No abstract

The present study examines the mechanism of neurotoxic action of a synthetic pyrethroid formulation deltamethrin in young rats. Newly weaned Wistar Albino male rats received deltamethrin of technical grade at a dose of 7.0 mg/kg body weight/day in corn oil, orally from postnatal day 22 to postnatal day 37. Deltamethrin significantly decreased the wet weight of the hippocampus without much affecting the weight of cerebellum, pons medulla, hypothalamus, frontal cortex and corpus striatum in comparison to respective controls. A significant increase in the activities of mitochondrial monoamine oxidase and microsomal acetylcholinesterase without any effect on microsomal Na+, K(+)-ATPase activity was observed in the brain of experimental animals. Our results further indicate that deltamethrin markedly impaired learning function and significantly increased the spontaneous locomotor activity while aggressive behaviour remained unaffected. An overall enhancement of polyamine levels in hypothalamus and corpus striatum accompanied with an overall decline in pon medulla and cerebellum was also noted. Maximum decrease of spermine and spermidine was registered in hippocampus, while these polyamines showed an increase in frontal cortex. In striatal membranes the binding of 3H-spiperone decreased and 3H-quinuclidinyl benzilate was elevated significantly. Deltamethrin-induced deviations in regional brain polyamine levels may be a possible cause for altered pathophysiology of the neurone.

Drug-induced QT prolongation has been reported in humans and animals. This potentially lethal effect can be induced by drugs interacting with a cardiac potassium channel, namely hERG (human ether-a go-go-related gene) leading to arrhythmia or torsade de pointes (TdP). Hence, in vitro evaluation of therapeutics for their effects on the rapid delayed rectifier current (IKr) mediated by the K(+) ion channel encoded by hERG is a valuable tool for identifying potential arrhythmic side effects during drug safety testing. Our objective was to evaluate the temperature-induced hERG channel blockade variation by human and veterinary drugs using the IonFlux 16 system. A panel of eight drugs was tested for IKr inhibition at both ambient (23 °C) and physiological (37 °C) temperatures at various concentrations using IonFlux 16, an automated patch clamp system. Our results established that both amiodarone (IC(50)  = 0.56 μM at 23 °C and 0.30 μM at 37 °C) and β-estradiol (IC(50)  = 24.72 μM at 23 °C and 8.17 μM at 37 °C) showed a dose-dependent IKr blockade with a higher blockade at 37 °C. Whereas, blockade of IKr by both ivermectin (IC(50)  = 12.52 μM at 23 °C and 24.41 μM at 37 °C) and frusemide (IC(50)  = 12.58 μM at 23 °C and 25.55 μM at 37 °C) showed a dose-dependent IKr blockade with a lower blockade at 37 °C. Gentamicin, enrofloxacin, xylazine and albendazole did not block IKr at both the assessed temperatures. Collectively, these results demonstrate that the effect of temperature variation should be taken into consideration during the evaluation of test drugs for their hERG channel blockade potential.

: Levels of biogenic amines and activities of monoamine oxidase and acetylcholine esterase were investigated in developing rat brain following acrylamide (ACR) exposure. The ACR exposed rats showed a significant reduction in noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) contents at 4, 8 and 15 days of age whereas the adult animals exhibited no such changes.Exposure of rats to ACR resulted in decrease of NA levels in basal ganglia, pons medulla and mid brain regions and of DA in cerebellum, mid brain, pons medulla and hypothalamus in age groups (12, 15 and 21 days). The 15 and 21 days old treated rats also showed a marked reduction in 5-HT content in pons medulla, hypothalamus and cerebral cortex. Exposure to ACR of 2, 4, 8 and 15 days old rats resulted in an increase in monoamine oxidase activity and decrease in acetylcholine esterase activity in brain. These results suggest that suckling and growing rats are more vulnerable to neurotoxic effects of ACR and such effects are not uniform in brain but are localized to certain brain regions which regulate motor activity and behaviour.

Neurotoxic effects of styrene on certain biochemical and behavioural indices were studied in young rats kept deficient in protein during the weaning period. Young rats fed a low-protein diet showed a significant decrease in the level of dopamine and an increase in frontocortical [3H]serotonin binding in comparison to the group of rats fed a normal protein diet. These rats also showed a significant increase in foot shock-induced aggressive behaviour, while no changes in amphetamine-induced locomotor activity, levels of norepinephrine and serotonin and binding of [3H]spiperone to striatal membrane were observed. On exposure to styrene, rats fed a normal protein diet showed a decrease in dopamine level and an increase in foot shock-induced aggressive behaviour only, with no significant change in other parameters, in comparison to the respective controls. It was, however, interesting to note that when rats fed a low-protein diet were exposed to styrene they showed a significant decrease in the levels of norepinephrine, dopamine and serotonin and an increase in the binding of [3H]spiperone and [3H]5-HT to striatal and frontocortical membranes, respectively. A significant increase in foot shock-induced aggressive behaviour and amphetamine-induced locomotor activity was also observed in this group of animals in comparison to those fed a low-protein diet. The biochemical and behavioural data indicate that protein deficiency makes young animals more vulnerable and it is an important predisposing factor in the neurobehavioural toxicity of styrene.