Influence of phenobarbital on ECoG phenomena induced by metrazol in rats during ontogenesis.

Effect of phenobarbital (PhB, 20 and/or 40 mg/kg) on epileptic ECoG phenomena induced by metrazol was studied in acute experiments in rats aged 7, 12, 18, 25 and 90 days. Fractionated administration of metrazol (20 mg/kg i.p. each 300 s) was used to quantify the effects of PhB. First signs of metrazol action (sharp elements and/or rhythmic metrazol activity) were not reliably influenced by PhB. On the contrary, the latency of the first EEG seizures as well as of the first generalized EEG seizures was prolonged and thus a dose necessary for their elicitation was increased in all age groups. These differences reached statistical significance in 12-, 18- and 25-day-old rats. A lack of effect of PhB against the rhythmic metrazol activity supports the adequacy of this activity as a model of human absences. Differences between the development of antiepileptic and hypnotic effects of PhB (described earlier) suggest two different mechanisms of action.     

Influence of ethosuximide and dipropylacetate on metrazol-induced electrocorticographic changes during ontogenesis in rats

Influence of ethosuximide (ESI, 125 mg/kg i.p.) and dipropylacetate (DPA, 300 mg/kg i.p.) pretreatment on electrocorticographic changes induced by pentamethylenetetrazole (PTZ, 20 mg/kg dose every 5 min) was studied in rats aged 7, 12, 18 and 90 days. PTZ alone induced isolated spikes and/or sharp waves as the first sign of its action in all age groups except in adult animals where rhythmic theta activity was elicited. The antiepileptic effect of DPA was observed in 12- and 18-day-old rats, ESI specifically inhibited rhythmic activity in adult rats. ECoG seizures induced by high doses of PTZ were inhibited by DPA in all age groups, ESI tended to be effective in adult rats only. DPA did not change the pattern of ECoG seizures, whereas ESI led to replacement of the spike-and-wave rhythm by serrated waves in adult animals. The low ability of immature brain to generalize ictal activity was further diminished by ESI.     

Rhythmic metrazol activity in rats as a model of human absences

Rhythmic activity of the spike-and-wave type was induced by administration of metrazol (25 or 50 mg/kg s.c.) in male rats with implanted cortical electrodes. The animals were deprived of water and then allowed to lick water from a tube. Under control conditions they licked for 3-4 min without an interruption. Rhythmic metrazol activity deranged the licking; when this pathologic activity represented about one third of the time, the licking was fully blocked. We conclude that the impairment of highly motivated behaviour confirms the adequacy of the rhythmic metrazol activity as a model of human primary generalized seizures of the absence type.     

Effect of propranolol on glycerol induced acute renal failure in rats

The effect produced by propranolol, administered for a prolonged period of time and in large doses, on renal function in rats has been studied, as well as the modifications induced by this treatment in an experimental model of acute renal failure, and the effects of a single dose of propranolol given 1 hour before provoking failure. Propranolol, administered chronically, causes sodium and water retention and increases creatinine clearance. Acute renal failure induced by glycerol in rats treated for 7 days with propranolol is less severe than the one produced in untreated animals. In this ARF model, a single dose of propranolol does not seem to have a protective effect.     

Influence of imidazole on behavioral effects induced by dopaminergic agonists in rats

Imidazole (IMI) (from 18.7 to 300 mg/Kg) i.p. injected in adult rats induced shaking, which was antagonized by both morphine (MOR) and haloperidol (HALO) but not by methysergide (MET). I.p. IMI pretreatment inhibited the penile erections (PE) and stretching and yawning (SY) typically elicited by N-n-propylnorapomorphine (NPA), a well-known CNS dopamine (DA) receptor stimulant, injected either i.p. or i.c.v., whereas it enhanced stereotyped behavior (SB). IMI had similar effects on the same parameters considered when injected before lisuride, an ergot derivative also active as a central DA receptor agonist. In this case not only SB but also and above all aggressiveness were markedly potentiated, both the signs appearing at doses of lisuride which were "per se" ineffective. Aggressiveness, like SB, was not sex linked and was antagonized by HALO and MOR, but not by MET. IMI alone potentiated the fighting induced by electrical shock, an effect which was abolished by HALO pretreatment. Considering the results obtained as a whole it is submitted that IMI antagonizes PE and SY through a selective blockade of a class of DA receptors, presumably DA presynaptic autoinhibitors, thus potentiating SB and aggressiveness, which involve stimulation of DA postsynaptic receptors.     

Influence of resveratrol on liver fibrosis induced by dimethylnitrosamine in male rats

Liver fibrosis is a significant health problem which represents the liver’s scarring process and response to injury through deposition of collagen and extracellular matrix, and ultimately leads to cirrhosis. Resveratrol is a naturally occurring phytoalexin found predominantly in grapes. This study aimed to investigate the antifibrotic role of resveratrol on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Rats were divided into four groups and treated for three weeks; control, resveratrol administered orally (20 mg/kg daily), DMN intraperitoneally injected (10 mg/kg 3 days/week), and the last group was pre-treated daily with resveratrol then injected with DMN, 3 days/week. DMN administration induced severe liver pathological alterations. However, oral administration of resveratrol before DMN significantly prevented the induced loss in body weight, as well as the increase in liver weight which arise from DMN administration. Resveratrol has also inhibited the elevation of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin levels. Furthermore, resveratrol significantly increased hepatic reduced glutathione (GSH) levels and reduced the levels of malondialdehyde (MDA) due to its antioxidants effect as well as increased serum protein levels. In addition, DMN induced elevation in hydroxyproline content. On the other hand, hydroxyproline level was significantly reduced in the resveratrol pretreated rats. Resveratrol has also remarkably maintained the normal liver lobular architecture. Moreover, resveratrol had displayed potent potentials to prevent collagen deposition, lymphocytic infiltration, necrosis, steatosis, vascular damage, blood hypertention, cholangiocyte proliferation. It can be concluded that resveratrol has a marked protective role on DMN-induced liver fibrosis in rats, and can be considered as antiproliferative, antihypertensive, as well as antifibrotic agent and may be used to block the development of liver fibrosis.     

Effect of GABAmimetics on electrocorticographic spike discharges induced by guanidinoethanesulfonic acid (amidino-taurine) in the rat

The effect of guanidinoethanesulfonic acid (GES) on rat electrocorticograms (ECoG) and the effects of -aminobutyric acid (GABA) and GABA-agonists on the ECoG changes induced by GES were studied. Sporadic spike discharges began 2–5 min after 1 mol GES/10 l on filter paper was applied to the pia mater of the left sensorimotor cortex; spike discharges extended to the opposite cerebral hemisphere 60 min after the onset of the ipsilateral spike discharges. The spike discharges with a frequency of 5–10 spikes/min lasted until the end of the 4 hour recording. The induced spike discharges were suppressed when the original GES soaked filter paper was replaced by one containing GES (1 mol) supplement combined with taurine (1 mol/10 l). GABA (1 mol) and its receptor agonist, muscimol (10nmol) and (3R)-(–)-4-amino-3-hydroxybutyric acid (1 mol) also suppressed the GES-induced spike discharges when applied topically. Diazepam (DZP) (10 mg/kg) suppressed the GES-induced spike discharges 10 min after i.p. injection, but phenobarbital (20 mg/kg) increased the frequency and voltage of spike discharges 100 min following subcutaneous administration. Intraperitoneal injection of either valproate (200 mg/kg) or phenytoin (25 mg/kg), after the completion of the spike discharges, showed no effect. These findings suggest that neurotransmission or neuromodulatory effects of taurine participate in GES-induced seizure activity, and that GABA_A and DZP receptors may play a role in the mechanism that suppresses GES-induced seizures.     

The temporal dimensions of anticonvulsant action of some newer benzodiazepines against metrazol induced seizures in mice and rats

In a time-distribution study, the anticonvulsant effects of four benzodiazepine compounds were compared with those of three standard antiepileptics against metrazol-induced seizures in mice and rats. Ethosuximide and trimethadione had the shortest duration of action in mice, but protected the rats up to 6 hr. Phenobarbitone, diazepam, flurazepam and nitrazepam protected the mice up to 12 hr, but the rats were effectively protected only up to 3-4 hr. Clonazepam, the most potent and effective agent, protected the mice from clonic-tonic seizures up to 18-20 hr and the rats up to 6-7 hr. Comparison of the PD50 from clonic seizure at the peak-effect hours revealed that the benzodiazepines were 16 to 96 times more potent than phenobarbitone on a molar basis, while phenobarbitone itself was 12 to 26 times more potent than ethosuximide and trimethadione. Tonic seizures and mortality were largely suppressed by all drugs until 18-20 hr in mice and 6-7 hr in rats. Seizure latency and mortality patterns varied from drug to drug but not in a dose-dependent manner.     

Change of mitochondrial buffering capacity induced by propranolol

Propranolol is able to increase the amount of the titratable groups of mitochondrial membranes. This effect occurs with sonicated particles and with liposomes, too. The phenomenon is only seen in the presence of salt solutions, not in sucrose. Propranolol increases the fluorescence of anilino-naphthalene sulphonate (ANS) in mitochondrial suspensions. The increase is counteracted by increasing concentrations of potassium chloride. It is suggested that the increase of the titratable groups results from a decrease of the aggregation of the phospholipids of the membranes. At the same time the environment of the bound ANS molecules is more hydrophobic in sucrose than in potassium chloride. The amount of the buffering groups and the hydrophilicity are in direct and the amount of the buffering groups and the fluorescence of ANS in inverse correlation.     

Influence of substance P on the behavioral changes induced by haloperidol in rats

Locomotor activity and grooming behavior of rats were recorded for a period of 30 min following intraventricular injections of substance P(SP) in doses of 0.60 and 2.50 microgram/rat. The lower dose of the peptide significantly increased locomotion for 10 min and time spent grooming for 25 min. The effects of the same two doses of SP on the hypokinesia induced by various pharmacological treatments modifying catecholaminergic systems were then examined. SP did not affect the behavioral depression produced by alpha-methyl-para-tyrosine (250 mg/kg), FLA-63 (25 mg/kg) and phenoxybenzamine (20 mg/kg). However, SP, in dose of 0.60 microgram/rat, systematically reversed the decrease in locomotor activity induced by a relatively small dose of haloperidol, 0.1 mg/kg. The dame dose of the peptide significantly counteracted the rigidity but not the hypokinesia and catalepsy resulting from the previous administration of a higher dose of haloperidol, 3 mg/kg. The results support the hypothesis that SP may exert direct or indirect function in motor behavior, possible via a modulatory action on brain dopaminergic systems.