Protective effect of α-lipoic acid against arsenic trioxide-induced acute cardiac toxicity in rats

The clinical use of arsenic trioxide (ATO) is often limited because of its adverse effects. We examined whether α-lipoic acid (LA) protects against the ATO-induced cardiac toxicity. In the chronic study, two of four rats suddenly died by the repeated dosing of ATO, whereas no deaths were observed in combination with LA. In the acute study, continuous ECG recording revealed that intravenous injection of ATO caused transient ST-T change, whereas pretreatment with LA abolished the ATO-induced ECG abnormality in all animals. These results suggest that LA protects against the ATO-induced acute cardiac toxicity and subsequent sudden death in rats.     

Protective effect of palm vitamin E and α-tocopherol against gastric lesions induced by water immersion restraint stress in Sprague-Dawley rats

Objective:

Stress can lead to various changes in the gastrointestinal tract of rats. The present study was designed to compare the effect of palm vitamin E (PVE) and α-tocopherol (α-TF) supplementations on the gastric parameters important in maintaining gastric mucosal integrity in rats exposed to water immersion restraint stress (WRS). These parameters include gastric acidity, plasma gastrin level, gastric prostaglandin E₂ (PGE₂), and gastric lesions.

Materials and Methods:

Sixty male Sprague-Dawley rats (200-250 g) were divided into three equal groups: a control group, which received a normal rat diet (RC), and two treatment groups, receiving oral supplementation of either PVE or α-TF at 60 mg/kg body weight for 28 days. Each group was further divided into two groups: the nonstress and stress groups. The stress groups were subjected to 3.5 h of WRS once at the end of the treatment period. Blood samples were then taken to measure the gastrin level, after which the rats were killed. Gastric juice was collected for measurement of gastric acidity and gastric tissue was taken for measurement of gastric mucosal lesions and PGE₂.

Results:

Exposure to stress resulted in the production of gastric lesions. PVE and α-TF lowered the lesion indices as compared to the stress control group. Stress reduced gastric acidity but pretreatment with PVE and α-TF prevented this reduction. The gastrin levels in the stress group were lower as compared to that in the nonstress control. However, following treatment with PVE and α-TF, gastrin levels increased and approached the normal level. There was also a significant reduction in the gastric PGE₂ content with stress exposure, but this reduction was blocked with treatment with both PVE and α-TF.

Conclusion:

In conclusion, WRS leads to a reduction in the gastric acidity, gastrin level, and gastric PGE₂ level and there is increased formation of gastric lesions. Supplementation with either PVE or α-TF reduces the formation of gastric lesions, possibly by blocking the changes in the gastric acidity, gastrin, and gastric PGE₂ induced by stress. No significant difference between PVE and α-TF was observed.     

Protective effect of acetyl-l-carnitine and α-lipoic acid against the acute toxicity of diepoxybutane to human lymphocytes

The biotransformation and oxidative stress may contribute to 1,2:3,4-diepoxybutane (DEB)-induced toxicity to human lymphocytes of Fanconi Anemia (FA) patients. Thus, the identification of putative inhibitors of bioactivation, as well as the determination of the protective role of oxidant defenses, on DEB-induced toxicity, can help to understand what is failing in FA cells. In the present work we studied the contribution of several biochemical pathways for DEB-induced acute toxicity in human lymphocyte suspensions, by using inhibitors of epoxide hydrolases, inhibitors of protective enzymes as glutathione S-transferase and catalase, the depletion of glutathione (GSH), and the inhibition of protein synthesis; and a variety of putative protective compounds, including antioxidants, and mitochondrial protective agents. The present study reports two novel findings: (i) it was clearly evidenced, for the first time, that the acute exposure of freshly isolated human lymphocytes to DEB results in severe GSH depletion and loss of ATP, followed by cell death; (ii) acetyl-l-carnitine elicits a significant protective effect on DEB induced toxicity, which was potentiated by α-lipoic acid. Collectively, these findings contribute to increase our knowledge of DEB-induce toxicity and will be very useful when applied in studies with lymphocytes from FA patients, in order to find out a protective agent against spontaneous and DEB-induced chromosome instability.     

Protective effect of L-Theanine against aluminium induced neurotoxicity in cerebral cortex,hippocampus and cerebellum of rat brain – histopathological,and biochemical approach

L-Theanine is an amino acid derivative primarily found in tea. It has been reported to promote relaxation and have neuroprotective effects. The present study was designed to investigate the role of oxidative stress and the status of antioxidant system in the management of aluminum chloride (AlCl₃) induced brain toxicity in various rat brain regions and further to elucidate the potential role of L-Theanine in alleviating such negative effects. Aluminium administration significantly decreased the level of reduced glutathione and the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, Na⁺/K⁺ ATPase, Ca²⁺ ATPase and Mg²⁺ ATPase and increased the level of lipid peroxidation and the activities of alkaline phosphatase, acid phosphatase, alanine transaminase and aspartate transaminase in all the brain regions when compared with control rats. Pre-treatment with L-Theanine at a dose of 200?mg/kg b.w. significantly increased the antioxidant status and activities of membrane bound enzymes and also decreased the level of LPO and the activities of marker enzymes, when compared with aluminium induced rats. Aluminium induction also caused histopathological changes in the cerebral cortex, cerebellum and hippocampus of rat brain which was reverted by pretreatment with L-Theanine. The present study clearly indicates the potential of L-Theanine in counteracting the damage inflicted by aluminium on rat brain regions.     

Antiapoptotic efficacy of folic acid and vitamin B₁₂ against arsenic-induced toxicity

Earlier, we proposed that the ability of folic acid and vitamin B₁₂ to preserve systemic and mitochondrial function after short‐term exposure to arsenic may prevent further progression to more permanent injury and pathological changes leading to cell death. To elucidate its mechanism, the present study examined the antiapoptotic efficacy of folic acid and vitamin B₁₂ against short‐term arsenic exposure‐induced hepatic mitochondria oxidative stress and dysfunction. Sixteen to eighteen weeks old male albino rats weighing 140–150 × g were divided into five groups: Control (A), Arsenic‐treated (B), Arsenic + folic acid (C), Arsenic +vitamin B₁₂ (D), and Arsenic + folic acid + vitamin B₁₂ (E). Data generated indicated that folic acid and vitamin B₁₂ separately or in combination can give significant protection against alterations in oxidative stress and apoptotic marker parameters and downstream changes in mitochondria, namely pro‐oxidative (NO, TBARS, OH^?) and antioxidative defense (SOD, CAT, GSH) markers, iNOS protein expression, mitochondrial swelling, cytochrome c oxidase and Ca²⁺‐ATPase activity, Ca²⁺ content, caspase‐3 activity. Additionally, results of hepatic cell DNA fragmentation, arsenic load of blood, hepatic tissue and urine, and histological observations, all strongly support that both these supplements have efficacy in preventing apoptotic changes and cellular damage. As the mechanisms of actions of both of these supplements are methylation related, a combined application was more effective. Results further reveal new molecular targets through which folic acid and vitamin B₁₂ separately or in combination work to alleviate one critical component of arsenic‐induced liver injury: mitochondria dysfunction. © 2010 Wiley Periodicals, Inc. Environ Toxicol, 2012.     

Genomic and proteomic analyses of 1,3-dinitrobenzene-induced testicular toxicity in Sprague–Dawley rats

1,3-Dinitrobenzene (DNB) is an industrial intermediate and testicular toxicant that has been shown to target Sertoli cells. The mechanism of action of DNB in the testis, however, is unclear. To investigate global alterations in gene or protein expression during testicular toxicity, testes from rats treated orally with DNB were subjected to microarray and two-dimensional gel electrophoresis (2-DE) analyses. Histopathological abnormalities were detected in the testes of the DNB-treated rats. Microarray analysis revealed that, during early testicular toxicity, several genes involved in apoptosis, germ cell/Sertoli cell junction, and tight junction signaling pathways were differentially expressed. Based on 2-DE analysis, 36 protein spots showing significantly different expression during early testicular toxicity were selected and identified. Network analysis of the identified proteins revealed that these proteins are associated with cellular development or reproductive system diseases. Collectively, these data will help clarify the molecular mechanism underlying testicular toxicity in DNB-exposed rats.     

Protective effect of fermented sea tangle against ethanol and carbon tetrachloride-induced hepatic damage in Sprague–Dawley rats

Sea tangle has long been used as Korean folk remedy to promote material health, and is one of the popular dietary supplement. This study was designed to evaluate the protective effect of fermented sea tangle (FST) against ethanol and carbon tetrachloride (CCl₄)-induced hepatotoxicity in rats. Sprague–Dawley rats were orally treated with FST (25, 250, 2500 mg/kg/day) with administration of ethanol (5 mL/kg) for 13 weeks and the single intraperitoneal (i.p.) dose of 50% CCl₄ (5 mL/kg/day, CCl₄ in olive oil) at 12 week, and repeated i.p. dose of 20% CCl₄ (2 mL/kg/day) for 1 week. Hepatotoxicity was evaluated by measuring the serum levels of glutamic pyruvate transaminase (GPT), gamma glutamyl transpeptidase (γ-GT) and malondialdehyde (MDA) as well as the tissue levels of antioxidant enzyme such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Ethanol and CCl₄-induced the rat liver damage, and significantly increased (p < 0.05) the GPT, γ-GT and MDA levels, and decreased the SOD, CAT and GPx levels. However, treatment with FST could decrease serum GPT, γ-GT, and MDA levels significantly in plasma, and increase the activities of SOD, CAT, and GPx in liver tissues compared with ethanol and CCl₄-treated group.     

Strain difference of cadmium-induced testicular toxicity in inbred Wistar–Imamichi and Fischer 344 rats

Previously, we reported that Wistar–Imamichi (WI) rats are highly resistant to cadmium (Cd)-induced lethality and hepatotoxicity compared to Fischer 344 (F344) rats. Since the testes are one of the most sensitive organs to acute Cd toxicity, we examined possible strain-related differences in Cd-induced testicular toxicity between inbred WI and F344 rats. Rats were treated with a single dose of 0.5, 1.0 or 2.0 mg Cd/kg, as CdCl₂, sc and killed 24 h later. Cd at doses of 1.0 and 2.0 mg/kg induced severe testicular hemorrhage, as assessed by pathological and testis hemoglobin content, in F344 rats, but not WI rats. After Cd treatment (2.0 mg/kg), the testicular Cd content was significantly lower in WI rats than in the F344 rats, indicating a toxiokinetic mechanism for the observed strain difference. Thus, the remarkable resistance to Cd-induced testicular toxicity in WI rats is associated, at least in part, with lower testicular accumulation of Cd. When zinc (Zn; 10 mg/kg, sc) was administered in combination with Cd (2.0 mg/kg) to F344 rats, the Cd-induced increase in testicular hemoglobin content, indicative of hemorrhage, was significantly reduced. Similarly, the testicular Cd content was significantly decreased with Zn co-treatment compared to Cd treatment alone. Thus, it can be concluded that the testicular Cd accumulation partly competes with Zn transport systems and that these systems may play an important role in the strain-related differences in Cd-induced testicular toxicity between WI and F344 rats.     

Protective effect of Diyarbak?r watermelon juice on carbon tetrachloride-induced toxicity in rats

The present study was designed to evaluate the effect of Diyarbak?r watermelon (Citrullus lanatus cv. Sürme) juice on lipid peroxidation states in rat liver, kidney and brain. In vivo administration of carbon tetrachloride (CCl₄) once a week for 28 days caused a significant elevation of serum markers of liver damage, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB) and decrease in albumin when compared to the control group. However, administration of carbon tetrachloride along with watermelon juice or ursodeoxycolic acid (UDCA) significantly reduces these changes. Increased lipid peroxide (LPO) level was observed in the liver, kidney and brain tissues after CCl₄ administration. However, watermelon juice and UDCA treatment prevented the increase in LPO. The results indicated that watermelon juice protects the liver, kidney and brain tissues from experimental CCl₄ toxicity in rats and that the protective effect of watermelon juice may be due to its antioxidant activity and inhibition of lipid peroxide formation. In conclusion, present study reveals biological evidence that supports the use of watermelon juice in the treatment of chemical-induced hepatotoxicity.     

Protective effect of hesperidin against γ-radiation induced oxidative stress in Sprague-Dawley rats

The high risk of human exposure to ionizing radiations during radiation therapy and also during space travel underscores the need to develop novel radioprotectors with improved efficacy. Increased oxidative stress and antioxidant deficit have been suggested to play a major role in radiation induced toxicity, and hence maintaining an antioxidant balance through dietary supplementation might provide beneficial effects during radiation exposure. The present study was designed to evaluate the effect of hesperidin, a flavanone glycoside found in citrus plants, on the antioxidant defense system and lipid peroxidation against γ-radiation induced damage in rats. Exposure of rats to γ-radiation (5 Gy) resulted in tissue damage characterized by significantly elevated levels of serum marker enzymes (AST, ALT, ALP, LDH, and CPK) and a decrease in their activities in the heart tissue. γ-Radiation induced oxidative stress was observed by elevated levels of lipid peroxidation and a decrease in the activities of endogenous antioxidants (SOD, CAT, GPx, and GSH) in the heart and kidney of rats. Post-treatment with hesperidin (50 and 100?mg/kg bw/day, orally) for 7 days following exposure to γ-radiation significantly attenuated these changes when compared to the radiation exposed groups. Histopathological examination of the heart tissue of rats exposed to γ-radiation and treated with hesperidin also showed minimal damage when compared to those exposed to γ-radiation alone. These findings indicate the protective effect of hesperidin on lipid peroxidation and the antioxidant tissue defense system during γ-radiation induced tissue damage in rats.     

Protective effects of stigmasterol against ketamine‐induced psychotic symptoms: Possible behavioral,biochemical and histopathological changes in mice

Background

Stigmasterol, a naturally occurring phytoestrogen has been reported to possess many pharmacological activities. The aim of the present study was to screen the effect of stigmasterol against ketamine-induced mice model of psychosis.

Protective effect of Salacia oblonga against tobacco smoke-induced DNA damage and cellular changes in pancreatic β-cells

Context: Tobacco smoking generates a tremendous amount of free radicals that induce oxidative stress (OS) in diabetics (pancreatic islet cells are defective). Salacia oblonga Wall. (Celastraceae) is a proven antioxidant and antidiabetic plant whose mechanism of action is yet to be explored.

Objective: The present study focuses on the protective ability of S. oblonga in tobacco smoke-induced oxidatively stressed pancreatic β-cell line.

Materials and methods: The RINm5f cell line was exposed to tobacco smoke concentrate (TSC) (0.5–10%, 24?h), plant extract (1–75?µg/ml, 3?h), and their combinations. Cell viability was determined through MTT assay. Microscopic analysis was carried out in unstained and nonyl acridine orange-stained cells. The effect of toxic doses of TSC on DNA integrity was analyzed through DNA fragmentation assay. The TSC-induced nitric oxide generation was determined spectrophototmetrically. The expression of anti-apoptotic protein Bcl-X under the above treatment conditions was carried out through RT-PCR.

Results: The LD₅₀ dose for TSC was found to be 1% TSC. Salacia oblonga extracts (10 and 15?µg/ml) were found to be optimum safe doses that significantly increased cell viability and decreased the nitric oxide production in TSC-treated cells. Pre-treatment with plant extract suppressed apoptosis through probable increase in the expression of anti-apoptotic protein Bcl-X in TSC-treated cells. Thus, the overall efficiency of plant extract in recovering cellular damage was proven.

Discussion and conclusion: The results suggest that TSC-induced cellular alterations are related to rise in nitric oxide and Bcl-X mRNA expression and propose that S. oblonga may confer significant cytoprotection against OS-mediated injury in β-cells.     

Protective effect of carnosine against NMDA -induced neurotoxicity in differentiated rat PC12 cells

Aim： To investigat the neuroprotective effects of carnosine and its mechanisms of action in an in vitro model of neurotoxicity. Methods： Cultured differentiated PC12 cells were exposed to N -methyl -D -aspartate （NMDA） in the presence or absence of carnosine or other histaminergic drugs. Cell viability was assayed by the MTT assay. Changes in the levels of carnosine, histidine, histamine, glutamate and GABAin PC12 cells were measured by high - performance liquid chromatography combined with electrochemical detection. Results： Pretreatment with carnosine effectively reduced neuronal cell death and decreased the number of apoptotic and necrotic cells induced by NMDA insult. The neuroprotection by carnosine was reversed by pyrilamine and thioperamide, selective central histamine H1 and H3 antagonists, α - fluoromethylhistidine, a selective and irreversible inhibitor of histidine decarboxylase （HDC） also significantly reversed the protection of carnosine. Pretreatment with carnosine significantly increased HDC activity and the intracellular and extracellular content of carnosine, histidine and histamine. Further, it inhibited glutamate release in the presence or absence of excitotoxic concentrations of NMDA, an effect that was reversed by thioperamide. Conclusions： Carnosine protects against NMDA - induced neurotoxicity in differentiated PC12 cells and its mechanism of action may not only involve the camosine- histidine -histamine pathway, but also H1/H3 receptors and the effective inhibition of glutamate release. This study indicates that carnosine may be an endogenous neuroprotective factor in the brain and may be useful as a new antiexcitotoxic drug.     

Protective effect of (+)–catechin against lipopolysaccharide-induced inflammatory response in RAW 264.7 cells through downregulation of NF-κB and p38 MAPK

Inflammopharmacology - Catechin, a flavonol belonging to the flavonoid group of polyphenols is present in many plant foods. The present study was done to evaluate the effect of catechin on various...     

Protective effect of centipedegrass against Aβ oligomerization and Aβ-mediated cell death in PC12 cells

Abstract

Context: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the abnormal accumulation of β-amyloid (Aβ). Multiple Aβ-aggregated species have been identified, and neurotoxicity appears to be correlated with the amount of non-fibrillar oligomers. Potent inhibitors of Aβ oligomer formation or Aβ-induced cell toxicity have emerged as attractive means of therapeutic intervention. Eremochloa ophiuroide Hack. (Poaceae), also known as centipedegrass (CG), originates from China and South America and is reported to contain several C-glycosyl flavones and phenolic constituents.

Objective: We investigated whether CG could suppress Aβ aggregation, BACE1 activity, and toxicity at neuronal cell.

Materials and methods: The inhibitory effect of CG extracts toward aggregation of Aβ42 was investigated in the absence and presence of 50?µg/mL CG. We investigated the inhibitory effects of CG (0–5?µg/mL) on BACE1 using fluorescence resonance energy transfer (FRET)-based assay. The effects of CG (0–75?µg/mL) on Aβ42-induced neurotoxicity were examined in PC12 cells in the presence or absence of maysin and its derivatives of CG.

Results: We isolated EA-CG fraction (70% MeOH fraction from EtOAc extracts) from methanol extracts of CG, which contained approximately 60% maysin and its derivatives. In the present studies, we found that several Aβ oligomeric forms such as the monomer, dimer, trimer, and highly aggregated oligomeric forms were remarkably inhibited in the presence of 50?µg/mL of EA-CG. EA-CG also inhibited BACE1 enzyme activity in a dose-dependent manner. EA-CG treatment generated approximately 50% or 85% inhibition to the control at the tested concentrations of 1 or 5?µg/mL, respectively. Moreover, the neurotoxicity induced by Aβ42 was significantly reduced by treatment of EA-CG, and the 75?µg/mL EA-CG treatment significantly increased cell viability up to 82.5%.

Discussion and conclusion: These results suggested that the anti-Alzheimer’s effects of CG occurred through inhibition of neuronal cell death by intervening with oligomeric Aβ formation and reducing BACE1 activity. Maysin in CG could be an excellent therapeutic candidate for the prevention of AD.     

Protective role of olesoxime against wild-type α-synuclein-induced toxicity in human neuronally differentiated SHSY-5Y cells

BACKGROUND AND PURPOSE

Parkinson''s disease (PD) is usually diagnosed clinically from classical motor symptoms, while definitive diagnosis is made postmortem, based on the presence of Lewy bodies and nigral neuron cell loss. α-Synuclein (ASYN), the main protein component of Lewy bodies, clearly plays a role in the neurodegeneration that characterizes PD. Additionally, mutation in the SNCA gene or copy number variations are associated with some forms of familial PD. Here, the objective of the study was to evaluate whether olesoxime, a promising neuroprotective drug can prevent ASYN-mediated neurotoxicity.

EXPERIMENTAL APPROACH

We used here a novel, mechanistically approachable and attractive cellular model based on the inducible overexpression of human wild-type ASYN in neuronally differentiated human neuroblastoma (SHSY-5Y) cells. This model demonstrates gradual cellular degeneration, coinciding temporally with the appearance of soluble and membrane-bound ASYN oligomers and cell death combining both apoptotic and non-apoptotic pathways.

KEY RESULTS

Olesoxime fully protected differentiated SHSY-5Y cells from cell death, neurite retraction and cytoplasmic shrinkage induced by moderate ASYN overexpression. This protection was associated with a reduction in cytochrome c release from mitochondria and caspase-9 activation suggesting that olesoxime prevented ASYN toxicity by preserving mitochondrial integrity and function. In addition, olesoxime displayed neurotrophic effects on neuronally differentiated SHSY-5Y cells, independent of ASYN expression, by promoting their differentiation.

CONCLUSIONS AND IMPLICATIONS

Because ASYN is a common underlying factor in many cases of PD, olesoxime could be a promising therapy to slow neurodegeneration in PD.     

Pro-oxidant–antioxidant balance in Iranian veterans with sulfur mustard toxicity and different levels of pulmonary disorders

Objective: Sulfur mustard (SM) is a strong alkylating agent that primarily targets the skin, eye and lung. The current study evaluated the pro-oxidant–antioxidant balance (PAB) assay in human serum of SM-exposed patients. Design and methods: sera of 35 SM-exposed patients and 19 healthy volunteers were recruited. Both groups had nonsmoker and nonalcoholic people with no diseases such as diabetes, heart disease and other pulmonary diseases (COPD because of smoking, asthma and so on). All patients had documented exposure to SM. The PAB was measured. Results: SM-exposed patients with normal values for pulmonary function test and severe obstructive pulmonary disease demonstrated a significant increase in PAB value in compared with healthy volunteers (the PAB values in healthy volunteers, normal and severe patients were 48.74?±?21.07 HK, 101.45?±?32.68 HK and 120.23?±?31.55 HK, respectively). However, the level of oxidation is not related to the severity of disease defined by spirometry findings. A significant negative correlation was established between the PAB value and FEV₁.

Conclusions: The increased PAB value in chemical casualties showed that these patients are exposed to oxidative stress.     

Alterations in Ca²⁺ homeostasis and oxidative damage induced by ethion in erythrocytes of Wistar rats: ameliorative effect of vitamin E

Organophosphate (OP) insecticides have been reported to induce oxidative stress due to lipid peroxidation and alteration in defense mechanisms. It is known that calcium content in erythrocytes plays a very important in normal physiology of cells. Erythrocytes are a very convenient model to understand the susceptibility of membrane to oxidative damage induced by various xenobiotic compounds. The aim of present study was to investigate the effects of ethion induced oxidative damage, alterations in membrane bound enzymes and Ca(2+) homeostasis and a possible protective role of vitamin E. Adult male albino rats of Wistar strain were orally administered ethion and vitamin E daily for 28 days. Animals were randomly divided into four groups: control; ethion treated (2.7 mg/kgbw/day); vitamin E treated (50mg/kg of bw/day); ethion+vitamin E treated. The animals were sacrificed after 7, 14, 21 and 28 days. Erythrocyte membranes were prepared and analyzed for protein, lipid peroxidation (LPO) and membrane bound ATPases. Furthermore, Ca(2+) homeostasis as function of time and concentration was evaluated in erythrocytes. The results from the present study show that in vivo administration of ethion resulted in oxidative damage to erythrocyte membranes as evident by increased lipid peroxidation. The increased LPO following ethion intoxication was accompanied by significant decrease in the activities of Na(+)/K(+)-ATPase, Mg(2+)-ATPase and Ca(2+)-ATPase and disturbed Ca(2+)homeostasis in erythrocytes. Furthermore, vitamin E treatment had a beneficial effect by decreasing lipid peroxidation; partially restoring activities of membrane bound ATPases and Ca(2+) homeostasis. The present study suggests that ethion exerts its toxic effect by increasing LPO, altering the activity of membrane bound enzymes and disturbing Ca(2+) homeostasis. Vitamin E treatment ameliorated the toxic effects of ethion suggesting its role as a potential antioxidant.     

Protective effects of mecamylamine and atropine against α(4)β(2) nicotinic receptor expression and functional toxicity in paraoxon-treated rats

Chronic and acute exposure to organophosphate pesticides or related nerve agents may lead to persistent neurological and neurobehavioral effects, which cannot be explained by acetylcholinesterase (AChE) inhibition alone. In the present study, the effects of mecamylamine (2mg/kg), or atropine (10mg/kg) alone, or in combination, on the expression of nicotinic acetylcholine receptors (nAChRs) subunits, functional signs of toxicity and lethality in paraoxon-treated rats were investigated. Surviving animals were sacrificed after 48h of paraoxon administration. Paraoxon, at dosage of 1× LD50, significantly reduced expression of α(4) and β(2) nAChR subunits mRNA and protein in rat brain homogenates. Mecamylamine, efficiently prevented reduction of the α(4) and β(2) nAChR mRNA and protein in paraoxon exposed rat brains, but atropine was not efficient. Concurrent treatment with mecamylamine and atropine restored nAChRs mRNA and protein level and prevented lethality and severe involuntary movements induced by paraoxon. Nicotinic receptors antagonists may be included in the cocktail of therapeutic agents targeting the various mechanisms for neuronal injury by organophosphates.