|Year : 2014 | Volume
| Issue : 2 | Page : 104-111
Neurotoxic effect of cypermethrin and protective role of resveratrol in Wistar rats
Poonam Sharma1, Sumaya Firdous1, Rambir Singh2
1 Department of Zoology, Bundelkhand University, Jhansi, Uttar Pradesh, India
2 Department of Biomedical Sciences, Bundelkhand University, Jhansi, Uttar Pradesh, India
|Date of Submission||11-Nov-2013|
|Date of Acceptance||01-Dec-2013|
|Date of Web Publication||29-Mar-2014|
Department of Biomedical Sciences, Bundelkhand University, Jhansi 284 128, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Cypermethrin is a synthetic pyrethroid commonly used in agriculture, veterinary, and household insects/pests management. Resveratrol a polyphenolic phytoalexin abundantly found in grapes and red wine is a potent antioxidant and cytoprotective agent. Objectives: Neurotoxicity of cypermethrin is well-known. The aim of this study was to evaluate neurotoxic effects of cypermethrin and protective role of resveratrol in Wistar rats. Materials and Methods: Thirty male Wistar rats were divided into five groups. Group A served as control. Rats of Group B were treated with cypermethrin at the dose of 3.83 mg/kg body weight (bw) for 7 days. Group C and D were post- and pretreatment of resveratrol (20 mg/kg bw) along with cypermethrin exposure. In Group E, resveratrol served as control. Results: Cypermethrin treated group showed elevation in lipid peroxidation (LPO 83.99%) and inhibition in glutathione (GSH 12.81%), superoxide dismutase (SOD 17.08%), catalase (CAT 11.51%), glutathione-S-transferase (GST 12.12%), glutathione reductase (GR 77.55%), glutathione peroxidase (GPX 23.78 %), total protein (42.95%), and acetylcholinesterase (AChE) activity (47.64%) in rat brain. Posttreatment, pretreatment, and treatment with resveratrol reversed the toxic effect induced by cypermethrin. Conclusion: Our findings strongly suggest that cypermethrin-induced neurotoxicity may be mediated through free radical formation, reduced antioxidant defense mechanism, and inhibition of acetylcholinestrase (AChE) activity. Cypermethrin may be showing AChE inhibitory activity by interacting with the anionic substrate binding site. Administration of resveratrol increased AChE activity and ameliorated cypermethrin-induced brain damage in Wistar rats.
Keywords: Acetyl cholinesterase, cypermethrin, oxidative stress, resveratrol
|How to cite this article:|
Sharma P, Firdous S, Singh R. Neurotoxic effect of cypermethrin and protective role of resveratrol in Wistar rats
. Int J Nutr Pharmacol Neurol Dis 2014;4:104-11
|How to cite this URL:|
Sharma P, Firdous S, Singh R. Neurotoxic effect of cypermethrin and protective role of resveratrol in Wistar rats
. Int J Nutr Pharmacol Neurol Dis [serial online] 2014 [cited 2021 Jan 25];4:104-11. Available from: https://www.ijnpnd.com/text.asp?2014/4/2/104/129598
| Introduction|| |
Neurotoxicity occurs when exposure to natural or manmade toxic substances (neurotoxicants) alters the normal activity of the nervous system. It may result from exposure to substances used in chemotherapy, radiation treatment, and drug therapies as well as exposure to heavy metals such as lead and mercury, certain foods and food additives, insecticides, pesticides, industrial and/or cleaning solvents, cosmetics, and some naturally occurring substances. Synthetic pyrethroids are considered least toxic and globally account for over 30% of insecticide use.  These pesticides are preferentially used because of their target oriented mechanism of action and rapid biodegradability. ,, Cypermethrin is a synthetic pyrethroid commonly used in agriculture, veterinary, and household insects/pests management.  Although considered to be safe for household applications, some studies indicated the adverse effects of cypermethrin on brain of laboratory animals. , It behaves as a fast-acting neurotoxin in insects. Cypermethrin cause neurotoxicity in mammals and insects by causing a long-lasting prolongation of the normally transient increase in sodium permeability of nerve membrane channels during excitation. These long-lasting trains can cause hundreds to thousands of repetitive nerve impulses in the sense organs. This repetitive activity is induced by pyrethroid damage to the voltage-dependent sodium channel, causing sodium channels to stay open much longer than normal. ,, Repetitive nerve impulses may induce oxidative stress, hence there is possibility of excessive reactive oxygen species (ROS) generation on cypermethrin exposure. In the present study, the effect of cypermethrin on oxidative stress parameters and acetylcholinestrase (AChE) activity was investigated.
Resveratrol (trans-3, 5, 4'- trihydroxystilbene), a polyphenolic phytoalexin abundantly found in grapes and red wine is a potent antioxidant and cytoprotective agent. Nephroprotective effect of resveratrol has been observed in various animal models,  heart,  and brain.  Recently, resveratrol has been shown to be a potent activator of sirtuins, which act in the regulation of apoptosis and cell differentiation  and it seems to protect neurons.  Therefore, the present study was designed to analyze the neuroprotective effects of resveratrol against cypermethrin-induced toxicity in Wistar rats.
| Materials and Methods|| |
Technical grade cypermethrin or alpha-cypermethrin (97%) was gifted from Gharda Chemicals Ltd., Mumbai. Resveratrol was purchased from the Sigma Aldrich (USA). All other chemicals were of analytical grade.
Thirty Wistar rats (250-300 g) of either sex, obtained from animal research division, Central Drug Research Institute, Lucknow (India) were used in this experiment. The animals were given food and water ad libitum and maintained in controlled temperature (22 ± 2°C) with a 12 hour light-dark cycle. Cypermethrin and resveratrol were administered orally by gavaging in dimethyl sulfoxide (0.5 ml) as per treatment schedule given in [Table 1]. Dose of cypermethrin and resveratrol were selected based on current literature in this area.
The animal experiments were carried out as per institutional animal ethical committee guidelines (BU/Pharma/IAEC/10/028). At the end of the experiment, rats were sacrificed, whole brain was removed, weighted, and used for estimation of lipid peroxidation (LPO), nonenzymatic, enzymatic antioxidants, protein content, and acetylcholinesterase (AChE) activity.
Preparation of homogenate
Brain tissues were homogenized with 10 times (w/v) homogenizing buffer (pH 7.4 + 150 mM KCl). Ten percent homogenate used for LPO and GSH estimations. The remaining 10% homogenate was centrifuged at 9,000 rpm. The supernatant (S) obtained was used for SOD, CAT, GPx, GR, GST, and protein estimations.
LPO was estimated by the method as described by Ohkawa.  One milliliter of 10% homogenate was incubated at 37°C for 10 min. One milliliter of 10% chilled (w/v) trichloroacetic acid (TCA) was added to it and centrifuged at 2,500 rpm for 15 min at room temperature. One milliliter of 0.67% thiobarbituric acid (TBA) was added to 1 ml of S and kept in a boiling water bath for 10-15 min. After cooling, 1 ml of distilled water was added to it and absorbance was taken at 530 nm. The results were expressed as nmol MDA/h/g tissue.
Nonenzymatic antioxidant: Reduced glutathione
GSH was estimated by the method described by Ellman.  One milliliter of 5% TCA (w/v) was added to 1 ml of 10% homogenate. The suspension was left for 30 min and centrifuged at 2,500 rpm for 15 min. 0.5 ml of S was taken and 2.5 ml of 5'5'-dithionitrobenzoic acid (DTNB) was added. The suspension was shaken thoroughly and read at 412 nm. The results were expressed as μmol/g tissue.
SOD was estimated by the method described by Kakkar et al.  A total of 650 μl of sodium pyrophosphate buffer was added to 50 μl of brain S fraction; 50 μl phenazine methosulfate (PMS), 150 μl of nitroblue tetrazolium (NBT), and 100 μl nicotinamide adenine dinucleotide phosphate (NADPH) were added and the mixture vortexed thoroughly. The reaction mixture was incubated for 90 s and 500 μl glacial acetic acid was added to stop the reaction. Two milliliter of n-butanol was added, vortexed thoroughly. It was kept at room temperature for 10 min. Absorbance was measured at 560 nm. The results were expressed in terms of μmol/min/mg protein.
CAT was estimated by the method described by Sinha.  One milliliter of phosphate buffered saline (PBS; 0.01 M, pH 7.0) and 0.4 ml water was added to 100 μl of S fraction. Reaction was started by adding 0.5 ml H 2 O 2 . The mixture was incubated at 37°C for 1 min. Reaction was stopped by adding 2 ml of dichromate: Acetic acid reagent and kept at boiling water bath for 15 min. The mixture was cooled, and absorbance was measured at 570 nm. CAT activity was calculated in terms of μmol/min/mg protein.
GPx was estimated by the method described by Rotruck.  0.4 ml tris-HCl buffer (pH 7.5, 0.1 M), 0.2 ml GSH, 0.1 ml sodium azide, 0.1 ml distilled water, 0.1 ml H 2 O 2 and 0.1 ml of enzyme (S fraction) was mixed well and incubated at 37°C for 15 min. After incubation, 0.5 ml TCA was added and centrifuged. 0.5 ml of S was taken, and 2 ml Na 2 HPO 4 2H 2 O and 0.5 ml Ellman's reagent was added. Absorbance was noted at 420 nm. The results were expressed as nmol/min/mg protein.
GR was estimated by the method described by Carlberg and Mannervik.  2.5 ml of buffer (pH 6.6), 0.2 ml NADPH, and 0.2 ml GSH disulfide (GSSG) and 0.1 ml S were mixed and allowed to stand for 30 s. Absorbance was recorded at 340 nm for 3 min at 30 s intervals. GR was calculated in terms of nmol/min/mg protein.
GST was estimated as per a method of Habig.  The reaction mixture consisting of 2.9 ml phosphate buffer + GSH (1 M, pH 6.5), 20 μl 1-chloro-2,4-dinitrobenzene (CDNB, 1 mM), 20 μl enzyme (S fraction) and 60 μl water was mixed to give a total volume of 3.0 ml. Absorbance was recorded at 340 nm, and the enzyme activity was calculated as μmole CDNB conjugate formed/min/mg protein using a molar extinction coefficient of 9.6 × 103 M -1 cm - 1 .
Protein content was estimated by the method of Lowry et al. 
AChE assay was estimated by Ellman.  Brain was weighed and homogenized into 0.1 M phosphate buffer (pH 8.0). 0.4 ml aliquot of the homogenate was added to a cuvette containing 2.6 ml phosphate buffer (0.1 M, pH 8.0) and 100 μl of DTNB. The contents of the cuvette were mixed thoroughly by bubbling air and absorbance was measured at 412 nm in a LKB spectrophotometer. When absorbance reaches a stable value, it was recorded as basal reading. Twenty microliter of substrate, that is, acetylthiocholine was added and change in absorbance was recorded for a period of 10 min at an interval of 2 min. Change in the absorbance/minute was determined. The results were expressed as nmol/min/g tissue.
Mean and standard error were determined for all the parameters, and the results were expressed as a mean ± standard error of the mean (SEM). The data were analyzed by employing analysis of variance (ANOVA) using statistical software Graph Pad In Stat Software Inc., v. 3.06, San Diego, USA. The Dunnett test for multiple comparisons of groups against control was performed to determine the significant differences among the groups.
| Results|| |
No significant (P > 0.05) change was observed in brain weight of rats exposed to cypermethrin, Posttreatment, pretreatment, and resveratrol treatment groups as compared to control [Table 2].
|Table 2: Effect of resveratrol against cypermethrin-induced neurotoxicity in Wistar rats |
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Cypermethrin exposure for 1 week elicited a significant (P < 0.01) increase (83.99%) in LPO as compared to the control. Posttreatment (17.02%) and pretreatment (15.02%) with resveratrol significantly (P < 0.05) increased the LPO level while a significant (P < 0.05) decrease in the LPO (28.52%) was observed only in resveratrol treatment group [Table 2].
GSH level was significantly (P < 0.05) decreases (12.81%) in brain on cypermethrin exposure as compared to the control group. Resveratrol showed a nonsignificant (P > 0.05) decrease in GSH in posttreatment group (5.42%) and pretreatment group (3.38%) as compared to control. The resveratrol treatment group showed a nonsignificant (P > 0.05) increase in GSH level (9.98%) as compared to the control group [Table 2].
SOD, CAT, GST, GR, and GPx
Significant (P < 0.05) decrease in SOD (17.08%), CAT (11.51%), GST (12.12%), GR (77.55%), and GPx (23.78%) activity was observed in cypermethrin exposed rats as compared to the control. Posttreatment and pretreatment with resveratrol nonsignificantly (P > 0.05) decreased the SOD (8.23 and 9.91%), CAT (2.94 and 2.39%), GST (4.24 and 4.84%), GR (24.27 and 22.25%), and GPx (13.56 and 10.30%) activity. Nonsignificant (P > 0.05) increase in SOD (10.48%), CAT (3.13%), GST (6.66%), and significant (P < 0.05) in GR (48.24%), GPx (25.48%) activity was observed on resveratrol treatment as compared to control [Table 2].
The cypermethrin treatment showed a significant (P < 0.01) decrease in protein content (42.95%). A nonsignificant (P > 0.05) decrease in the posttreatment (11.38%) and pretreatment (9.06%) and significant (P < 0.05) increase in treatment (26.39%) group was observed as compared to control [Table 2].
The present study showed that cypermethrin exposure resulted in a significant (P < 0.01) decrease in brain AChE activity (47.64%) compared to control. The post- and pretreatment of resveratrol nonsignificantly (P > 0.05) decreased (12.63 and 11.49%, respectively) AchE activity; however, the treatment group showed significant (P < 0.05) increase in AchE (23.40%) activity as compared to control [Table 2].
| Discussion|| |
The brain is vital part of the organism functioning as coordinating and regulating system for body parts. Any damage due to physical, physiological, and chemical stress may have serious impact on the entire organism. Pesticides are persistent organic pollutants accumulating in various physiological systems of terrestrial animals including human beings and causing adverse health effects. Cypermethrin accumulation causes endocrine disruption,  immunotoxicity,  deoxyribonucleic acid (DNA) damage,  neurotoxicity,  and reproductive toxicity.  Induction of oxidative stress is one of the mechanisms of cell and tissue damage by cypermethrin. Brain is considered highly vulnerable to oxidative stress than other organs of the body as it consumes high amount of oxygen, contains high amounts of polyunsaturated fatty acid (PUFA) and has low levels of antioxidant enzymes.  Although considered to be safe, there are some recent reports on neurotoxicity of cypermethrin in animal models. Cypermethrin is reported to cross blood brain barrier. , Presence of PUFA in brain and lipophilic nature of cypermethrin may be the reason for its preferential accumulation. In this study decrease in weight of brain was observed in rats exposed to cypermethrin as compared to control. Cypermethrin accumulation may cause brain damage which may be responsible for decrease in weight of brain.
Pesticide accumulation in tissue is associated with induction of oxidative stress and production of ROS.  Increase in LPO on 7 days exposure to cypermethrin was observed in this study. Increase in LPO was also associated with decrease in GSH and enzymatic antioxidants. It is postulated that accumulation of cypermethrin increased oxidative stress with increase in ROS. Increased ROS depleted the cellular level of GSH pool. The decrease in cellular level of GSH pool has further enhanced oxidative stress. The enhanced ROS damaged cell membrane structure leading to loss of function and reduced cell viability. , The reduction in GSH level may be due to direct conjugation of GSH with electrophiles species produced by cypermethrin exposure or due to inhibition of GR and GPx. Significant reduction in SOD activity was observed in brain of rats exposed to cypermethrin. Reduction in SOD level may be due to excessive ROS. The excessive ROS may attack the thiol group of cysteine residues and PUFAs of biological membranes leading to cell damage. , Reduction in SOD shall further increase ROS which in turn inactivated CAT. 
In the present study CAT level was decreased, which may be due to the excessive production of superoxides anions after cypermethrin exposure. GPx is the enzyme which plays a primary role in minimizing oxidative damage. Cypermethrin exposure depleted GPx level in rat brain in this study. This reduction may be due to depleted level of GSH. GR is a member of the pyridine-nucleotide disulfide oxidoreductase family of flavoenzymes which catalyzes the reduction of oxidized GSH disulfide to GSH in the presence of NADPH. Sufficient amount of GSH is needed for protection of cells against oxidative stress especially on pesticides exposure.  It is also reported that high level of GSSG inhibits a number of important enzyme systems, including protein synthesis.  In the present study, significant decrease in the GR level of brain was observed in the exposure group as compared to the control. GST catalyzes the conjugation of GSH via a sulfhydryl group to electrophilic centers on a wide variety of substrates. This activity helps in detoxification of breakdown products of pesticides. Binding of GST with cypermethrin or its metabolic products may be responsible of GST depletion. GST was reported to be decreased in cypermethrin exposed group. Decrease in antioxidant enzyme activity was concomitant with decrease in the total protein content in the rat brain. Decrease in total protein contents may be due to the inhibition of protein synthesis and low cell survival due to defective antioxidant enzyme.
Moderate to severe sign of neurobehavioral alterations were observed in cypermethrin exposed rats. The rats showed overt cholinergic activity such as salivation, muscles twisting followed by tremors, choreoathetosis, progressive stretching of hind limbs and immediate thirst for water. These symptoms are indicative of impairment in AChE activity in brain. ,,, Apart from the above symptoms, significant decrease in AChE activity was observed in this study. AChE is an enzyme that is essential for the normal functioning of the central and peripheral nervous system  and is widely distributed in the neural and non-neural tissues.  Previously, decrease in AChE activity in rat brain was observed on B-cyfluthrin (41) and chlorpyrifos and deltamethrin  administration. The active site of AChE is mainly constructed by Phe (338), Try (86), Ser (203), Glu (327), and His (440) residues [Figure 1]. Trp and Phe constitute the cationic where as Ser and His constitute the esteratic binding site of the enzyme. Neurotransmitter acetylcholine binds with both esteratic and anionic sites of AChE. The presence of aromatic amino acids in the active site of the enzyme also creates a hydrophobic region. It is assumed that pesticides including cypermethrin may interact with this hydrophobic region and cause inhibition in AChE activity. We also assume that since CN of cypermethrin is not as much cationic as N of AChE, the cationic-anionic interaction is less possible. Instead the pi-pi interaction between Phe and Trp present in active site of AChE and diphenylether of cypermethrin is more feasible. This interaction may be further stabilized by hydrogen bonding of carbonyl and CN of cypermethrin with side chains of different amino acids in the AChE active site. Finally cypermethrin may bind with Ser, possibly through transestrification or through Michael addition type intermediate interaction with double bond [Figure 1].
A promising approach in the prophylaxis and treatment of neurodegenerative diseases is the use of medicinal plants.  Plants have been reported to improve cognitive behavior in dementia  possess antidepressant and  anticonvulsant activity.  Increase in AChE activity has also been reported from medicinal plants. 
|Figure 1: Schematic representation of possible binding sites of acetylcholinestrase enzyme with cypermethrin|
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Resveratrol is well-known for its antioxidant and anti-inflammatory activity in various body systems. ,, Resveratrol crosses blood brain barrier and exerts neuroprotective activity by upregulating several antioxidant enzymes. , It has been showed that resveratrol prevents apoptotic cell death induced by oxidative stress.  In the present study treatment with resveratrol, decreased LPO in pre- and posttreatment group as compared to cypermethrin exposure. It is assumed that resveratrol may have facilitated removal of ROS during posttreatment and also conferred oxidative stress resistance on pretreatment.
Improvement in weight of brain was observed in rats treated with resveratrol with or without exposure to cypermethrin. Increase in nonenzymatic antioxidant (GSH) and enzymatic antioxidants (SOD, CAT, GPx, GR, GST) was also observed on resveratrol treatment. The antioxidant property of resveratrol may be due to its metal chelating property and increasing concentration of the endogenous antioxidant GSH. , There are reports that resveratrol is capable of transcriptionally activating a battery of genes that includes antioxidant enzymes like SOD, CAT, GPx, and GST. , ROS scavenging and antioxidant enzyme activity of resveratrol  helped in alleviating the oxidative stress, helping in cell survival, and increasing level of total proteins and AChE activity. Pretreatment with resveratrol showed better protective activity as compared to posttreatment. Pretreatment with resveratrol may have toned up the antioxidant defense in the brain of rat and conferred oxidative stress resistance. Increase in the activity of antioxidant enzymes by the non-toxic phytochemical, that is, resveratrol might have resulted in enhanced and timely removal of cypermethrin like xenobiotics. We are further planning to study the dose-dependent effect of resveratrol and the dynamics of its movement across blood brain barrier.
| Conclusions|| |
The findings suggested that cypermethrin-induced neurotoxicity may be mediated through free radical formation, reduced antioxidant defense mechanism, and inhibition of AChE activity. Cypermethrin may be showing AChE inhibitory activity by interacting with the anionic substrate binding site. The study concluded that resveratrol ameliorated cypermethrin-induced brain damage by reducing oxidative stress and by enhancing AChE activity in Wistar rats.
| Acknowledgments|| |
The authors are thankful to Bundelkhand University, Jhansi, India, for providing research facilities for undertaking this work.
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[Table 1], [Table 2]
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