Imidacloprid-based commercial pesticide causes behavioral, biochemical, and hematological impairments in Wistar rats.

Imidacloprid (IMI) is a neonicotinoid insecticide employed worldwide for crop protection. IMI's mode of action occurs through the agonism of postsynaptic nicotinic acetylcholine receptors (nAChRs), with high specificity for insect nAChRs although there are reports of mammals' toxicity. Studies on IMI's neurotoxicity are not conclusive; therefore, the aim of this study was to evaluate the subchronic toxic effects of an IMI based commercial pesticide on rats. Adult male Wistar rats received an IMI suspension via the oral route at doses of 1.5, 5, and 15 mg/kg for 45 consecutive days. IMI caused an increase in rearing and time spent at the periphery in the locomotor activity test and a decrease in time spent to finish the OX maze task (p < 0.05; ANOVA/Bonferroni). In blood, there was a decrease in mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration (p < 0.05; ANOVA/Bonferroni) and an increase in serum butyrylcholinesterase activity (p < 0.001; ANOVA/Bonferroni). Therefore, subchronic administration of an IMI-based-pesticide caused behavioral and systemic impairments in rats.

6-Shogaol Exerts a Neuroprotective Factor in Offspring after Maternal Immune Activation in Rats.

6-Shogaol is one of the main active phenolic components of ginger and has neuroprotective effects by protecting brain against the oxidative stress and regulate the levels of neurotrophic factors. The objective of the present study was to verify the effect of 6-shogaol on neurochemical parameters in offspring after maternal immune activation by lipopolysaccharide (LPS) in rats. Twelve pregnant Wistar rats received 100 µg/kg of LPS or saline solution on the gestational day 9.5. Male offspring participated in the study and from the postnatal days (PND) 30 and 55, respectively, they were supplemented with 6-shogaol or saline solution, by gavage at a dose of 10 mg/kg/day, orally for 5 days. In PND 37 and 62, analysis of kinase signaling regulated by extracellular signal 1/2 (ERK 1/2), levels of neurotrophic factor derived from the brain (BDNF), and neuron-specific enolase (NSE), lipid and protein oxidative damage was evaluated by 4-hydroxy-2-nonenal (HNE) and 3-nitrotyrosine (3-NT), respectively, and myeloperoxidase (MPO) activity was performed in the hippocampus. Prenatal exposure to LPS significantly decreased ERK and BDNF levels in PND 37 and 62, increased NSE levels and lipid damage in rats in PND 37, and increased 3-NT level in rats in PND 62. With treatment using 6-shogaol, an increase in ERK and BDNF levels was identified in PND 37 and 62 and a reduction in HNE and MPO activity in rats in PND 37 and 62, respectively. 6-Shogaol positively increased markers of neuronal growth, plasticity and synaptic activity and reduced oxidative damage in the hippocampus in an animal model of autism by maternal immune activation.

6-Shogaol improves behavior and memory in Wistar rats prenatally exposed to lipopolysaccharide.

OBJECTIVE: 6-Shogaol, bioactive compound of Zingiber officinale Roscoe, has anti-inflammatory, antioxidant, and neuroprotective properties. The objective of the present study was to verify the effect of 6-shogaol on behavioral parameters in a preclinical model based on a maternal immune activation (MIA) by lipopolysaccharide (LPS). METHODOLOGY: Twelve pregnant Wistar rats received 100-µg/kg LPS or saline solution on gestational day (GD) 9.5. Male offspring participated in the study and in the postnatal day (PND) 30 and 55 were supplemented with 6-shogaol or saline solution, by gavage at a dose of 10 mg/kg/day, orally for 5 days. In the PND 35 and 60 was performed the behavioral tests: grooming, crossing, and rearing that evaluated repetitive movements, anxiety, and interest in the new, respectively, and the inhibitory avoidance test that evaluated short-term (STM) and long-term memory (LTM). RESULT: Prenatal exposure to LPS increased the grooming and crossing episodes at different ages and reduced rearing episodes in PND 37. Treatment with 6-shogaol reversed these parameters. In the inhibitory avoidance test, an improvement of memory was identified with 6-shogaol in the STM and LTM at both ages comparing training and test session of treated groups and between groups. CONCLUSION: Administration of 6-shogaol reverses the stereotypy, exploratory behavior, and memory impairment in prenatal LPS-exposed offspring, acting as a promising therapeutic component against brain disorders associated with the process of MIA.

Levamisole, a cocaine cutting agent, induces acute and subchronic systemic alterations in Wistar rats.

The use of the anthelmintic levamisole as a cocaine adulterant has been increasing worldwide. Complications caused by this association include systemic vasculitis, agranulocytosis, neutropenia, tissue necrosis, pulmonary hemorrhage, and renal injury. Data about toxicity of levamisole are scarce, therefore the aim of this study was to evaluate the acute and subchronic toxic effects of levamisole in rats. Male Wistar rats received saline or levamisole by intraperitoneal route at the doses of 12, 24 and 36 mg/kg in the acute toxicity test; and at 3, 6 and 12 mg/kg in the subchronic toxicity test. Toxicity was evaluated using behavioral, cognitive, renal, hematological, biochemical and histopathological parameters. Acute administration of levamisole caused behavioral and histopathological alterations. Subchronic administration caused behavioral, cognitive and hematological alterations (p < 0.0001 and p < 0.05, respectively), impairment of liver and kidney functions (p < 0.05), and changes of antioxidant defenses (p ≤ 0.0001). Both administrations produced toxic effects of clinical relevance, which make levamisole a dangerous cutting agent. Furthermore, the knowledge of these effects can contribute to the correct diagnosis and treatment of cocaine dependents with unusual systemic alterations.

Fish oil-rich lipid emulsion modulates neuroinflammation and prevents long-term cognitive dysfunction after sepsis.

OBJECTIVES: Sepsis is a severe organic dysfunction caused by an infection that affects the normal regulation of several organ systems, including the central nervous system. Inflammation and oxidative stress play crucial roles in the development of brain dysfunction in sepsis. The aim of this study was to determine the effect of a fish oil (FO)-55-enriched lipid emulsion as an important anti-inflammatory compound on brain dysfunction in septic rats. METHODS: Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) or sham (control) and treated orally with FO (600 µL/kg after CLP) or vehicle (saline; sal). Animals were divided into sham+sal, sham+FO, CLP+sal and CLP+FO groups. At 24 h and 10 d after surgery, the hippocampus, prefrontal cortex, and total cortex were obtained and assayed for levels of interleukin (IL)-1ß and IL-10, blood-brain barrier permeability, nitrite/nitrate concentration, myeloperoxidase activity, thiobarbituric acid reactive species formation, protein carbonyls, superoxide dismutase and catalase activity, and brain-derived neurotrophic factor levels. Behavioral tasks were performed 10 d after surgery. RESULTS: FO reduced BBB permeability in the prefrontal cortex and total cortex of septic rats, decreased IL-1ß levels and protein carbonylation in all brain structures, and diminished myeloperoxidase activity in the hippocampus and prefrontal cortex. FO enhanced brain-derived neurotrophic factor levels in the hippocampus and prefrontal cortex and prevented cognitive impairment. CONCLUSIONS: FO diminishes the negative effect of polymicrobial sepsis in the rat brain by reducing inflammatory and oxidative stress markers.

Effects of prenatal exposure to temephos on behavior and social interaction.

The neurodevelopment period is susceptible to alterations by genetic and environmental factors, such as the exposure to organophosphates (OP). The OP is neurotoxic and has been associated with neurological diseases pathophysiology. The OP temephos is widely used against Aedes aegypti in Brazil's public health programs. PURPOSE: To evaluate behavioral effects of prenatal exposition to temephos in Wistar rats. METHODS: First, we divided pregnant females into groups: those who received temephos diluted in distilled water by gavage between gestational days 6-13 and those who received only distilled water in the same period and volume. Then, we divided pups according to sex and exposure, and we made the behavioral tests on postnatal day 30. RESULTS: Prenatal exposure to temephos caused hyperactivity, stereotyped behavior, and social impairment in animals. CONCLUSION: These results are similar to the altered behavior presented in some neurobiological diseases models, like Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorders, and this study may bring a red alert to the large use of temephos in Brazil, due to the damage caused by its exposure.

Oxidative stress and mitochondrial dysfunction contributes to postoperative cognitive dysfunction in elderly rats.

Postoperative cognitive dysfunction (POCD) is defined by cognitive impairment determined by neuropsychological tests from before to after surgery. Several mechanisms have been proposed in this bidirectional communication between the immune system and the brain after surgery. We aimed at understanding the mechanisms underlying POCD elderly rats in an experimental tibial fracture model. Elderly male Wistar rats were subjected to tibial fracture (TF) model. Control (sham) and fracture (TF) groups were followed to determine nitrite/nitrate concentration; oxidative damage to lipids and proteins; the activity of antioxidant enzymes (superoxide dismutase-SOD and catalase-CAT), mitochondrial respiratory chain enzymes, and creatine kinase (CK); and BDNF levels in the hippocampus and prefrontal cortex (at 24 h and at seven days) and cognitive function through habituation to the open field task and novel object recognition task (only at seven days). TF group presented increased concentration of nitrite/nitrate, hippocampal lipid peroxidation at seven days, protein oxidative damage in the prefrontal cortex and hippocampus at 24 h, decreased antioxidant activity in both structures on the first postoperative day and compromised function of the mitochondrial respiratory chain complexes as well as the CK enzyme. In addition, the levels of BDNF were reduced and memory function was impaired in the TF group. In conclusion, elderly rats submitted to an experimental model of tibial fracture displayed memory impairment accompanied by an increase in oxidative stress, mitochondrial dysfunction and reduced neurotrophin level.

Dimethyl Fumarate Limits Neuroinflammation and Oxidative Stress and Improves Cognitive Impairment After Polymicrobial Sepsis.

Sepsis is caused by a dysregulated host response to infection, often associated with acute central nervous system (CNS) dysfunction, which results in long-term cognitive impairment. Dimethyl fumarate (DMF) is an important agent against inflammatory response and reactive species in CNS disorders. Evaluate the effect of DMF on acute and long-term brain dysfunction after experimental sepsis in rats. Male Wistar rats were submitted to the cecal ligation and puncture (CLP) model. The groups were divided into sham (control) + vehicle, sham + NAC, sham + DMF, CLP + vehicle, CLP + NAC, and CLP + DMF. The animals were treated with DMF (15 mg/kg at 0 and 12 h after CLP, per gavage) and the administration of n-acetylcysteine (NAC) (20 mg/kg; 3, 6, and 12 h after CLP, subcutaneously) was used as positive control. Twenty-four hours after CLP, cytokines, myeloperoxidase (MPO), nitrite/nitrate (N/N), oxidative damage to lipids and proteins, and antioxidant enzymes were evaluated in the hippocampus, total cortex, and prefrontal cortex. At 10 days after sepsis induction, behavioral tests were performed to assess cognitive damage. We observed an increase in cytokine levels, MPO activity, N/N concentration, and oxidative damage, a reduction in SOD and GPx activity in the brain structures, and cognitive damage in CLP rats. DMF treatment was effective in reversing these parameters. DMF reduces sepsis-induced neuroinflammation, oxidative stress, and cognitive impairment in rats subjected to the CLP model.

Vitamin B6 Reduces Neurochemical and Long-Term Cognitive Alterations After Polymicrobial Sepsis: Involvement of the Kynurenine Pathway Modulation.

Neurological dysfunction as a result of neuroinflammation has been reported in sepsis and cause high mortality. High levels of cytokines stimulate the formation of neurotoxic metabolites by kynurenine (KYN) pathway. Vitamin B6 (vit B6) has anti-inflammatory and antioxidant properties and also acts as a cofactor for enzymes of the KYN pathway. Thus, by using a relevant animal model of polymicrobial sepsis, we studied the effect of vit B6 on the KYN pathway, acute neurochemical and neuroinflammatory parameters, and cognitive dysfunction in rats. Male Wistar rats (250-300 g) were submitted to cecal ligation and perforation (CLP) and divided into sham + saline, sham + vit B6, CLP + saline, and CLP + vit B6 (600 mg/kg, s.c.) groups. Twenty-four hours later, the prefrontal cortex and hippocampus were removed for neurochemical and neuroinflammatory analyses. Animals were followed for 10 days to determine survival rate, when cognitive function was assessed by behavioral tests. Vitamin B6 interfered in the activation of kynurenine pathway, which led to an improvement in neurochemical and neuroinflammatory parameters and, consequently, in the cognitive functions of septic animals. Thus, the results indicate that vit B6 exerts neuroprotective effects in acute and late consequences after sepsis.

Alpha-lipoic acid attenuates acute neuroinflammation and long-term cognitive impairment after polymicrobial sepsis.

Sepsis is a complication of an infection which imbalance the normal regulation of several organ systems, including the central nervous system (CNS). Evidence points towards inflammation and oxidative stress as major steps associated with brain dysfunction in sepsis. Thus, we investigated the α-lipoic acid (ALA) effect as an important antioxidant compound on brain dysfunction in rats. Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) or sham (control) and treated orally with ALA (200 mg/kg after CLP) or vehicle. Animals were divided into sham + saline, sham + ALA, CLP + saline and CLP + ALA groups. Twelve, 24 h and 10 days after surgery, the hippocampus, prefrontal cortex and cortex were obtained and assayed for levels of TNF-α and IL-1ß, blood brain barrier (BBB) permeability, nitrite/nitrate concentration, myeloperoxidase (MPO) activity, thiobarbituric acid reactive species (TBARS) formation, protein carbonyls, superoxide dismutase (SOD) and catalase (CAT) activity and neurotrophins levels. Behavioral tasks were performed 10 days after surgery. ALA reduced BBB permeability and TNF-α levels in hippocampus in 24 h and IL-1ß levels and MPO activity in hippocampus and prefrontal cortex in 24 h. ALA reduced nitrite/nitrate concentration and lipid peroxidation in 24 h in all structures and protein carbonylation in 12 and 24 h in hippocampus and cortex. CAT activity increased in the hippocampus and cortex in all times. ALA enhanced NGF levels in hippocampus and cortex and prevented cognitive impairment. Our data demonstrates that ALA reduces the consequences of polymicrobial sepsis in rats by decreasing inflammatory and oxidative stress parameters in the brain.

Effects of ω-3 fatty acids on stereotypical behavior and social interactions in Wistar rats prenatally exposed to lipopolysaccarides.

OBJECTIVE: Supplementation with ω-3 polyunsaturated fatty acids (PUFAs) can positively contribute to neurologic development, modulating inflammatory responses, promoting homeostasis, and having a positive effect on animal behaviors associated with mental disorders. The aim of this study was to evaluate behavioral and biochemical effects of ω-3 fatty acid supplementation in an animal model for mental disorders by prenatal maternal exposure to lipopolysaccardies (LPS) from the maternal immune activation. METHODS: Twelve pregnant Wistar rats were used. Each rat received 100 µg/kg of LPS or saline solution on gestational day (GD) 9.5. The offspring remained with mothers until weaning and from postnatal day (PND) 30 were supplemented with ω-3 PUFA or saline solution by gavage at a dose of 0.8 g/kg orally for 21 d. On PND 52, the animals underwent behavioral tests; then, they were sacrificed, and the brain structures were dissected and analyzed by levels: neuron-specific enolase (NSE), brain-derived neurotrophic factor, and transforming growth factor (TGF)-ß. RESULT: Prenatal exposure to LPS significantly increased the episodes of stereotyped movements and decreased social interaction in the offspring (P = 0.009 and P = 0.001, respectively), after ω-3 PUFA supplementation these parameters reversed (P = 0.005 and P = 0.013, respectively). Significant changes also were identified in the biochemical analysis in NSE and TGF-ß in the brain structures; these conditions were reversed after ω-3 PUFA supplementation. CONCLUSION: Supplementation with ω-3 PUFA reversed animal behaviors that often are observed in autism and other mental disorders in rats prenatally exposed to LPS, and also exerted neuroprotective effects in marker levels of neuronal damage and expression of TGF-ß.