Attenuation of the behavioural effects of ethanol in mice by des-enkephalin-gamma-endorphin (ORG 5878).

This study shows inhibition of the increase in locomotor activity induced by ethanol (2 g/kg i.p.) in mice by a low dose (0.1 mg/kg i.p.) of the non-opioid beta-endorphin fragment ORG 5878 (des-enkephalin-gamma-endorphin). ORG 5878 (0.1 mg/kg i.p.) also significantly antagonised the large increase in electroshock seizure threshold produced by ethanol (1.5 g/kg i.p.). In contrast, the hypothermia induced by ethanol (2 g/kg i.p.) was not altered by ORG 5878 (0.1 mg/kg i.p.). The effects of ORG 5878 showed an abnormal dose-response relationship, in that a high dose (1 mg/kg i.p.) did not significantly suppress any of the behavioural effects of ethanol examined although there was some indication that it attenuated the stimulant action of ethanol. ORG 5878 (0.1, 1 mg/kg i.p.) did not have any intrinsic effects on locomotion, seizure threshold or body temperature in mice. These results are the first demonstration that ORG 5878 may act as an ethanol antagonist in some paradigms.     

Effect of digoxin on experimental adrenaline-induced hyperglycemia and insulin-induced hypoglycemia.

The effect of digoxin (0.035 mg/kg b.w., i.v.) on adrenaline-induced hyperglycemia (adrenaline: 50 micrograms/kg b.w., s.c.) and on insulin-induced hypoglycemia (insulin: 0.4 mU/kg b.w., s.c.) was studied in experiments on rabbits. Digoxin intensified the adrenaline-induced hyperglycemia at the 30th and 60th minutes of application. The hyperglycemia in this case subsided more rapidly. Digoxin alone caused on elevation of the blood sugar levels that was most pronounced at the 30th minute of introduction. These elevated levels fell to the initial value by the 180th minute. The blood sugar levels in the rabbits treated with physiological solution rose slightly. This was most noticeable at the 120th minute. Digoxin attenuated the insulin-induced hypoglycemia significantly at the 120th, 150th, and 180th minutes (p < 0.05). We suggest that the increase of the adrenaline-induced hyperglycemia and the attenuation of the insulin-induced hypoglycemia could be linked to the release of catecholamines in the acute stage of the action of Digitalis glycosides.     

Metadoxine (pyrrolidone carboxylate of pyridoxine) antagonizes the locomotor-stimulatory effect of ethanol in mice.

The effects of metadoxine (pyrrolidone-carboxylic acid; PCA) and pyridoxine on the locomotor responses to ethanol in mice were compared. Metadoxine (200 and 400 mg/kg i.p.) and PCA (86 and 172 mg/kg) prevented, in a dose-related manner, the locomotor stimulant effect of a low dose of ethanol (1.5 g/kg i.p.), whereas pyridoxine (228 mg/kg i.p.) was completely ineffective. Neither compound modified the sedative effect of a high ethanol dose (2.5 g/kg i.p.). The results indicate that the antagonistic effect of metadoxine on ethanol stimulant response is due to the PCA component of the molecule.     

Amelioration by BAL (2,3-dimercapto-1-propanol) and DMPS (sodium 2,3-dimercapto-1-propanesulfonic acid) of arsenite developmental toxicity in mice.

Inorganic arsenic is embryotoxic and teratogenic in chicks, golden hamsters, mice, and rats. Certain dithiol chelators have been reported to protect against arsenite-induced lethality and to decrease arsenic body burden. The present study evaluated the influence of BAL (2,3-dimercapto-1-propanol) and DMPS (sodium 2,3-dimercapto-1-propanesulfonic acid), a water-soluble analogue of BAL, on arsenic-induced embryotoxic and teratogenic effects in the mouse. A series of four BAL or DMPS injections was administered sc to pregnant mice immediately after a single ip injection of 12 mg/kg of sodium arsenite given on Day 9 of gestation and at 24, 48, and 72 hr thereafter. Controls received sc corn oil with or without arsenite. Amelioration by BAL and DMPS of arsenite developmental toxicity was assessed at 15, 30, and 60 mg/kg/day, and 75, 150, and 300 mg/kg/day, respectively. BAL given following arsenite was not able to ameliorate the developmentally toxic effects of arsenite seen in mice, whereas treatment with DMPS at 150 and 300 mg/kg showed significant protective effects against arsenite embryotoxicity and teratogenicity. DMPS administration at 300 mg/kg also protected the dams against arsenite-induced maternal toxicity.     

Pharmaco-EEG-based assessment of interaction between ethanol and levetiracetam.

Recent research suggests a potential role for a new generation of anticonvulsant drugs, including levetiracetam, in the treatment of alcohol dependence. Some elements of the central mechanism of action that levetiracetam has in common with ethanol, give rise to the question of whether there is an interaction between these two agents and whether there is any risk associated with the enhanced depressive effect of these agents on the central nervous system. In this study, we have used a pharmaco-electroencephalographic (EEG) method to examine the interaction of ethanol with levetiracetam. The influence of levetiracetam on the effect of ethanol on EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex) was determined. Levetiracetam was administered p.o. as a single dose (50mg/kg or 200mg/kg) or repeatedly at a dose of 100mg/kg/day for 14 days. Ethanol was injected i.v. at a dose of 0.8 g/kg 60 min after the administration of levetiracetam. Ethanol caused an increase in the low frequencies (0.5-4 Hz) in the recording, as well as a marked decrease in the higher frequencies (13-30 Hz and 30-45 Hz). Changes in the EEG recordings after levetiracetam alone were more significant when the drug was given in repeated doses. Combined administration of ethanol and levetiracetam (200mg/kg) resulted in a markedly synergistic effect in the frontal cortex and the midbrain reticular formation. The drug decreases the sensitivity of the hippocampus to ethanol, an observation that may be important in the treatment of alcohol addiction.     

Enhancement of Ketone Supplements-Evoked Effect on Absence Epileptic Activity by Co-Administration of Uridine in Wistar Albino Glaxo Rijswijk Rats

Both uridine and exogenous ketone supplements decreased the number of spike-wave discharges (SWDs) in a rat model of human absence epilepsy Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. It has been suggested that alleviating influence of both uridine and ketone supplements on absence epileptic activity may be modulated by A₁ type adenosine receptors (A₁Rs). The first aim was to determine whether intraperitoneal (i.p.) administration of a specific A₁R antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 0.2 mg/kg) and a selective adenosine A_2A receptor antagonist (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine) (SCH 58261; 0.5 mg/kg) have a modulatory influence on i.p. 1000 mg/kg uridine-evoked effects on SWD number in WAG/Rij rats. The second aim was to assess efficacy of a sub-effective dose of uridine (i.p. 250 mg/kg) combined with beta-hydroxybutyrate salt + medium chain triglyceride (KSMCT; 2.5 g/kg, gavage) on absence epilepsy. DPCPX completely abolished the i.p. 1000 mg/kg uridine-evoked alleviating effect on SWD number whereas SCH 58261 was ineffective, confirming the A₁R mechanism. Moreover, the sub-effective dose of uridine markedly enhanced the effect of KSMCT (2.5 g/kg, gavage) on absence epileptic activity. These results demonstrate the anti-epilepsy benefits of co-administrating uridine and exogenous ketone supplements as a means to treat absence epilepsy.     

河豚毒素对小鼠和家兔的毒性研究

为研究抗河豚毒素 (TTX)的实验疫苗。测得昆明小鼠经ip ,sc ,ig三种TTX中毒途径的LD50 分别为 1 0 7、1 2 5、532 μg kg ;LD99分别为 1 2 5、1 4 6、62 2 μg kg。毒性反应具性别差异 ,♂性比♀性更敏感 ;无明显蓄积毒性。报告了大耳白家兔经im、ivTTX中毒毒性 ,最小致死剂量 (MLD)分别为 5 3、3 1 μg kg ;全死剂量(LD)分别为 5 8、3 8μg kg。描述了两种动物及各种途径中毒的症状特征。小鼠毒性剂量反应关系曲线均非常陡峭 ,家兔的MLD与LD非常接近 ,提示在致死量中毒时免疫抗毒较易实现 ,而在高倍致死量时要困难得多。TTX经口服中毒死亡潜伏期长 ,中毒者具备急救的有利时机     

Evaluation of the protective activity of 2,3-dimercaptopropanol and sodium 2,3-dimercaptopropane-1-sulfonate on methylmercury-induced developmental toxicity in mice

The embryotoxic and teratogenic effects of methylmercury in experimental animals have been established by several investigators. The protective activity of 2,3-dimercaptopropanol (BAL) and sodium 2,3-dimercaptopropane-1-sulfonate (DMPS, a chelator used in the treatment of inorganic and organic mercury) on methylmercury chloride (MMC)-induced maternal and developmental toxicity in mice has been evaluated in the present study. BAL and DMPS were administered subcutaneously or by gavage to pregnant mice immediately after a single oral administration of 30 mg MMC/kg given on day 10 of gestation and at 24, 48, and 72 h thereafter. Amelioration by BAL and DMPS of MMC embryo/fetotoxicity was assessed at 15, 30, and 60 mg/kg/day and at 90, 180, and 350 mg/kg/day, respectively. Treatment with BAL did not ameliorate the maternal toxicity or the developmental toxicity of MMC observed in the mouse. In contrast, DMPS at 90, 180, and 360 mg/kg/day significantly reduced the maternal lethality of MMC, whereas treatment with 180 and 360 mg DMPS/kg/day showed significant protective activity against MMC-induced embryotoxicity and teratogenicity. Based on the present findings, DMPS might be a useful chelator against the maternal and developmental toxicity induced by methylmercury.     

Antidepressant-like activity of n-hexane extract of nutmeg (Myristica fragrans) seeds in mice

The present study was undertaken to investigate the effect of an n-hexane extract of Myristica fragrans seeds on depression in mice by using the forced swim test (FST) and the tail suspension test (TST). M. fragrans extract (5, 10, and 20 mg/kg) was administered orally for 3 successive days to different groups of Swiss male young albino mice. M. fragrans extract significantly decreased immobility periods of mice in both the FST and the TST. The 10 mg/kg dose was found to be most potent, as indicated by the greatest decrease in the immobility period compared with the control. Furthermore, this dose of the extract was found to have comparable potency to imipramine (15 mg/kg i.p.) and fluoxetine (20 mg/kg i.p.). The extract did not have a significant effect on locomotor activity of mice. Prazosin (62.5 microg/kg i.p.; an alpha (1)-adrenoceptor antagonist), sulpiride (50 mg/kg i.p.; a selective D(2) receptor antagonist), and p-chlorophenylalanine (100 mg/kg i.p.; an inhibitor of serotonin synthesis) significantly attenuated the M. fragrans extract-induced antidepressant-like effect in the TST. Thus, extract of M. fragrans elicited a significant antidepressant-like effect in mice, when assessed in both the TST and the FST. The antidepressant-like effect of the extract seems to be mediated by interaction with the adrenergic, dopaminergic, and serotonergic systems.     

Effect of propranolol on brain electrical activity during hyperbaric oxygenation in the rat

The effect of 1, 2, and 5 mg/kg propranolol on the neuroelectrophysiological manifestations of CNS oxygen toxicity was studied in conscious rats. Cortical electrodes for electrocorticographic (ECoG) recording and femoral venous cannula for i.v. infusion were implanted 7 and 3 d, respectively, before the experiment. The rats were divided into 5 groups. Groups I to III were treated with 1, 2, and 5 mg/kg propranolol, respectively, and Group IV with saline. Groups I-IV were exposed to 5 ATA O2 until the appearance of the first cortical paroxysmal electrical discharges (FED), considered to be a preconvulsive electrophysiological manifestation of CNS oxygen toxicity. Rats in Group V were exposed to 5 ATA N2-O2 normoxia and treated with 5 mg/kg propranolol. After the hyperbaric exposures and the i.v. administration of propranolol a typical ECoG pattern consisting of frequent bursts of high amplitude spindle-like waves of 6-7 c/s activity was observed. In hyperbaric oxygen-exposed rats, the paroxysmal electrical discharges were always preceded by the propranolol-induced spindle wave activity (in theta range) and oxygen-induced slow wave activity (in delta range) in ECoG. Infusion of 2 and 5 mg/kg propranolol significantly delayed the time of onset of the oxygen-induced slow wave activity and the FED. It is suggested that the protective effect of propranolol against the neurological manifestations of oxygen toxicity, may be related to its multiple effects on physiological systems rather than beta adrenergic blocking action alone.