg, i.p.), L-NOARG (20 and 40 mg/kg, i.p.) and their combination induced an anxiolytic effect. Furthermore, the values for the representatives of different litters tended to be either above or below the group mean, irrespective of the drug treatment. Chronic ethanol administration (23 days by inhalation) induced an anxiolytic effect and ethanol withdrawal induced an anxiogenic effect in the plus-maze. The administration of L-NOARG (20 mg/kg, i.p.) induced an anxiolytic effect in control mice and had no effect on ethanol-intoxicated mice, but attenuated the anxiogenic effect of ethanol withdrawal in the plus-maze. However, after chronic ethanol administration and withdrawal, litter had no effect on the behaviour of mice. If the litter is a significant determinant in the behaviour of outbred mice, then the use of information about the litter origin of animals could serve for the purposes of reduction. But only if this information is available from breeders.