Nephrotoxicity of cyclosporin A in diabetic breeding rats breeding rats

A considerable number of studies were carried out on patients receiving Cyclosporin A (CSA) after bone marrow, heart and kidney transplants. More recently this drug has been used as an immunosuppressive agent in the management of type 1 diabetes. Moreover the increase of creatinine levels in CSA-treated patients and animals has led the researchers to believe that this drug may be responsible for irreversible nephrotubular side effects.Our aim was, therefore, to study the hispathological effects of CSA on kidneys of bio breeding (BB) rats, which develop diabetes spontaneously.Animals were treated for 30 and 60 days with daily injections of 8 mg/kg body wt of CSA, dissolved in 2 ml of Intralipid 10% (Pierrel), given intraperitoneally (control animals received only Intralipid). At the end of the experiments animals were sacrificed under ether anaesthesia and the kidneys removed and processed for light microscopy, using standard procedures. After a 30-day administration of CSA, the tubular and glomerular structures appeared unchanged or, in some cases, only a few cells, in the proximal tubules, showed slight vacuolation. After 60 days of CSA administration, the elements of the proximal profiles showed a considerable degree of cytoplasmic vacuolation. These vacuoles resulted positive to PFABB, Sudan Black B, PAS and alkaline tetrazolium reactions. Distal tubular profiles, loops of Henle and glomeruli were unaffected.Our morphological findings demonstrate that CSA causes nephrotubular modifications, when administered in therapeutic doses of only 10 mg/kg body wt, as in many clinical schedules. Moreover data could be consistent with a possible reversion to the normal structural appearance.     

Neuroprotective properties of aucubin in diabetic rats and diabetic encephalopathy rats

In this study, we determined the neuroprotective effect of aucubin on diabetes and diabetic encephalopathy. With the exception of the control group, all rats received intraperitoneal injections of streptozotocin (STZ; 60?mg/kg) to induce type 1 diabetes mellitus (DM). Aucubin (1, 5, 10?mg/kg ip) was used after induction of DM (immediately) and diabetic encephalopathy (65?days after the induction of diabetes). The diabetic encephalopathy treatment groups were divided into short-term and long-term treatment groups. Treatment responses to all parameters were examined (body weight, plasma glucose, Y-maze error rates and proportion of apoptotic cells). In diabetic rats, aucubin controlled blood glucose levels effectively, prevented complications, and improved the quality of life of diabetic rats. In diabetic encephalopathy, aucubin significantly rescued neurons in the hippocampal CA1 subfield and reduced working errors during behavioral testing. The significant neuroprotective effect of aucubin could be seen not only in the short term (15?days) but also in the long term (45?days), which was a highly encouraging finding. These data suggest that aucubin may be a potential neuroprotective agent.     

Chronopharmacology of trichlormethiazide in rats; (II). Examination in aged rats

We have previously demonstrated a time-dependent variability in the diuretic effects of trichlormethiazide, a thiazide diuretic agent, in young rats. The study suggested that the time-dependent variations in urinary trichlormethiazide and susceptibility of renal tissues to the agent might be involved in this phenomenon. The present study was undertaken to test a hypothesis that such a daily variation in the effects of trichlormethiazide is blunted by age. Trichlormethiazide (0.5 and 2.0 mg/kg) was given orally at 1200 hrs (day trial) or at 2400 hrs (night trial) in young (10-11 week old) and aged (23-24 month old) Wistar rats. Urine was collected for 8 hours after the agent and urinary excretions of sodium, chloride and trichlormethiazide were determined. Urine volume and urinary excretions of sodium, chloride and trichlormethiazide following the agent were significantly greater at 1200 hrs than at 2400 hrs in the young rats. However these administration time-dependent changes in the effects of trichlormethiazide and its urinary amount diminished in the aged rats. In the day and night trials, there were significant correlations between urinary trichlormethiazide and its effects (urine volume, urinary sodium and chloride) in both groups of rats. The regression lines in each parameter of two trials differed in the young, but not in the aged group of rats. These data indicate that the mode of the time-dependent changes in the effects of trichlormethiazide is altered in aged Wistar rats. Dampening of the time-dependent variations in urinary trichlormethiazide and susceptibility to the agent might be involved in these chronopharmacological alterations in aged rats.     

Pulmonary surfactant system of newborn rats in alcoholic intoxication of pregnant rats

Data, received in investigation of the lungs of 45 newborn rats, show, that there is the suppression of the surface active properties of surfactant in animals, born from female rats with simulated alcoholic intoxication in pregnancy period. The decrease of the surface activity of surfactant may be connected with direct injury influence of alcohol on surfactant as well as with inactivation of surfactant with serum proteins, which appear in the alveolar space because of the increase of the permeability of components of air-haematic barrier. The suppression of the surface active properties of surfactant is accompanied by reinforcement of the functional activity of the 2nd type pneumocytes and appearance of the hypertrophic forms of these cells.     

Teratogenicity of carbamazepine in rats

The teratogenicity of carbamazepine (CBZ) was investigated in Sprague-Dawley CD rats at doses of 0, 200, 400, and 600 mg/kg administered by gavage in corn oil on days 7-18 of gestation in a dosage volume of 2 ml/kg. The CBZ-600 dose was maternally toxic in that dams in this group weighed 30.6% less than controls by E20. This group had significantly increased resorptions, reduced live fetal weight (51.6% less than controls), and increased skeletal and visceral abnormalities. The CBZ-400 dose also significantly reduced maternal weight gain during gestation to 26.6% less than controls by E20. No significant increase in resorptions occurred in this group; live fetuses weighted 42.9% less than controls and showed an increase in visceral, but not skeletal, abnormalities. The CBZ-200 dose did not significantly affect maternal weight gain or increase resorptions or fetal abnormalities but did reduce fetal body weight (20.3% less than controls). Maternal serum total CBZ concentrations 1 hr after the final dose were 22.9, 27.9, and 34.4 micrograms/ml for the 200, 400, and 600 mg/kg groups, respectively. These levels were little changed 6 h post-treatment. CBZ was 65-70% serum protein bound across dose groups. Human therapeutic levels of CBZ are 4-12 micrograms/ml and the drug is typically 80% serum protein bound. This suggests that abnormalities in rats occur at concentrations well above the human therapeutic range. However, a no-effect level was not found for fetal body weight. Further experiments will be required to determine how much lower doses will need to be in order to find a no-effect level for fetal body weight. Nevertheless, the present data suggest that CBZ is not potent at inducing malformations in rats.     

Chronotoxicity of nedaplatin in rats

Chronotoxicologic profiles of nedaplatin, a platinum compound, were evaluated in rats maintained under a 12 light/12 dark cycle with light from 07:00h to 19:00 h. Nedaplatin (5 mg/kg) was injected intravenously, once a week for 5 weeks at 08:00h or 20:00h. The suppression of body weight gain and reduction of creatinine clearance were significantly greater with the 20:00h than 08:00h treatment. Accumulation of nedaplatin in the renal cortex and bone marrow were also greater with 20:00 h treatment. There were significant relationships between the nedaplatin content in the kidney and bone marrow and degree of injury to each. These results suggest that the nedaplatin-induced toxicity depends on its dosing-time, and it is greater with treatment at 20:00 h, during the active phase. The dosing-time dependency in the accumulation of nedaplatin in the tissue of the organs might be involved in this chronotoxicologic phenomenon.     

Self-administration of haloperidol in rats

Rats were found to self-administer haloperidol at i.v. unit infusion doses of 1.0 and 2.0 μg/kg but not at 0.25 μg/kg. Apomorphine, when administered i.p., antagonized haloperidol self-administration. These data support other recent findings with respect to a role of central dopaminergic neurons in reward mechanisms.     

Investigations of erythropoiesis in newborn rats. Erythropoiesis in newborn rats in physiological conditions.

Erythropoiesis was investigated in suckling rats from the 1st to the 19th day of life when the use of 59Fe. In 2-day and 5-day old rats it was less intensive than in later days. The haemopoietic processes were most intensive between the 7th and 14th day of life. Following this period the activity gradually decreased.     

Spectral analysis of EEG in normal rats and in rats genetically predisposed to seizures

Spectral and visual analyses were performed on the EEG of the motor and visual cortex, hippocampus, caudate nucleus, and intralaminary thalamic nuclei in two strains of rats; animals were maintained in a state of "awake immobility." It was found that KM rats, genetically predisposed to audiogenic fits, differed from the Wistar strain not subject to this genetic predisposition in that mean relative intensity of theta rhythm diminished and high amplitude slow irregular hippocampal activity intensified in the neocortex, as did generalized spindling. Susceptibility to seizure was reduced in KM rats as a result of protracted and graded increasing camphor administration to match the level of mean EEG spectral density changes characteristic of the Wistar strain. The part which brainstem reticular formation mechanisms may play in raising susceptibility to seizures is discussed, together with the EEG pattern characteristic of this condition.Institute of Higher Nervous Activity and Neurophysiology, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 19, No. 2, pp. 171–179, March–April, 1987.