Nano-curcumin versus curcumin in amelioration of deltamethrin-induced hippocampal damage.

We aimed to prove that oxidative stress is the main mechanism responsible for hippocampal neurotoxicity induced by deltamethrin (DLM). The protective role of curcumin (CMN) and nano-curcumin (NCMN) over this toxicity was studied. The rats were categorized into four groups: control, DLM, CMN and NCMN. The study continued for 30 days. Hippocampus was processed for histological, biochemical and immunohistochemical studies. Caspase-3, glial fibrillar acidic protein (GFAP), acetylcholinesterase (AChE), malondialdehyde (MDA), glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) were measured for DLM-induced oxidative stress (increased MDA by 354%/decreased GSH by 61%, SOD by 61%, CAT 57%). Oxidative stress induced apoptosis of hippocampal neurons through increasing Nrf2, gamma-glutamyl cysteine synthetase heavy subunit (GCS-HS) and light subunit (GCS-LS) and decreasing AChE. It increases the activity of astrocytes through increasing GFAP. Finally, oxidative stress has a bad impaction on cognitive function. Improvement of oxidative stress was observed with use of CMN and NCMN (decrease of MDA/increase of GSH, SOD, CAT). The level of Nrf2, GCS-HS and GCS-LS decreased, while AChE, GFAP increased. Improvement of cognitive function was observed in both groups. In conclusion, oxidative stress is the common mechanism responsible for DLM-induced hippocampal neurotoxicity. It exerts apoptosis of hippocampal neurons through increasing Nrf2, HS-GCS, LS-GCS and decreasing AChE. In addition, it activates astrocytes through increasing expression of GFAP. The protective role of CMN and CMMN is related to their potent antioxidant effect. Much improvement has been detected with NCMN as compared to CMN.

Endosulfan and Cypermethrin Pesticide Mixture Induces Synergistic or Antagonistic Effects on Developmental Exposed Rats Depending on the Analyzed Behavioral or Neurochemical End Points.

Exposure to pesticides has been associated with neurodevelopmental toxicity. Usually people are exposed to mixtures of pesticides. However, most studies analyze the effects of individual pesticides. Developmental exposure to mixtures of pesticides may result in additive effects or in antagonistic or synergistic effects. The aim of this work was to compare the effects of developmental exposure of rats to cypermethrin or endosulfan with the effects of its mixture on cognitive and motor function and on some underlying mechanisms. Exposure to individual pesticides or the mixture was from gestational day 7 to postnatal day 21. We analyzed the effects, in males and females, on spatial learning and memory, associative learning, anxiety, motor coordination, and spontaneous motor activity. We also analyzed neuroinflammation and NMDA receptor subunits in hippocampus and extracellular GABA in cerebellum. Exposure to the mixture, but not to individual pesticides, impaired spatial memory in males, associative learning in females, and increased motor activity in males and females. This indicates a synergistic effect of cypermethrin and endolsufan exposure on these end points. In contrast, motor coordination was impaired by individual exposure to endosulfan or cypermethrin, associated with increased extracellular GABA in cerebellum, but these effects were prevented in rats exposed to the mixture, indicating an antagonistic effect of cypermethrin and endolsufan exposure on these end points. The results show different interaction modes (synergism or antagonism) of the pesticides, depending on the end point analyzed and the sex of the rats.

Protective effect of α-lipoic acid against α-cypermethrin-induced changes in rat cerebellum.

Alfa cypermethrin is a pyrethroids extensively used as ectoparasiticide in domestic animals, insecticidal spray on cotton, vegetables and other crops and to kill cockroaches, fleas and termites in house and other buildings. Previous studies have shown the adverse effect of α -cypermethrin on brain. This study was planned to evaluate the possible role of α-lipoic acid in α -cypermethrin induced toxicity in brain of male albino rats. Rats were divided into four groups. The control, α-cypermethrin, α-lipoic acid and α -cypermethrin plus α-lipoic acid treated groups. The duration of the experiment was four weeks. Our results showed that the administration of α-cypermethrin caused a significant decreased in γ- aminobutyric acid level, acetylcholinesterase, catalase, superoxide dismutase activities and increase in lipid peroxidation in cerebellum. Furthermore, the co-administration of α-lipoic acid mitigates the toxicity of α-cypermethrin by partially normalizing the biochemical parameters. The biochemical observations were supported by histopathological examinations. The findings of this investigation suggest that α-lipoic acid may play a protective role against α-cypermethrin induced toxicity in cerebellum of treated rats.

mTOR inhibition by rapamycin protects against deltamethrin-induced apoptosis in PC12 Cells.

The autophagy pathway can be induced and upregulated in response to intracellular reactive oxygen species (ROS). In this study, we explored a novel pharmacotherapeutic approach involving the regulation of autophagy to prevent deltamethrin (DLM) neurotoxicity. We found that DLM-induced apoptosis in PC12 cells, as demonstrated by the activation of caspase-3 and -9 and by nuclear condensation. DLM treatment significantly decreased dopamine (DA) levels in PC12 cells. In addition, we observed that cells treated with DLM underwent autophagic cell death, by monitoring the expression of LC3-II, p62, and Beclin-1. Exposure of PC12 cells to DLM led to the production of ROS. Treatment with N-acetyl cysteine (NAC) effectively blocked both apoptosis and autophagy. In addition, mitogen-activated protein kinase (MAPK) inhibitors attenuated apoptosis as well as autophagic cell death. We also investigated the modulation of DLM-induced apoptosis in response to autophagy regulation. Pretreatment with the autophagy inducer, rapamycin, significantly enhanced the viability of DLM-exposed cells, and this enhancement of cell viability was partially due to alleviation of DLM-induced apoptosis via a decrease in levels of cleaved caspase-3. However, pretreatment of cells with the autophagy inhibitor, 3-methyladenine (3MA), significantly increased DLM toxicity in these cells. Our results suggest that DLM-induced cytotoxicity is modified by autophagy regulation and that rapamycin protects against DLM-induced apoptosis by enhancing autophagy. Pharmacologic induction of autophagy by rapamycin may be a useful treatment strategy in neurodegenerative disorders. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 109-121, 2017.

PPAR-γ activation attenuates deltamethrin-induced apoptosis by regulating cytosolic PINK1 and inhibiting mitochondrial dysfunction.

Central events in the mitochondrial-dependent cell death pathway include the disruption of mitochondrial membrane potential, which causes the release of apoptogenic molecules leading to cell death. Based on the cytotoxic mechanism of deltamethrin (DLM), we examined the neuroprotective mechanisms of rosiglitazone (RGZ), which is against DLM-induced neuronal cell death. In this study, we found that DLM induces apoptosis in SH-SY5Y cells as demonstrated by the activation of caspase-3 and nuclear condensation. In addition, neuronal cell death in response to DLM was due to mitochondrial dependent-apoptosis pathways since DLM increased cytochrome c release into the cytosol and activated caspase-9. DLM exposure reduced PINK1 expression, and pretreatment with RGZ significantly reduced cytochrome c release and caspase-9 activation. RGZ also attenuated the reduction of complex I activity, mitochondrial membrane potential, and ATP levels. Pretreatment with RGZ significantly enhanced PINK1 expression in DLM-exposed cells. In addition, RGZ increased cytosolic PINK1 by inhibiting mitochondrial translocation of PINK1. Interestingly, RGZ fails to rescue DLM-induced mitochondrial dysfunction both in PINK1 knockdown and PPAR-γ antagonist treated cells. Results from this study suggest that RGZ exerts anti-apoptotic effects against DLM-induced cytotoxicity by attenuation of mitochondrial dysfunction through cytosolic PINK1-dependent signaling pathways.

Occurrence of current-use fungicides and bifenthrin in Rainwater Basin wetlands.

Wetlands in the Rainwater Basin (RWB) of Nebraska are commonly in close proximity to or embedded within row-crop agriculture. Several fungicides and bifenthrin are applied aerially to corn throughout the RWB during tassel stage. Thus, aerial spray drift and runoff may result in pesticide contamination of wetlands. The primary objective of this study was to determine water concentrations of five fungicides and bifenthrin in wetlands located in and near fields during a heavy application period (July 16th-26th 2014) to evaluate the influence of distance from crop field on wetland contamination. In addition, the sampling sites were grouped based upon the type of water body sampled and environmental concentrations were compared to relevant "levels of concern" (LOCs) from invertebrates, fish, and amphibians selected from the literature based upon relevant toxicity data. Bifenthrin was the most frequently detected analyte, appearing in 83% of the samples. The 95th percentile concentrations across all wetlands were found to be 0.07 µg/L for bifenthrin, 0.28 µg/L for pyraclostrobin, 0.28 µg/L for azoxystrobin, and <0.14 µg/L for all other analytes. Analyte concentrations did not differ by wetland type and were not correlated with distance from closest crop. Environmental concentrations of fungicides were lower than LOCs, indicating limited acute toxicity risk. However, bifenthrin concentrations were frequently higher than LOCs for aquatic arthropods. Because the water samples included particulate bound pesticides, further work is needed to determine if this bifenthrin is bioavailable and contamination levels within the sediment.

Ca²âº Movement Induced by Deltamethrin in PC3 Human Prostate Cancer Cells.

This study explored the effect of deltamethrin, a pesticide, on intracellular free Ca²âº concentration ([Ca²âº]i) in PC3 human prostate cancer cells. Deltamethrin at concentrations between 5 µM and 20 µM evoked [Ca²âº]i rises in a concentration-dependent manner. This Ca²âº signal was inhibited by 22% by removal of extracellular Ca²âº. Nifedipine, econazole, and SKF96365 also inhibited the Ca²âº signal. Treatment with the endoplasmic reticulum Ca²âº pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) in Ca²âº-free medium nearly abolished deltamethrin-induced [Ca²âº]i rises. Treatment with deltamethrin also inhibited most of BHQ-induced [Ca²âº]i rises. Inhibition of phospholipase C (PLC) with U73122 failed to alter deltamethrin-evoked [Ca²âº]i rises. Deltamethrin killed cells at concentrations of 20-100 µM in a concentration-dependent fashion. Chelation of cytosolic Ca²âº with 1,2-bis (2-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid/acetoxymethyl ester (BAPTA/AM) did not prevent deltamethrin's cytotoxicity. Together, in PC3 human prostate cancer cells, deltamethrin induced [Ca²âº]i rises that involved Ca²âº entry through store-operated Ca²âº channels and PLC-independent Ca²âº release from the endoplasmic reticulum. Deltamethrin induced cytotoxicity in a Ca²âº-independent manner.

Deltamethrin-induced oxidative stress and mitochondrial caspase-dependent signaling pathways in murine splenocytes.

Deltamethrin (DLM) is a well-known pyrethroid insecticide used extensively in pest control. Exposure to DLM has been demonstrated to cause apoptosis in various cells. However, the immunotoxic effects of DLM on mammalian system and its mechanism is still an open question to be explored. To explore these effects, this study has been designed to first observe the interactions of DLM to immune cell receptors and its effects on the immune system. The docking score revealed that DLM has strong binding affinity toward the CD45 and CD28 receptors. In vitro study revealed that DLM induces apoptosis in murine splenocytes in a concentration-dependent manner. The earliest markers of apoptosis such as enhanced reactive oxygen species and caspase 3 activation are evident as early as 1 h by 25 and 50 µM DLM. Western blot analysis demonstrated that p38 MAP kinase and Bax expression is increased in a concentration-dependent manner, whereas Bcl 2 expression is significantly reduced after 3 h of DLM treatment. Glutathione depletion has been also observed at 3 and 6 h by 25 and 50 µM concentration of DLM. Flow cytometry results imply that the fraction of hypodiploid cells has gradually increased with all the concentrations of DLM at 18 h. N-acetyl cysteine effectively reduces the percentage of apoptotic cells, which is increased by DLM. In contrast, buthionine sulfoxamine causes an elevation in the percentage of apoptotic cells. Phenotyping data imply the effect of DLM toxicity in murine splenocytes. In brief, the study demonstrates that DLM causes apoptosis through its interaction with CD45 and CD28 receptors, leading to oxidative stress and activation of the mitochondrial caspase-dependent pathways which ultimately affects the immune functions. This study provides mechanistic information by which DLM causes toxicity in murine splenocytes. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 808-819, 2016.

The protective role of glutamine against acute induced toxicity in rats.

CONTEXT: Deltamethrin (DLM) is an insecticide commonly used to protect agricultural crops against pests. QT prolongation with malignant ventricular arrhythmias are amongst the most common cardiovascular complications. DLM intoxication cause decreased level of antioxidant enzymes. Glutamine is the precursor of glutathione which is an antioxidant and has been demonstrated to improve outcome after several critical illnesses. OBJECTIVE: We hypothesized that glutamine, by means of antioxidant characteristics, may antagonize the cardiotoxic effects of DLM. MATERIALS AND METHODS: All experiments were performed on 8-week-old male Wistar albino rats. The rats were divided into following groups (n = 10); Group I: control, Group II: l-glutamine, Group III: DLM, Group IV: DLM and after 4 h l-glutamine. Total antioxidant status (TAS), total oxidant status (TOS) and parameter analyses were performed in cardiac tissue. RESULTS: We found that TAS was higher and TOS lower in DLM group. We also found that interstitial edema and inflammatory cell infiltration was significantly more frequent in DLM group and QT and QTc of DLM group were higher than others. DISCUSSION: Recent studies have shown that several special amino acids, such as glutamine, glycine, arginine and taurine, exhibit cytoprotective effect on the cardiocyte, and have established the cardioprotective properties of glutamine. CONCLUSION: In this study, we showed the protective role of glutamine against cardiotoxic effects of DLM in rats. This protective effect was confirmed by showing both tissue level improvement in oxidative stress markers and improvement in prolonged QT interval.

Protective effects of garlic extract and vitamin C against in vivo cypermethrin-induced cytogenetic damage in rat bone-marrow.

The cytogenetic damage inflicted by the synthetic pyrethroid insecticide cypermethrin (CYP) on the bone-marrow of male white rats, as well as possible protective role of two natural elements: garlic extract (GRE, 500mg/kg) and vitamin C (VTC, 20mg/kg) against the mutagenic potential of the insecticide were assessed. CYP was orally intubated in a single treatment (1/2 LD(50)) or in repeated treatments (1/5 LD(50) daily, for 5 successive days), either alone, or concomitantly with repeated oral intubations (5 successive days) of each individual putative protector, or with their combination (GRE or/and VTC). One hundred and twenty male rats were divided over into five groups of each 24 animals. The groups received nothing, a single dose or repeated treatments with insecticide alone, or associated with putative natural elements, separately or in combinations. Animals were sacrificed at their scheduled times and their femoral bone-marrows were flushed out to be utilized in the micronucleus test and metaphase chromosomal aberration assay. The results show that CYP administration significantly induced clastogenic effects, as revealed by the significant increase in the mean frequencies of micronucleated polychromatic erythrocytes and various structural chromosomal aberrations in bone-marrow metaphase cells of all groups of treated rats. On the other hand, this investigation clearly revealed the protective role of GRE and VTC, either each alone or in combination, against the mutagenic potential of cypermethrin: the garlic extract was often more efficient in its protective action against the insecticide toxicity than vitamin C. while the combination of both natural elements produced, in most cases, a more pronounced protective effect than when each was administered alone.

Potentiation/Antagonism of pyrethroids with organophosphate insecticides in Bemisia tabaci (Homoptera: Aleyrodidae).

The binary mixtures of pyrethroids cypermethrin, alpha-cypermethrin, zeta-cypermethrin, bifenthrin, fenpropathrin, lambda-cyhalothrin, and deltamethrin plus organophosphates ethion, profenofos, chlorpyrifos, quinalphos, acephate, methamidophos, methyl parathion, and triazophos were evaluated on putatively resistant field populations of Bemisia tabaci (Gennadius) (Homoptera: Aleyrodidae) from Pakistan using a leaf-dip bioassay. Ethion exhibited good potentiation with all the pyrethroids. Quinalphos potentiated cypermethrin, fenpropathrin, and lambda-cyhalothrin but not bifenthrin. Acephate was potentiating with bifenthrin and fenpropathrin but antagonistic with zeta-cypermethrin. A potentiation effect was also found when methamidophos was mixed with bifenthrin and fenpropathrin. However, profenofos was antagonistic with cypermethrin, bifenthrin, and lambda-cyhalothrin. Similarly, bifenthrin + methyl parathion and deltamethrin + triazophos mixtures were antagonistic when tested on several populations of B. tabaci. Chlorpyrifos was antagonistic with cypermethrin but had an additive effect with fenpropathrin.

PolicosanolPlus and Neuroprevin ameliorate pesticide-mediated inhibition of neurite outgrowth and neurite degeneration.

BACKGROUND: Pesticide exposure is a recognized risk factor for neurodegenerative diseases. Recently, bifenthrin, a pyrethroid pesticide, was shown to inhibit the formation of neurites and cause neurite retraction, raising concern that these newer and less toxic pesticides may also contribute to neurodegenerative diseases. PolicosanolPlus and Neuroprevin are nutraceutical supplements which promote the survival of neurites in neuronal cell cultures. Here we determine if PolicosanolPlus and Neuroprevin can ameliorate the neurodegenerative effects of bifenthrin. MATERIAL/METHODS: PC12 cells were treated with NGF, bifenthrin, PolicosanolPlus and Neuroprevin in various combinations and the formation of neurites was assessed microscopically at times ranging from 12 to 72 hours post treatment. Bifenthrin was also withheld at the time of NGF, PolicosanolPlus and Neuroprevin treatment and added after neurite formed to assess neurite retraction. RESULTS: Bifenthrin (1 x 10(-6) M) inhibits neurite outgrowth, in the absence of cell death, by more than 50% at 12 hours and by more than 80% at 72 hours. With addition of PolicosanolPlus and/or Neuroprevin at the time of cell seeding, bifenthrin does not inhibit neurite outgrowth. Addition of bifenthrin to differentiated cells results in a retraction of 90% of neurites, while those with PolicosanolPlus and Neuroprevin show no significant retraction of neurites. CONCLUSIONS: The pesticide, bifenthrin, inhibits neurite formation and causes neurite retraction. PolicosanolPlus and Neuroprevin are nutraceutical supplements which ameliorate the effects of bifenthrin on neurite outgrowth and retraction. Dietary supplementation with PolicosanolPlus and Neuroprevin may protect against developmental and long-term neurodegenerative events that result from exposure to pesticides.

Copper modulates non-enzymatic antioxidants in the freshwater fish Channa punctata (Bloch) exposed to deltamethrin.

The assessment of the ecotoxicological risks caused by pesticides to ecosystems are based on data on the toxicity and effects of pesticide preparations to non-target organisms like fish. Deltamethrin is a widely used pesticide based on pyrethroids, which is reported to be extremely toxic to fish species. Modulatory effect of copper pre-exposure (10 ppb) on deltamethrin (0.75 microg l-1)-induced oxidative stress was investigated in freshwater fish Channa punctata (Bloch). Non-enzymatic antioxidants were studied as biomarkers of exposure to deltamethrin and possible protection afforded by copper pre-exposure. Glutathione levels were reduced significantly (P<0.05) in liver of copper-acclimatized deltamethrin-exposed group when compared with deltamethrin-exposed groups. The total thiol levels of copper-acclimatized deltamethrin-exposed group was significantly lowered (P<0.01) in liver when compared with deltamethrin-exposed group, while non-protein thiol levels recorded a significant (P<0.01) increase in liver of copper-acclimatized deltamethrin-exposed group when compared with deltamethrin-exposed group. The lipid peroxidation levels of copper-acclimatized deltamethrin-exposed groups were significantly lowered (P<0.01) in liver when compared with deltamethrin-exposed group. Deltamethrin is known to induce toxic responses by generating reactive oxygen species and to neutralize its toxic effect various non-enzymatic antioxidants were found to be modulated thus implicating their role as biomarkers in pollution control programmes.

Deltamethrin, a pyrethroid insecticide, is a potent inducer for the activity-dependent gene expression of brain-derived neurotrophic factor in neurons.

The mRNA expression of brain-derived neurotrophic factor (BDNF) is controlled in an activity-dependent manner through Ca(2+) influx into neurons. Pyrethroids are widely used insecticides of low acute toxicity in mammals, but their effects on sodium channels are known to lead to hyperexcitation in neuronal cells of insects. In this study, we found that deltamethrin, a type II pyrethroid insecticide, was highly effective in inducing BDNF expression in culture and in the rat brain. Addition of deltamethrin to rat cortical cells in culture markedly increased the expression of BDNF exon III-V mRNA and protein, dependent upon the neuronal activity accompanying the influx of Ca(2+) into neurons and the Ca(2+) influx-dependent phosphorylation of extracellular signal-regulated kinases 1/2. The elevated expression was maintained for at least 48 h, even after deltamethrin was withdrawn from the culture medium. Comparison of the effects of selected pyrethroids on the expression revealed that type II but not type I pyrethroids effectively induced BDNF mRNA expression. In addition, administration of deltamethrin to rats increased the level of BDNF protein in the cerebral cortex and hippocampus. These results indicate that deltamethrin is a potent inducer of BDNF expression in neurons and that it may induce neuronal hyperexcitation if it reaches the brain.

Effect of mexiletine on fenvalerate-induced nociceptive response in diabetic mice.

The effect of mexiletine on the nociceptive behavior induced by the intrathecal injection of fenvalerate, which predominantly activates tetrodotoxin-resistant (TTX-R) sodium channels, was studied in diabetic mice. The intrathecal injection of fenvalerate induced a characteristic behavioral syndrome that mainly consisted of reciprocal hind limb scratching directed toward caudal parts of the body and biting or licking of the hind legs in mice. The intensity of fenvalerate-induced nociceptive responses was significantly greater in diabetic mice than non-diabetic mice. This fenvalerate-induced behavior was dose-dependently inhibited by mexiletine (3-30 mg/kg, i.p.). Intrathecal pretreatment with fenvalerate produced thermal hyperalgesia and allodynia in the tail-flick test in naive mice. Furthermore, mexiletine at doses of 10 and 30 mg/kg, i.p., dose-dependently and significantly reduced fenvalerate-induced thermal hyperalgesia and allodynia in the tail-flick test in naive mice. These present data suggest that i.p. pretreatment with mexiletine produced dose-dependent inhibition of fenvalerate-induced hyperalgesia and allodynia in mice, especially diabetic mice. This effect may be, at least in part, mediated by the inhibition of TTX-R sodium channel-mediated nociceptive transmission in the spinal cord.

Lymphocyte DNA damage in rats exposed to pyrethroids: effect of supplementation with Vitamins E and C.

Pesticides have been considered potential chemical mutagens. In fact, some studies show that various agrochemical ingredients possess mutagenic properties inducing mutations, chromosomal alterations or DNA damage. Experimental evidence shows a marked correlation between mutagenicity and carcinogenicity and indicates that short-term mutagenicity tests are useful for predicting carcinogenicity. The present study on rat exposed to two pyrethroids, cypermethrin and permethrin, showed different lymphocyte DNA damage depending on the type of pyrethroid, the dose, and the period of treatment. Data obtained from comet assay showed that oral treatment with 150 mg/kg body weight/day of permethrin (corresponding to 1/10 of LD50) for 60 days, induced a significant increase in all comet parameters. No lymphocyte DNA damage was measured after treatment with 25 mg/kg body weight/day of cypermethrin (corresponding to 1/10 of LD50) for the same period. A higher dose of permethrin (300 mg/kg body weight/day), for a shorter period (22 days), did not induce lymphocyte DNA damage, while supplementation with 200 mg/kg of Vitamins E and C protected erythrocytes against plasma membrane lipids peroxidation. Moreover, treatment with Vitamins E and C maintained the activity of glutathione peroxidase, which was reduced in the presence of permethrin, and reduced the osmotic fragility, which had increased following permethrin treatment.

Vitamin C protects against in vitro cytotoxicity of cypermethrin in rat hepatocytes.

The objective of this study was to investigate the effect of ascorbic acid (AA) on the in vitro cytotoxicity of cypermethrin (CM), and on glutathione (GSH) metabolism in rat hepatocytes. In vitro cell viability, lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) leakage were measured, as indicators of hepatic damage, at 1, 15 and 30 min of exposure to CM. Glutathione and the activities of glutathione-S-transferase (GST) and gamma glutamyl transpeptidase (gamma-GT) were also measured. CM hepatotoxicity increased in a time and dose-dependent manner. In the presence of 30 microM CM, ALT and AST also increased 49 and 130% (P < 0.05), respectively, indicating metabolic hepatocyte damage. AA (1 mM) was capable to preserve 100% of cell integrity and modulated ALT and AST. Furthermore, CM induced a 27% reduction in the endogenous antioxidant GSH, and increased 203% GST and 283% gamma-GT (P < 0.05), indicating an oxidative insult. The presence of AA showed chemopreventive capacity against CM, recovering 60% of GSH and a 54% decrease in gamma-GT activity. These results suggest that AA in a 1:33 (CM:AA) ratio can modulate up to 90% of the damage caused to the cells by CM. It also demonstrates that AA can act as a primary antioxidant and hepatoprotector in rat hepatocytes.

Pyrethroid stimulation of ion transport across frog skin.

Pyrethroids are grouped into two classes (types I and II) because of the absence or presence of an alpha-cyano substituent and the production of a different intoxication syndrome in rodents. In this study, we investigated the effect of pyrethroids on the ion transport across frog skin (Rana esculenta). The short-circuit current value (estimate of ion transport) was increased by each of the eight pyrethroids tested, with the following order of potency: lambda-cyhalothrin > deltamethrin > alpha-cypermethrin = beta-cyfluthrin > bioallethrin > permethrin > bioresmethrin > phenothrin. The first four compounds are type II pyrethroids. Therefore, ion transport is stimulated more by type II pyrethroids than by type I. Experiments performed in the presence of amiloride support the conclusion that pyrethroids mainly increase Na+ absorption and to a lesser extent Cl- secretion. In these experiments, no systematic difference between type I and II pyrethroids was found. Finally, the stimulation by pyrethroids was inhibited by indomethacin and W7 (inhibitors of cyclooxygenases and the Ca2+/calmodulin system, respectively). These observations suggest that pyrethroids do not directly affect the epithelial Na+ channel (ENaC) but indirectly influence an intracellular event involved in ENaC modulation and linked to the Ca2+ signaling cascade.

Toxicity of cypermethrin in Labeo rohita fingerlings: biochemical, enzymatic and haematological consequences.

The effect of exposure to sub-lethal concentrations of cypermethrin, a synthetic pyrethroid pesticide, on biochemical parameters of muscle, blood and enzyme activities in brain, liver and kidney of the Indian major carp, Labeo rohita was studied. The sub-lethal exposure studies were done for up to 45 days at 1/10 and 1/50 of 96 h LC(50) of cypermethrin. The 96 h LC(50) was found to be 0.139 ppm. RNA levels decreased while DNA levels were elevated. Acid phosphatase was unchanged while alkaline phosphatase was depleted. Brain acetylcholinesterase activity was decreased significantly (P<0.05) over a period of 45 days at both cypermethrin concentrations. Lactate dehydrogenase activity in brain and liver was elevated, but inhibited in kidney. Succinate dehydrogenase and ATPase activities were depleted in brain, kidney and liver. There was a decrease in serum protein level over control at both concentrations of the pyrethroid. Blood glucose level and total leucocytes were elevated compared with controls at either concentration from day 15 to day 45. Haemoglobin percentage and total erythrocytes decreased in both sub-lethal concentrations. Extracts of the herb Datura stramonium were effective in countering the toxicity of this pesticide. Our data suggest that sub-lethal exposure of cypermethrin alters the biochemical, haematological parameters and enzymes of organs tissue and exert stress on the fish. Plant extracts may be useful in counteracting some of these effects.

Modification of the fenvalerate-induced nociceptive response in mice by diabetes.

We examined the effect of diabetes on the fenvalerate-induced nociceptive response in mice. The intrathecal (i.t.) or intraplantar (i.pl.) injection of fenvalerate, a sodium channel activator, induced a characteristic behavioral syndrome mainly consisting of reciprocal hind limb scratching directed towards caudal parts of the body and biting or licking of the hind legs in both non-diabetic and diabetic mice. However, the intensity of such fenvalerate-induced nociceptive responses was significantly greater in diabetic mice than in non-diabetic mice. Calphostin C (3 pmol, i.t.), a selective protein kinase C inhibitor, significantly inhibited intrathecal fenvalerate-induced nociceptive behavior with a rightward shift of the dose-response curve for fenvalerate-induced nociceptive behavior to the level those observed in non-diabetic mice. On the other hand, when non-diabetic mice were pretreated with phorbol-12, 13-dibutyrate (50 pmol, i.t.), the dose-response curve for intrathecal fenvalerate-induced nociceptive behavior was shifted leftward to the level those observed in diabetic mice. These results suggest that the sensitization of sodium channels, probably tetrodotoxin-resistant (TTX-R) sodium channels, by the long-term activation of protein kinase C may play an important role in the enhancement of the duration of fenvalerate-induced nociceptive behavior in diabetic mice.