Neurochemical actions of vigabatrin and tiagabine alone and in combination in mouse cortex

• 1.1. The effects of repeated administration of the anticonvulsant compounds, vigabatrin (VGB) and tiagabine (TGB), on γ-aminobutyric acid (GABA) concentration and the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD) were investigated in mouse cortex.
• 2.2. VGB alone increased GABA levels and decreased GABA-T and GAD activities.
• 3.3. TGB alone was essentially without effect.
• 4.4. Low doses of VGB and TGB in combination increased GABA levels when neither drug had such an effect alone.
• 5.5. Despite this observation, this study failed to establish any conclusive evidence for an interaction between VGB and TGB that might help to explain their reported clinical synergism.

     

Effects of lithium on rat parotid and submandibulary gland functions

• 1.1. Pure submandibular and parotid saliva were collected intraorally by micro polyethylene canula from anesthetized lithium treated and control rats using pilocarpine as secretagogue.
• 2.2. Acute intraperitoneal injection of a single dose of lithium chloride (10 mg/kg), caused a significant decrease in protein, calcium, potassium and sodium concentrations of parotid saliva and also a significant decrease in protein, potassium and calcium concentrations of submandibular saliva.
• 3.3. Chronic treatment of rats for 10 days by LiCl solution (1200 mg/l) also caused some marked changes in saliva compositions similar to those observed in acute experiment.
• 4.4. The results of this study suggest that lithium as a drug used in the treatment of affective disorders can influence the secretory mechanisms of both submandibular and parotid glands.
• 5.5. These effects of lithium in composition of parotid and submandibular saliva are not related to duration of treatment.

     

Effects of chronic lithium pretreatment on apomorphine-induced penile erection

• 1.1. The effects of chronic lithium pretreatment (600 mg/l in drinking rats, 30 days) on penile erection (PE) induced by apomorphine were investigated in rats. This treatment resulted in a serum Li concentration after 30 days of 0.31 ± 0.01 mmol/l.
• 2.2. Subcutaneous (s.c.) administration of mixed Dl/D2 dopamine receptor agonist apomorphine (0.05–0.5 mg/kg) induced PE in a biphasic manner. The maximum effect was obtained with 0.1 mg/kg of the drug while the response decreased with increasing doses of apomorphine from 0.1 to 0.5 mg/kg.
• 3.3. Pretreatment of animals with 0.0125-0.1 mg/kg of D1 dopamine receptor antagonist SCH 23390 or D2 dopamine receptor antagonist sulpiride (12.5–100 mg/kg) decreased apomorphine-induced PE. Combination of SCH 23390 (0.025 mg/kg) with sulpiride (12.5 mg/kg) caused a stronger inhibitory effect on apomorphine response. This indicates that both D1 and D2 dopamine receptors may be involved in PE induced by apomorphine.
• 4.4. The response induced by apomorphine (0.05-0.5 mg/kg) was decreased in animals pretreated with chronic lithium. The inhibitory effect of sulpiride on apomorphine response, increased in animals pretreated with lithium, in contrast the inhibitory effect of SCH 23390 did not change in this condition. However, a combination of SCH 23390 with sulpiride increased inhibitory effect on apomorphine response in lithium pretreated rats.
• 5.5. It is concluded that chronic lithium inhibits PE induced by dopaminergic mechanism(s).

     

Role of endothelium in the vasodilating effect of progestins and androgens on the rat thoracic aorta

• 1.1. In the rat thoracic aorta, contractions induced by noradrenaline were inhibited by the steroids progesterone, pregnanolone, testosterone and 5α- and 5β-dihydrotestosterone.
• 2.2. Removal of endothelium did not prevent relaxation to the steroids, suggesting that the vasodilating effect of steroids occurred on the smooth muscle cells.
• 3.3. γ-Aminobutyric acid (GABA) did not modify noradrenaline-induced contraction. Thus, the vasodilation elicited by steroids is not apparently mediated by GABA receptors.
• 4.4. On the basis that noradrenaline opens receptor-operated calcium channels to induce contraction, we suggest that relaxation by steroids involves a blockade of this type of channels.

     

CI-966, a GABA uptake inhibitor,antagonizes ischemia-induced neuronal degeneration in the Gerbil

• 1.1. Cerebral ischemia of 5 min duration was induced in unanesthetized gerbils by bilateral occlusion of the carotid arteries.
• 2.2. The extent of cerebral damage was assessed by the elevation of motor activity in comparison with pre-ischemic levels and by a histological assessment of the extent of neuronal degeneration of the CAI area of the hippocampus.
• 3.3. The GABA transport inhibitor CI-966 (10 mg/kg i.p.) was tested for cerebroprotective activity in a gerbil stroke model. CI-966 reduced the extent of stroke injury as assessed by locomotor activity and measurement of hippocampal CAI pyramidal cell injury.
• 4.4. It is proposed that enhancement of extracellular GABA levels during ischemia accounts for the cerebroprotective actions of CI-966.

     

Only some anticonvulsants protect against seizures induced by aminophylline in quinolone-treated genetically epilepsy prone rats

• 1.1. The effects of some anticonvulsant drugs against seizures induced by a combined treatment with aminophylline and quinolone in genetically epilepsy-prone rat have been investigated.
• 2.2. Animals were intraperitoneally pretreated with carbamazepine, diazepam, phenobarbital, CPPene and dizocilpine or saline and 15 min later administered orally with 51.86 μmol/kg b. wt of either cinoxacin or ciprofloxacin. 60 min after quinolones, rats received intraperitoneally aminophylline (100, 120, 140, 160 or 180 mg/kg b. wt).
• 3.3. Ciprofloxacin showed to be more effective than cinoxacin in potentiating the aminophylline convulsant effects.
• 4.4. Neither carbamazepine nor diazepam and phenobarbital, at the lowest dose used, elicited any effect in reducing the aminophylline-induced seizures in both cinoxacin- and ciprofloxacin-treated animals. Whereas, diazepam and phenobarbital when administered i.p. at 2.5 and 60 mg/kg b. wt respectively demonstrated protective properties.
• 5.5. CPPene and dizocilpine, two excitatory amino acid antagonists, were both very effective in antagonizing the seizures produced by concomitant treatment with cinoxacin or ciprofloxacin plus aminophylline.
• 6.6. The present results suggest an involvement of the excitatory amino acid receptors in mediating the seizures induced by the combined treatment with quinolones and aminophylline.

     

Thermoregulatory activity of sodium nitroprusside and arginine vasopressin

• 1.1. Thermal responses to sodium nitroprusside (SNP, 3 mg/kg/hr) and arginine vasopressin (AVP, 3μg/kg) were investigated in normothermic and febrile rabbits (LPS, 1μg/kg) at ambient temperature of 20.0 ±1.0°C. Furthermore, blood pressure after these drugs was tested on a separate group of animals.
• 2.2. I.v. infusion of SNP produced hypothermia and attenuated pyrogen fever. On the other hand, AVP increased body temperature and intensified the febrile response.
• 3.3. Both drugs affected in an opposite way blood pressure, i.e. SNP produced falls and AVP increases in this parameter.
• 4.4. The relationship between the activity of the vascular and thermoregulatory systems in normothermic or febrile state is discussed.

     

Hemodynamic effects of barnidipine hydrochloride in conscious squirrel monkeys

• 1.1. The effects of barnidipine, a new dihydropyridine Ca²⁺ antagonist, on cardiovascular and renin-angiotensin-aldosterone systems were investigated in conscious squirrel monkeys.
• 2.2. Barnidipine (0.3–3 mg/kg p.o.) produced a dose-related decrease in systolic blood pressure. The hypotensive action after 3 mg/kg p.o. lasted more than 8 hr.
• 3.3. Barnidipine increased heart rate, but did not affect the PQ-interval of the electrocardiograph.
• 4.4. Barnidipine (1 and 3 mg/kg p.o.) increased plasma renin activity dose-dependently. However, it had no significant effect on plasma aldosterone concentration.
• 5.5. These results indicate that barnidipine produces a sustained hypotension without affecting atrioventricular conduction time and plasma aldosterone concentration in conscious squirrel monkeys.

     

Propionate regulates lymphocyte proliferation and metabolism

• 1.1. The effect of propionate on lymphocyte proliferation and metabolism was investigated. Lymphocytes obtained from human blood and rat mesenteric lymph nodes were utilized.
• 2.2. Propionate at concentrations of 0.04 and 1.0 mmol/1 stimulated the amount of [³H]thymidine incorporated either in cultured human T lymphocytes or rat T and B lymphocytes.
• 3.3. Concentrations of propionate between 2 and 5 mmol/1 caused a marked inhibition of lymphocyte proliferation.
• 4.4. This short-chain fatty acid was metabolized by these cells and produced succinate in significant amounts; however, its oxidation was low.
• 5.5. Propionate did not alter glucose, glutamine and pyruvate utilization and oxidation in incubated rat lymphocytes but increased the formation of lactate and aspartate.
• 6.6. In contrast, propionate inhibited by 50% the synthesis of lymphocyte lipid from [1-¹⁴C]acetate at concentrations of 0.5 and I mmol/1 and reduced by half the incorporation of ³H₂O into lipids at 1 and 5 mmol/1.
• 7.7. The results suggest that inhibition of lipid synthesis is a possible mechanism leading to reduction of lymphocytes proliferation.

     

Noradrenergic-GABAergic interaction in anterior hypothalamus from normotensive and sinoaortic denervated rats

• 1.1. GABA content is decreased in anterior hypothalamus and medulla oblongata of hypertensive rats by sinoaortic denervation (SAD) when compared to control animals which underwent a sham-operation (sham).
• 2.2. Lesion of noradrenergic pathways by 6-hydroxydopamine (6-OHDA), intracerebroventricularly administered, induced depletion of noradrenergic content in frontal cortex, anterior and posterior hypothalamus in both SAD and sham-operated rats.
• 3.3. As a consequence of this noradrenergic depletion there was an increase of GABA content in anterior hypothalamus only, from sham- and SAD-operated animals, without changes in other areas.
• 4.4. There is a noradrenergic-GABAergic interaction in the anterior hypothalamus of normotensive rats which is not impaired in hypertensive rats by sinoaortic denervation.

     

Protection from acetaminophen-induced liver damage by the synergistic action of low doses of the poly(ADP-ribose) polymerase-inhibitor nicotinamide and the antioxidant N-acetylcysteine or the amino acid l-methionine

• 1.1. An array of therapeutically used analgetic and antirheumatic drugs cause severe liver damage. The present study investigates the hepatoprotective effects of inhibitors of NAD-dependent adenoribosylation reactions and of antioxidants in analgesic-induced hepatic injury.
• 2.2. Male NMRI mice were treated PO with 500 mg/kg of acetaminophen, and the activities of both glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) were determined in serum.
• 3.3. The acetaminophen-induced release of both GOT and GPT from injured liver cells could be inhibited in a dose-dependent manner, when mice were injected additionally either with increasing amounts (from (25 mg/kg to 100 mg/kg IP) of the PARP-inhibitor nicotinamide, with increasing amounts (from 25 mg/kg to 100 mg/kg IP) of the antioxidant N-acetylcysteine, or with increasing amounts (from 50 mg/kg to 300 mg/kg IP) of the amino acid l-methionine.
• 4.4. A combination of both nicotinamide and N-acetylcysteine (at the low dose of 12.5 mg/kg IP each) results in a complete protection from acetaminophen-induced release of GOT and GPT from injured liver cells.
• 5.5. A combination of both L-methionine and N-acetylcysteine or nicotinamide (at the low dose of 12.5 mg/kg IP each) resulted also in complete protection from acetaminophen-induced release of GOT and GPT.

     

The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord

• 1.1. The aim of this review is to consider the relative roles of inhibitory and excitatory amino acid receptor-mediated events in the processes leading to pain transmission in the spinal cord.
• 2.2. Emphasis will be on the roles of the inhibitory and excitatory amino acids, GABA and glutamate, and how the relative balance between activity in these systems appears to determine the level of pain transmission.
• 3.3. The N-methyl-d-aspartate (NMDA) receptor for glutamate has been implicated in the generation and maintenance of central (spinal) states of hypersensitivity. It has been shown that activation of this receptor underlies wind-up, whereby the level of transmission of noxious messages is potentiated. Antagonists at this receptor-channel complex prevent or block enhanced (hyperalgesic) pain states induced by tissue damage, inflammation, nerve damage and ischemia.
• 4.4. Information concerning amplification systems in the spinal cord, such as the NMDA receptor, is a step toward understanding why and how a painful response is not always matched to the stimulus. Such events have parallels with other plastic events such as long-term potentiation (LTP) in the hippocampus.
• 5.5. However, the roles of inhibitory transmitter systems can also change insofar as opioid, adenosine and GABA transmission in the spinal cord can vary in different pain states.
• 6.6. Changes in GABA systems have been well-documented and discussion will center on whether this has clinical implications.
• 7.7. In addition to behavioral and electrophysiological approaches to the pharmacology of pain the current status of the use of markers of early onset genes such as c-fos, as monitors of activity, will be discussed.
• 8.8. Hyperalgesia would appear to be balanced by inhibitions during inflammatory conditions but not in neuropathic states, pains due to nerve damage. In the latter case, events reminiscent of LTP may predominate, whereas they are held in check by inhibitions under conditions of inflammation.

     

Effects of long-term treatment with dicyclic,tricyclic, tetracyclic,and noncyclic antidepressant drugs on monoamine oxidase activity in mouse brain

• 1.1. The individual long-term effects of the antidepressant drugs zimeldine, viloxazine, imipramine, amitriptyline, nortriptyline, maprotiline, or nomifensine, on brain mitochondrial monoamine oxidase (MAO) activity, were studied in mice that were given daily intraperitoneal injections (30 mg/kg) of these reagents for 4 weeks.
• 2.2. Both the A-form (MAO-A) and B-form (MAO-B) of MAO were inhibited after long-term administration of all the drugs except nortriptyline (MAO-A was not affected) and maprotiline (neither MAO-A nor MAO-B were affected).
• 3.3. Kinetic analysis showed a significant decrease in V_max values, and an increase in K_m values for MAO-B during treatment.
• 4.4. All seven drugs are competitive inhibitors of MAO-A, noncompetitive inhibitors of MAO-B, and were more potent in vitro for MAO-B.
• 5.5. MAO-A was inhibited by the following drugs (in ascending order of potency): nortriptyline, amitriptyline, imipramine, maprotiline, zimeldine, nomifensine, and viloxazine.
• 6.6. MAO-B was inhibited by the following drugs (in ascending order of potency): nortriptyline, imipramine, maprotiline, amitriptyline, zimeldine, nomifensine, and viloxazine.

     

The Localization of Endogenous Zinc and the in vitro Effect of Exogenous Zinc on the GABA Immunoreactivity and Formation of Reactive Oxygen Species in the Retina*

• 1.Endogenous zinc is localized mainly in the retinal photoreceptors and retinal pigment epithelial cells in the mammalian retina. No other types of retinal neurons contain large amounts of zinc.
• 2.Low concentrations of exogenous zinc, like the N-methyl-D-aspartate (NMDA) antagonist MK-801, counteract the NMDA-induced changes in the γ-aminobutyric acid (GABA) immunoreactivity in the rabbit retina. However, greater concentrations of zinc exacerbate the effects of NMDA and ischemic-like insults (lack of glucose and oxygen) on GABA immunoreactivity. The data suggest that low concentrations of zinc are neuroprotective, but higher concentrations of zinc have a negative effect.
• 3.When low concentrations of zinc are present during ischemic-like insults to the retina, the GABA immunoreactivity is localized to the Müller cells, suggesting that the metabolism of GABA in the Müller glial cells is prevented.
• 4.Ascorbate/iron-induced generation of reactive oxygen species (ROS) in the retina is prevented by deferoxamine but not by zinc. High concentrations of zinc potentiate the ascorbate/iron induced formation of ROS.

     

Valproic acid differs in its in vitro effect on glutamic acid decarboxylase activity in neonatal and adult rat brain

• 1.1. The in vitro effect of valproic acid (VA) (10⁻⁶ to 10⁻³ M) on glutamic acid decarboxylase (GAD) activity in whole brain and cerebral cortex (CC) of neonates and of adult rats was examined
• 2.2. VA did not induce changes on GAD activity either in CC or in the rest of the brain (RB) of adult animals.
• 3.3. But at 10^-3 M, VA induced an increase in GAD activity in homogenates of noncortical brain areas of neonates; no increments were found in CC of these animals. This latter increase was detected in the membrane-bound fraction of the enzyme and was not due to physicochemical nonspecific changes related to the potential solvent activity of VA at this high concentration.
• 4.4. We may conclude that VA induces changes on GAD activity in neonatal stages of development but not in adult brain. Therefore, although a direct enhancement of GAD activity may play a role in the mechanism of action of VA in pediatric patients, this cannot be verified in the adult population.

     

The effect of short term lithium treatment on the leukocyte,liver and muscle carbohydrate metabolism of guinea-pigs

• 1.1. The effect of lithium treatment on the leukocyte, liver and muscle glycogen levels of guinea-pigs has been studied.
• 2.2. A 4-week treatment with lithium chloride (5 mmol/l i.p. in saline) increased leukocyte, liver and muscle glycogen and decreased blood glucose levels.
• 3.3. These results strongly suggest that a lithium-induced insulin-like effect may be related to the long term effect.

     

Anxiolytic effect of cannabidiol derivatives in the elevated plus-maze

• 1.1. In order to assess the presence of anxiolytic properties in cannabidiol (CBD) derivatives HU-219, HU-252 and HU-261, these drugs were tested in rats submitted to the elevated plus-maze model of anxiety.
• 2.2. Additional groups received diazepam or CBD. HU-219 (0.03-1 mg/kg) and CBD (5 mg/kg) significantly increased the percentage of open arm entries without changing the total number of entries, an anxiolytic-like effect.
• 3.3. Both HU-252 and HU-261 increased the percentage of time spent in open arms and the total number of entries, but only at the dose of 1 mg/kg.
• 4.4. Diazepam (2.5 mg/kg) increased both the percentage of entries and time spent on open arms and the total number of entries.
• 5.5. The results confirm previous findings with CBD and indicate that its derivative HU-219 may possess a similar anxiolytic-like profile.
• 6.6. Results from HU-252 and HU-261 are less apparent and suggest that the compounds may increase general exploratory activity in a limited range of doses.

     

Effect of dimethyl sulfoxide (DMSO) on the electrocardiogram (ECG) in freely moving male Balb/c mice

• 1.1. Since dimethyl sulfoxide (DMSO) is a solvent which is often used for drugs in animal studies, we investigated the effect of a daily administration of DMSO on the telemetrically obtained electrocardiogram (ECG) in freely moving male Balb/c mice.
• 2.2. During treatment with 4.5 ml 100% DMSO/kg i.p. 5 days per week during 3 weeks, DMSO caused substantial cardiotoxicity. The ST-interval increased significantly after 1 week by 2.2 ± 1.3 msec and also the ECG wave form changed completely in time.
• 3.3. During treatment with 4.5 ml 50% DMSO/kg i.p. 5 days per week during 3 weeks, no significant difference was observed compared with the control animals.
• 4.4. During the entire study the maximal heart rate and body weight remained constant in all treated groups.
• 5.5. The data indicate that DMSO can not be used in a 100% concentration to dissolve compounds that are tested for protection against the cardiotoxicity of cytostatics.

     

Antinociceptive effects of clebopride in the mouse

• 1.1. The effects of the substituted benzamide clebopride, an orthopramide, on nociception of chemical and thermal stimuli were investigated.
• 2.2. Clebopride (0.5, 1.0 and 2.0 mg/kg) promoted significant analgesia in the tail-flick and hot-plate tests and against abdominal constrictions produced by acetic acid or acetylcholine.
• 3.3. The analgesic effects of clebopride were not influenced by pretreatment with naltrexone (1-3 mg/kg).
• 4.4. These results suggest that clebopride induces analgesia against both thermal and chemical nociceptive stimuli, which is not mediated via opioid mechanisms.

     

Peculiar effects of isradipine and darodipine on the rat brain dopaminergic system

• 1.1. Darodipine and isradipine are dihydropyridine calcium antagonists which easily cross the blood-brain barrier displaying high affinity and specificity for the brain “L” type voltage-sensitive calcium channel. In rat striatum and fronto-parietal cortex the effects of i.p. administration of these drugs on the dopaminergic system were evaluated.
• 2.2. Both drugs showed neuroleptic-like activity on spontaneous motility at a dose of 5 mg/kg or more.
• 3.3. Isradipine, being almost ineffective in the frontoparietal cortex, affected the striatal DA turnover. On the contrary, darodipine affected the DA turnover of the frontoparietal cortex, being almost ineffective in the striatum.
• 4.4. Both drugs, unlike nimodipine, appeared to display their antidopaminergic effects by enhancing the intraneuronal DA metabolism.
• 5.5. It was concluded that the antidopaminergic properties of isradipine and darodipine are characterized by their regional specificity and a peculiar profile of actions. However, these drugs (as well as nimodipine and other calcium antagonists) show neuroleptic-like effects at doses which should markedly affect the cardiovascular system.