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There is an increasing belief that organophosphorus compounds (OPCs) impair glucose homeostasis and cause hyperglycemia and diabetes mellitus. The present study was undertaken to investigate the putative diabetogenic effect of sub-lethal and sub-chronic exposure to paraoxon (POX), an extremely hazardous OPC used in pesticides. The effect of paraoxon on streptozotocin-induced diabetic rats was also examined. Each rat was injected with 100 nmol of POX 5 days per week for 6 weeks. Blood glucose levels and red blood cell acetylcholinesterase activity were measured weekly. Biochemical analysis and morphological studies were performed at the end of the experiment. The results revealed that POX neither induces nor exacerbates diabetes mellitus in experimental rats. Liver and kidney/body weight ratios revealed statistically insignificant differences when compared with controls. Biochemical analysis of urine samples showed a small but not significant increase in protein level in all groups. Urine bilirubin was significantly higher in the diabetes + POX group when compared with the control group. The number of blood cells in urine was significantly higher in the POX-treated group compared with the control group. Hyperglycemia was noted in the diabetes and diabetes + POX groups, but neither in the saline control nor in POX-treated normal rats. Electron microscopy of POX-treated pancreas did not show any morphological changes in beta cells. These results suggest that POX does not cause diabetes mellitus at sub-lethal sub-chronic exposure. Copyright © 2012 John Wiley & Sons, Ltd.

Reversible acetylcholinesterase (AChE) inhibitors can protect against the lethal effects of irreversible organophosphorus AChE inhibitors (OPCs), when administered before OPC exposure. We have assessed in vivo the mortality-reducing efficacy of a group of known AChE inhibitors, when given in equitoxic dosage before exposure to the OPC paraoxon. Protection was quantified in rats by determining the relative risk (RR) of death. Best in vivo protection from paraoxon-induced mortality was observed after prophylactic administration of physostigmine (RR = 0.30) or the oxime K-27 (RR = 0.34); both treatments were significantly superior to the pre-treatment with all other tested compounds, including the established substance pyridostigmine. Tacrine (RR = 0.67), ranitidine (RR = 0.72), pyridostigmine (RR = 0.76), tiapride (RR = 0.80) and 7-MEOTA (RR = 0.86) also significantly reduced the relative risk of paraoxon-induced death, but to a lesser degree. Methylene blue, amiloride and metoclopramide had an unfavorable effect (RR ≥ 1), significantly increasing mortality. When CNS penetration by prophylactic is undesirable K-27 is a promising alternative to pyridostigmine. Copyright © 2012 John Wiley & Sons, Ltd.

Epileptic women do not withdraw antiepileptic drug (AED) therapy during pregnancy, therefore, exposure to AED during preimplantation stages might result in considerable embryonic concentrations endangering development. Neither clinical nor experimental research has addressed this important issue adequately. Vigabatrin (VGB), a second generation AED, is both effective and well tolerated as an add-on therapy in epilepsy with partial seizures. However, there is little data on the possible reproductive toxicity of this widely used drug. The objective of the present study was to evaluate the effects of VGB on pregnancy and pregnancy outcome in an experimental model. VGB was administered in single doses of 450 mg/kg intraperitoneally (i.p.) to groups of mice on one of gestation days (GD) 1, 3, or 5. The treated animals consumed moderately reduced amounts of food and water on the day of treatment, so the controls were saline-injected and food and water-restricted to match the amounts consumed by the experimental animals. All animals were killed on GD 18. VGB treatment did not interfere with implantation, nor did it cause significant embryo resorption. However, it caused significant reduction in fetal bodyweight and increased frequency of growth restricted fetuses which weighed two standard deviations (SD) less than the mean of the controls. The VGB group fetuses also had retarded development of the skeletal system in terms of delay in maturity of the suproccipital bone development, cervical and coccygeal vertebral hypoplasia, and poor ossification of the bones of the fore and hind paws. Another major finding was the increased incidence of minor malformations, such as the presence of cervical ribs and sternal anomalies. The results of this study show that VGB administered at preimplantation stages of development causes intrauterine growth restriction (IUGR) and augments minor malformation rates in mice. Future studies must address the mechanisms of VGB-induced IUGR and minor malformations.

In vivo biotelemetry studies have demonstrated a variety of heart rhythm disturbances in type 1 diabetes mellitus. In the streptozotocin (STZ)-induced diabetic rat, these disturbances have included reductions in heart rate (HR) and heart rate variability (HRV) and an electrocardiogram that displays prolonged QRS duration and Q-T interval. The aim of this study was to investigate the chronic effects of type 2 diabetes mellitus on heart rhythm in the Goto-Kakizaki (GK) rat. Transmitter devices were surgically implanted in the peritoneal cavity of young male GK and age-matched Wistar control rats. Electrodes from the transmitter were arranged in Einthoven bipolar lead II configuration. Electrocardiogram, physical activity and body temperature data were recorded in rats from age 2 to 15 months. Data were acquired for 2 weeks each month. Non-fasting blood glucose, glucose tolerance and body weight were measured periodically. In GK rats, growth rate and maximal attained body weight were significantly reduced and non-fasting blood glucose was progressively increased compared with age-matched Wistar control animals. Heart rate was significantly lower in GK compared with control rats at 2, 7 and 15 months of age. At 2 months of age, HR was 316 +/- 6 beats min(-1) in GK rats compared with 370 +/- 7 beats min(-1) in Wistar control animals. There was a progressive age-dependent decline in HRV in Wistar control rats; however, HRV in GK rats did not alter significantly with age. Heart rate variability was significantly reduced in GK compared with Wistar control rats at 2 and 7 months. At 2 months of age, HRV was 28 +/- 2 beats min(-1) in GK rats compared with 38 +/- 3 beats min(-1) in Wistar control rats. Reduced HR in GK rats may be an inherited characteristic. The absence of age-dependent reductions in HRV in GK rats may be a consequence of an underlying impairment of autonomic control which manifests at early age.

Type 2 diabetes mellitus accounts for more than 90% of all cases of diabetes mellitus, and cardiovascular complications are the major cause of mortality and death in diabetic patients. The chronic effects of type 2 diabetes mellitus on heart function have been investigated in the Goto-Kakizaki (GK) rat. Experiments were performed in GK rats and age-matched Wistar control rats at 18 months of age. The progressive effects of diabetes on glucose metabolism were monitored periodically by application of the glucose tolerance test. Ventricular action potentials were measured in isolated, perfused heart. Shortening and intracellular Ca(2+) were measured in electrically stimulated ventricular myocytes. The GK rats displayed mild fasting hyperglycaemia and progressively worsening glucose tolerance. At 18 months of age and 180 min after intraperitoneal injection of glucose (2 g (kg body weight)(-1)), blood glucose was 436 +/- 47 mg dl(-1) in GK rats compared with 153 +/- 18 mg dl(-1) in control animals. Heart weight to body weight ratio was significantly increased in GK rats (4.10 +/- 0.09 mg g(-1), n = 5) compared with control animals (3.36 +/- 0.22 mg g(-1), n = 4). Spontaneous heart rate was slightly reduced in GK rats compared with control rats. Although the amplitude of shortening was not altered, the amplitude of the Ca(2+) transient was significantly increased in myocytes from GK rats (0.78 +/- 0.11 ratio units) compared with control rats (0.50 +/- 0.06 ratio units). Despite progressively worsening glucose metabolism, at 18 months of age the contractile function of the heart appears to be well preserved.

Exposure to cadmium (Cd) poses a deleterious health effects and its toxicity has been attributed to oxidative stress. Therefore, we examined the sub-acute systemic and thrombotic influence of Cd ex...

Tribulus terrestris L (TT) is used in the Arabic folk medicine to treat various diseases. The aim of this article was to investigate the protective effects of TT in diabetes mellitus (DM). Diabetes is known to increase reactive oxygen species (ROS) level that subsequently contributes to the pathogenesis of diabetes. Rats were divided into six groups and treated with either saline, glibenclamide (Glib), or TT for 30 days. Rats in group 1 were given saline after the onset of streptozotocin (STZ)-induced diabetes; the second diabetic group was administered Glib (10 mg/kg body weight). The third diabetic group was treated with the TT extract (2 g/kg body weight), while the first, second, and third nondiabetic groups were treated with saline solution, Glib, and TT extract, respectively. At the end of the experiment, serum and liver samples were collected for biochemical and morphological analysis. Levels of serum alanine aminotransferase (ALT) and creatinine were estimated. In addition, levels of malondialdehyde (MDA) and reduced glutathione (GSH) were assayed in the liver. The tested TT extract significantly decreased the levels of ALT and creatinine in the serum (P < 0.05) in diabetic groups and lowered the MDA level in liver (P < 0.05) in diabetic and (P < 0.01) nondiabetic groups. On the other hand, levels of reduced GSH in liver were significantly increased (P < 0.01) in diabetic rats treated with TT. Histopathological examination revealed significant recovery of liver in herb-treated rats. This investigation suggests that the protective effect of TT for STZ-induced diabetic rats may be mediated by inhibiting oxidative stress.

Infants of epileptic women treated with valproic acid (VPA) during pregnancy have a higher risk of developing spina bifida than those of the general population. VPA induces exencephaly in experimental animal embryos. But the pathogenetic mechanism remains rather elusive. Antiepileptic drugs (AED) in general accentuate pregnancy-imposed fall in maternal folate levels. Periconceptional folic acid supplementation is reported to protect embryos from developing neural tube defects (NTD). Conflicting results have been reported by experimental studies that attempted to alleviate VPA-induced NTD by folic acid. Our objectives were to determine the critical developmental stages and an effective dose of folic acid for the prevention of VPA-induced exencephaly in mouse fetuses. A single teratogenic dose of 400 mg/kg of VPA was administered to TO mice on gestation day (GD) 7 or 8. It was followed by (1) a single dose of 12 mg/kg of FA (folinic acid) or (2) 3 doses of FA 4 mg/kg each. In experiment (3), FA (4 mg/kg) was administered thrice daily starting on GD 5 and continued through GD 10. These animals received VPA on GD 7 or 8. VPA and B12 concentrations were determined by radioimmunoassay. The single heavy dose of FA had no rescue effect on NTD. Three divided doses of FA on GD 7 and continuous dosing of FA from GD 5 through GD 10 substantially reduced the VPA-induced exencephaly in the fetuses. In the later experiments, the neural folds elevated faster than the non-supplemented group. VPA considerably reduced maternal plasma folate and B12 concentrations. The heavy dose of FA only moderately improved vitamin levels. Three divided doses of FA elevated the vitamin levels slightly better but it was the prolonged dosing of FA that was associated with sustained elevation of plasma levels higher than the control levels and acceleration of neural tube closure thus accounting for the pronounced protection against VPA-induced NTD development. These data suggest that plasma levels of FA and B12 have to be kept substantially elevated and maintained high throughout organogenesis period to protect embryos against VPA-induced NTD in this mouse model.