Exposure to a high dose of amoxicillin causes behavioral changes and oxidative stress in young zebrafish.

Autistic spectrum disorder (ASD) is a group of early-onset neurodevelopmental disorders characterized by impaired social and communication skills. Autism is widely described as a behavioral syndrome with multiple etiologies where may exhibit neurobiological, genetic, and psychological deficits. Studies have indicated that long term use of antibiotics can alter the intestinal flora followed by neuroendocrine changes, leading to behavioral changes. Indeed, previous studies demonstrate that a high dose of amoxicillin can change behavioral parameters in murine animal models. The objective was to evaluate behavioral and oxidative stress parameters in zebrafish exposed to a high dose of amoxicillin for 7 days. Young zebrafish were exposed to a daily concentration of amoxicillin (100 mg/L) for 7 days. Subsequently, the behavioral analysis was performed, and the brain content was dissected for the evaluation of oxidative stress parameters. Zebrafish exposed to a high dose of amoxicillin showed locomotor alteration and decreased social interaction behavior. In addition, besides the significant decrease of sulfhydryl content, there was a marked decrease in catalase activity, as well as an increased superoxide dismutase activity in brain tissue. Thus, through the zebrafish model was possible to note a central effect related to the exposition of amoxicillin, the same as observed in murine models. Further, the present data reinforce the relation of the gut-brain-axis and the use of zebrafish as a useful tool to investigate new therapies for autistic traits.

Effects of Mood Stabilizers on Brain Energy Metabolism in Mice Submitted to an Animal Model of Mania Induced by Paradoxical Sleep Deprivation.

There is a body of evidence suggesting that mitochondrial dysfunction is involved in bipolar disorder (BD) pathogenesis. Studies suggest that abnormalities in circadian cycles are involved in the pathophysiology of affective disorders; paradoxical sleep deprivation (PSD) induces hyperlocomotion in mice. Thus, the present study aims to investigate the effects of lithium (Li) and valproate (VPA) in an animal model of mania induced by PSD for 96 h. PSD increased exploratory activity, and mood stabilizers prevented PSD-induced behavioral effects. PSD also induced a significant decrease in the activity of complex II-III in hippocampus and striatum; complex IV activity was decreased in prefrontal cortex, cerebellum, hippocampus, striatum and cerebral cortex. Additionally, VPA administration was able to prevent PSD-induced inhibition of complex II-III and IV activities in prefrontal cortex, cerebellum, hippocampus, striatum and cerebral cortex, whereas Li administration prevented PSD-induced inhibition only in prefrontal cortex and hippocampus. Regarding the enzymes of Krebs cycle, only citrate synthase activity was increased by PSD in prefrontal cortex. We also found a similar effect in creatine kinase, an important enzyme that acts in the buffering of ATP levels in brain; its activity was increased in prefrontal cortex, hippocampus and cerebral cortex. These results are consistent with the connection of mitochondrial dysfunction and hyperactivity in BD and suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania.

Effects of chronic administration of fenproporex on cognitive and non-cognitive behaviors.

Fenproporex (Fen) is an amphetamine-based anorectic; amphetamine use causes a broad range of severe cognitive deficits and anxiogenic-like effects. In this study we evaluated pharmacological effects of the chronic administration of Fen on cognitive and non-cognitive behaviors. Male adult Wistar rats received intraperitoneal administration of vehicle (control group) or Fen (6.25, 12.5 or 25 mg/kg) for 14 days; the animals were then subjected to habituation and object recognition tasks in open-field apparatus, and elevated plus-maze task. The administration of Fen (12.5 and 25 mg/kg) impaired habituation during the second exposure to the habituation task. In addition, the same doses of Fen also impaired the performance in object recognition task. In elevated plus-maze task, the administration of Fen (in all doses tested) induced anxiogenic-like effects in rats. Our results suggest that chronic Fen administration alters memory and induces anxiogenic-like effects in rats.

Omega-3 fatty acids alter behavioral and oxidative stress parameters in animals subjected to fenproporex administration.

Studies have consistently reported the participation of oxidative stress in bipolar disorder (BD). Evidences indicate that omega-3 (ω3) fatty acids play several important roles in brain development and functioning. Moreover, preclinical and clinical evidence suggests roles for ω3 fatty acids in BD. Considering these evidences, the present study aimed to investigate the effects of ω3 fatty acids on locomotor behavior and oxidative stress parameters (TBARS and protein carbonyl content) in brain of rats subjected to an animal model of mania induced by fenproporex. The fenproporex treatment increased locomotor behavior in saline-treated rats under reversion and prevention model, and ω3 fatty acids prevented fenproporex-related hyperactivity. Moreover, fenproporex increased protein carbonyls in the prefrontal cortex and cerebral cortex, and the administration of ω3 fatty acids reversed this effect. Lipid peroxidation products also are increased in prefrontal cortex, striatum, hippocampus and cerebral after fenproporex administration, but ω3 fatty acids reversed this damage only in the hippocampus. On the other hand, in the prevention model, fenproporex increased carbonyl content only in the cerebral cortex, and administration of ω3 fatty acids prevented this damage. Additionally, the administration of fenproporex resulted in a marked increased of TBARS in the prefrontal cortex, hippocampus, striatum and cerebral cortex, and prevent this damage in the prefrontal cortex, hippocampus and striatum. In conclusion, we are able to demonstrate that fenproporex-induced hyperlocomotion and damage through oxidative stress were prevented by ω3 fatty acids. Thus, the ω3 fatty acids may be important adjuvant therapy of bipolar disorder.

The many faces of microbiota-gut-brain axis in autism spectrum disorder.

The gut-brain axis is gaining more attention in neurodevelopmental disorders, especially autism spectrum disorder (ASD). Many factors can influence microbiota in early life, including host genetics and perinatal events (infections, mode of birth/delivery, medications, nutritional supply, and environmental stressors). The gut microbiome can influence blood-brain barrier (BBB) permeability, drug bioavailability, and social behaviors. Developing microbiota-based interventions such as probiotics, gastrointestinal (GI) microbiota transplantation, or metabolite supplementation may offer an exciting approach to treating ASD. This review highlights that RNA sequencing, metabolomics, and transcriptomics data are needed to understand how microbial modulators can influence ASD pathophysiology. Due to the substantial clinical heterogeneity of ASD, medical caretakers may be unlikely to develop a broad and effective general gut microbiota modulator. However, dietary modulation followed by administration of microbiota modulators is a promising option for treating ASD-related behavioral and gastrointestinal symptoms. Future work should focus on the accuracy of biomarker tests and developing specific psychobiotic agents tailored towards the gut microbiota seen in ASD patients, which may include developing individualized treatment options.

Risk factors and clinical profile of autism spectrum disorder in southern Brazil.

In Brazil, as in other countries, it is expected a significant variation of epidemiological and clinical characteristics among individuals with autism spectrum disorder (ASD). This study was performed to explore maternal risk factors and clinical characteristics of children with ASD in a population located in southern Brazil. Data were collected from medical records and analyzed to explore biomarkers associated with ASD. Out of 321 children with ASD, 86.5% were males with a male-to-female ratio of 5.7:1, 50.7% were mild/moderate while 49.3% presented severe ASD. Between the risk factors investigated, gestational infection was significantly associated with severe ASD patients. There was also an association between epilepsy and severe autism. Several gastrointestinal (GI) symptoms were significantly associated with severe ASD. Obesity, followed by lower levels of cholesterol, were also significant factors associated with an ASD diagnosis when compared to age-matched controls. Finally, severe ASD was associated with significantly higher serum serotonin levels when compared to age-matched controls and mild/moderate ASD cases. Our findings demonstrate that our population shares many features associated with ASD around the world, such as GI symptoms, epilepsy, and high serotonin levels. It is worth highlighting the low cholesterol levels associated with obesity as an unusual feature that deserves more attention.

Sodium butyrate reverses the inhibition of Krebs cycle enzymes induced by amphetamine in the rat brain.

There is increasing interest in the possibility that mitochondrial impairment may play an important role in bipolar disorder (BD). The Krebs cycle is the central point of oxidative metabolism, providing carbon for biosynthesis and reducing agents for generation of ATP. Recently, studies have suggested that histone deacetylase (HDAC) inhibitors may have antimanic effects. The present study aims to investigate the effects of sodium butyrate (SB), a HDAC inhibitor, on Krebs cycle enzymes activity in the brain of rats subjected to an animal model of mania induced by D-amphetamine (D-AMPH). Wistar rats were first given D-AMPH or saline (Sal) for 14 days, and then, between days 8 and 14, rats were treated with SB or Sal. The citrate synthase (CS), succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) were evaluated in the prefrontal cortex, hippocampus, and striatum of rats. The D-AMPH administration inhibited Krebs cycle enzymes activity in all analyzed brain structures and SB reversed D-AMPH-induced dysfunction analyzed in all brain regions. These findings suggest that Krebs cycle enzymes' inhibition can be an important link for the mitochondrial dysfunction seen in BD and SB exerts protective effects against the D-AMPH-induced Krebs cycle enzymes' dysfunction.

Effects of acute and chronic administration of fenproporex on DNA damage parameters in young and adult rats.

Obesity is a chronic and multifactorial disease, whose prevalence is increasing in many countries. Pharmaceutical strategies for the treatment of obesity include drugs that regulate food intake, thermogenesis, fat absorption, and fat metabolism. Fenproporex is the second most commonly consumed amphetamine-based anorectic worldwide; this drug is rapidly converted in vivo into amphetamine, which is associated with neurotoxicity. In this context, the present study evaluated DNA damage parameters in the peripheral blood of young and adult rats submitted to an acute administration and chronic administration of fenproporex. In the acute administration, both young and adult rats received a single injection of fenproporex (6.25, 12.5 or 25 mg/kg i.p.) or vehicle. In the chronic administration, both young and adult rats received one daily injection of fenproporex (6.25, 12.5, or 25 mg/kg i.p.) or Tween for 14 days. 2 h after the last injection, the rats were killed by decapitation and their peripheral blood removed for evaluation of DNA damage parameters by alkaline comet assay. Our study showed that acute administration of fenproporex in young and adult rats presented higher levels of damage index and frequency in the DNA. However, chronic administration of fenproporex in young and adult rats did not alter the levels of DNA damage in both parameters of comet assay. The present findings showed that acute administration of fenproporex promoted damage in DNA, in both young and adult rats. Our results are consistent with other reports which showed that other amphetamine-derived drugs also caused DNA damage. We suggest that the activation of an efficient DNA repair mechanism may occur after chronic exposition to fenproporex. Our results are consistent with other reports that showed some amphetamine-derived drugs also caused DNA damage.

Inhibition of acetylcholinesterase activity in brain and behavioral analysis in adult rats after chronic administration of fenproporex.

Fenproporex is an amphetamine-based anorectic and it is rapidly converted in vivo into amphetamine. It elevates the levels of extracellular dopamine in the brain. Acetylcholinesterase is a regulatory enzyme which is involved in cholinergic synapses and may indirectly modulate the release of dopamine. Thus, we investigated whether the effects of chronic administration of fenproporex in adult rats alters acquisition and retention of avoidance memory and acetylcholinesterase activity. Adult male Wistar rats received repeated (14 days) intraperitoneal injection of vehicle or fenproporex (6.25, 12.5 or 25 mg/kg i.p.). For behavioral assessment, animals were submitted to inhibitory avoidance (IA) tasks and continuous multiple trials step-down inhibitory avoidance (CMIA). Acetylcholinesterase activity was measured in the prefrontal cortex, hippocampus, hypothalamus and striatum. The administration of fenproporex (6.25, 12.5 and 25 mg/kg) did not induce impairment in short and long-term IA or CMIA retention memory in rats. In addition, longer periods of exposure to fenproporex administration decreased acetylcholinesterase activity in prefrontal cortex and striatum of rats, but no alteration was verified in the hippocampus and hypothalamus. In conclusion, the present study showed that chronic fenproporex administration decreased acetylcholinesterase activity in the rat brain. However, longer periods of exposure to fenproporex did not produce impairment in short and long-term IA or CMIA retention memory in rats.

Beneficial effects and neurobiological aspects of environmental enrichment associated to major depressive disorder and autism spectrum disorder.

A suitable enriched environment favors development but can also influence behavior and neuronal circuits throughout development. Studies have shown that environmental enrichment (EE) can be used as an essential tool or combined with conventional treatments to improve psychiatric and neurological symptoms, including major depressive disorder (MDD) and autism spectrum disorder (ASD). Both disorders affect a significant percentage of the wofrld's population and have complex pathophysiology. Moreover, the available treatments for MDD and ASD are still inadequate for many affected individuals. Experimental models demonstrate that EE has significant positive effects on behavioral modulation. In addition, EE has effects on neurobiology, including improvement in synaptic connections and neuroplasticity, modulation of neurotransmissions, a decrease in inflammation and oxidative stress, and other neurobiology effects that can be involved in the pathophysiology of MDD and ASD. Thus, this review aims to describe the leading behavioral and neurobiological effects associated with EE in MDD and ASD.

Non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine inhibit cytochrome C oxidase in mouse brain regions.

The highly active antiretroviral therapy completely changed the clinical evolution of HIV infection, reducing the morbidity and mortality among human immunodeficiency virus (HIV)-1 infected patients. Therefore, in the present study we evaluated the effect of chronic efavirenz (EFV) and nevirapine (NVP) administration on mitochondrial respiratory chain complexes activities (I, II, II-III, IV) in different brain regions of mice. Mice were orally administered via gavage with EFV 10 mg/kg, NVP 3.3 mg/kg or vehicle (controls) once a day for 36 days. We observed that the complex IV activity was inhibited by both EFV and NVP in cerebral cortex, striatum and hippocampus of mice, but not in cerebellum, as compared to control group. In contrast, chronic EFV and NVP administration did not alter complexes I, II and II-III. We speculated that brain energy metabolism dysfunction could be involved in the CNS-related adverse effects.

Inhibition of mitochondrial respiratory chain in the brain of rats after hepatic failure induced by acetaminophen.

Hepatic encephalopathy is an important cause of morbidity and mortality in patients with severe hepatic failure. This disease is clinically characterized by a large variety of symptoms including motor symptoms, cognitive deficits, as well as changes in the level of alertness up to hepatic coma. Acetaminophen is frequently used in animals to produce an experimental model to study the mechanisms involved in the progression of hepatic disease. The brain is highly dependent on ATP and most cell energy is obtained through oxidative phosphorylation, a process requiring the action of various respiratory enzyme complexes located in a special structure of the inner mitochondrial membrane. In this context, the authors evaluated the activities of mitochondrial respiratory chain complexes in the brain of rats submitted to acute administration of acetaminophen and treated with the combination of N-acetylcysteine (NAC) plus deferoxamine (DFX) or taurine. These results showed that acetaminophen administration inhibited the activities of complexes I and IV in cerebral cortex and that the treatment with NAC plus DFX or taurine was not able to reverse this inhibition. The authors did not observe any effect of acetaminophen administration on complexes II and III activities in any of the structures studied. The participation of oxidative stress has been postulated in the hepatic encephalopathy and it is well known that the electron transport chain itself is vulnerable to damage by reactive oxygen species. Since there was no effect of NAC + DFX, the effect of acetaminophen was likely to be due to something else than oxidative stress.

Skeletal muscle electron transport chain dysfunction after sepsis in rats.

BACKGROUND: The derangement in oxygen utilization occurring during sepsis is likely to be linked to impaired mitochondrial functioning. Skeletal muscle comprises 50%-60% of body cell mass and represents the largest organ potentially affected by systemic inflammation. Thus, we investigated whether sepsis induced by cecal ligation and puncture (CLP) modifies mitochondrial activity in respiratory and nonrespiratory skeletal muscle. MATERIALS AND METHODS: Wistar rats were subjected to CLP and at different times, diaphragm and quadriceps were removed for the determination of electron transfer chain activities and mitochondrial oxidative stress. In addition, we determined diaphragm contractile strength. RESULTS: In the quadriceps, 12 h after CLP we demonstrated a significant diminution on complex II-III activity. At late times (48 h after CLP), we demonstrated a decrease in the activity of all electron transfer chain complexes, which seemed to be secondary to early oxidative stress and correlates with diaphragm contractile strength. Differently from diaphragm, electron transfer chain was not decreased after sepsis and even oxidative stress was not increased at all times tested. CONCLUSION: Our results suggest that quadriceps mitochondria are more resistant to sepsis-induced dysfunction.

Sex-related patterns of the gut-microbiota-brain axis in the neuropsychiatric conditions.

Sex differences are often observed in psychiatric patients, especially major depressive disorders (MDD), schizophrenia, and developmental disorders, including autism spectrum disorders (ASDs). The prevalence rates between males and females seem variate according to the clinical condition. Although the findings are still incipient, it is suggested that these differences can involve neuroanatomical, neurochemical, and physiological sex differences. In this context, the microbiota-gut-brain axis hypothesis arises to explain some aspects of the complex pathophysiology of neuropsychiatric disorders. The microbiota composition is host-specific and can change conforming to age, sex, diet, medication, exercise, and others. The communication between the brain and the gut is bidirectional and may impact the entire system homeostasis. Many pathways appear to be involved, including neuroanatomic communication, neuroendocrine pathways, immune system, bacteria-derived metabolites, hormones, neurotransmitters, and neurotrophic factors. Although the clinical and preclinical studies are sparse and not very consistent, they suggest that sex differences in the gut microbiota may play an essential role in some neuropsychiatric conditions. Thus, this narrative review has as a mainly aim to show the points sex-related patterns associated to the gut-microbiota-brain axis in the MDD, ASDs, and schizophrenia.

Effects of N-acetylcysteine/deferoxamine, taurine and RC-3095 on respiratory chain complexes and creatine kinase activities in rat brain after sepsis.

The pathogenesis of sepsis is characterized by an overwhelming systemic inflammatory response that can lead to multiple organ failure. Considering that we have recently demonstrated that mitochondrial respiratory chain and creatine kinase (CK) are altered in the brain of rats after cecal ligation and perforation (CLP) and that a combination of N-acetylcysteine/deferoxamine (NAC/DFX), taurine and RC-3095 were shown to be an effective treatment of sepsis, we investigated whether the alterations of these enzymes may be reversed by these drugs. The results demonstrated that CLP inhibited complexes I and II, and that all the treatments were able to reverse this inhibition in all brain areas studied in the present work. On the other hand, complexes III and IV were not affected by sepsis neither by any of the treatments. An increase in CK activity in brain of rats 12 h after CLP was also verified; the administration of NAC/DFX and taurine reversed the increase in CK activity in hippocampus, cerebral cortex, cerebellum and striatum. On the other hand, RC-3095 significantly decreased CK activity, when compared to sham group in all brain areas studied. This is a preliminary study which showed beneficial effects of the treatments we proposed.

Evaluation of citrate synthase activity in brain of rats submitted to an animal model of mania induced by ouabain.

Bipolar disorder (BD) is a psychiatric disorder characterized by alternating episodes of mania and depression. The intracerebroventricular (i.c.v) administration of ouabain (a Na(+)/K(+)-ATPase inhibitor) in rats has been used as an animal model of mania, because present face, construct and predictive validities. Several studies strongly suggest that mitochondrial dysfunction play a central role in the pathophysiology of BD. Citrate synthase (CS) is an enzyme localized in the mitochondrial matrix and represents one of the most important steps of Krebs cycle. The aim of this study was to investigate CS activity in brain of rats after the administration of ouabain. Adult male Wistar rats received a single i.c.v. administration of ouabain (10(-2) and 10(-3) M) or vehicle (control group). Locomotor activity was measured using the open field task. CS activity was measured in the brain of rats immediately (1 h) and 7 days after ouabain administration. Our results showed that spontaneous locomotion was increased 1 h after ouabain administration, and that the hyperlocomotion persists 7 days after the administration. Moreover, CS activity was inhibited immediately after the administration of ouabain in the prefrontal cortex at the doses of 10(-3) and 10(-2) M. This inhibition remains by 7 days after the administration of ouabain. On the other hand, it was not observed any difference in CS activity in the hippocampus and striatum. Considering that inhibition of CS activity may reflect a mitochondrial dysfunction, it is tempting to speculate that the reduction of brain energy metabolism might be related to the pathophysiology of BD.

Inhibition of mitochondrial respiratory chain in the brain of rats after renal ischemia is prevented by N-acetylcysteine and deferoxamine.

We evaluated the activities of mitochondrial respiratory chain complexes in the brain of rats after renal ischemia and the effect of administration of the antioxidants N-acetylcysteine (NAC) and deferoxamine (DFX). The rats were divided into the groups: sham (control) or renal ischemia treated with saline, NAC 20 mg/kg, DFX 20 mg/kg or both antioxidants. Complex I activity was inhibited in hippocampus, striatum, prefrontal cortex and cerebral cortex of rats 1 and 6 h after renal ischemia and that the treatment with a combination of NAC and DFX prevented such effect. Complex I activity was not altered in hippocampus, striatum, prefrontal cortex and cerebral cortex of rats 12 h after renal ischemia. Complexes II and III activities were not altered in hippocampus, striatum, prefrontal cortex and cerebral cortex of rats 1, 6 and 12 h after renal ischemia. Complex IV activity was inhibited in hippocampus, striatum, prefrontal cortex and cerebral cortex of rats 1 h after renal ischemia, but the treatment with the combination of NAC and DFX was able to prevent this inhibition. Complex IV activity was not altered in hippocampus, striatum, prefrontal cortex and cerebral cortex of rats 6 and 12 h after renal ischemia. These results suggest that the inhibition of mitochondrial respiratory chain after renal ischemia might play a role in the pathogenesis of uremic encephalopathy.

Inhibition of mitochondrial respiratory chain in brain of rats subjected to an experimental model of depression.

Depressive disorders, including major depression, are serious and disabling. However, the exact pathophysiology of depression is not clearly understood. Life stressors contribute in some fashion to depression and are an extension of what occurs normally. In this context, chronic stress has been used as an animal model of depression. Based on the hypothesis that metabolism impairment might be involved in the pathophysiology of depression, in the present work we evaluated the activities of mitochondrial respiratory chain complexes and creatine kinase in brain of rats subjected to chronic stress. After 40 days of mild stress, a reduction in sweet food ingestion was observed, as well as increased adrenal gland weight, when compared to control group. We also verified that control group gained weight after 40 days, but stressed group did not. Moreover, our findings showed that complex I, III and IV were inhibited in stress group only in cerebral cortex and cerebellum. On the other hand, complex II and creatine kinase were not affected in stressed group. Although it is difficult to extrapolate our findings to the human condition, the inhibition of mitochondrial respiratory chain by chronic stress may be one mechanism in the pathophysiology of depressive disorders.

Agmatine attenuates depressive-like behavior and hippocampal oxidative stress following amyloid ß (Aß1-40) administration in mice.

Depression is one of the most common psychiatric symptoms in Alzheimer's disease (AD), and several studies have shown that oxidative stress plays a key role in the etiopathology of both AD and depression. Clinical studies indicate reduced efficacy of the current antidepressants for the treatment of depression in AD. In this regard, agmatine emerges as a neuroprotective agent that presents diverse effects, including antidepressant and antioxidant properties. Here we investigated the antioxidant and antidepressant-like effects of agmatine in a mouse model of AD induced by a single intracerebroventricular (i.c.v.) administration of amyloid-ß 1-40 (Aß). Mice were treated with agmatine (10 mg/kg, intraperitoneally) once a day during seven consecutive days. The first administration of agmatine was 24 h before the i.c.v. injection of aggregated Aß 1-40 (400 pmol/mouse). Ten days after Aß injection, mice were evaluated in the forced swimming test (FST) and open field test for assessment of depressive-like behavior and locomotor activity, respectively. Oxidative parameters were evaluated in the hippocampus of mice 24 h after Aß injection. Agmatine prevented Aß-induced increase in hippocampal lipid peroxidation levels and Aß-induced decrease in catalase activity. In addition, agmatine prevented the increase in immobility time in the FST and the decrease in the latency to the first immobility episode induced by Aß, without changing locomotion in the open field test. These results demonstrate the antioxidant and antidepressant-like effects of agmatine in a mouse model of AD, indicating the potential of agmatine for the treatment of depression associated to AD.

Effect of acute and long-term administration of gold nanoparticles on biochemical parameters in rat brain.

The present study investigated stress oxidative parameters and activities of enzymes of the energy metabolism in various brain structures. Rats were subjected to acute and long-term administration of gold nanoparticles (GNPs) with mean diameters of 10nm and 30nm. Adult (60days old) male Wistar rats received a single intraperitoneal injection (acute administration; 70µg·kg-1) or repeated injections once daily for 28days (long-term administration; 70µg·kg-1) of saline solution or GNPs (10nm or 30nm). Twenty-four hours after administration of the final dose, the animals were killed and the cerebral structures were isolated for enzyme analysis. In this study, we observed that the thiobarbituric acid-reactive species and carbonyl protein levels were decreased after acute administration of GNPs, whereas the superoxide dismutase activity was increased after acute and long-term of GNPs. The catalase activity was affected by the administration of GNPs. Furthermore, we have not found change in the citrate synthase activity. The succinate dehydrogenase, malate dehydrogenase, complexes I, II, II-III and IV, and creatine kinase activities were altered. These results indicate that inhibition energy metabolism can be caused by oxidative stress.