Rescue of social behavior impairment by clozapine and alterations in the expression of neuronal receptors in a rat model of neurodevelopmental impairment induced by GRPR blockade

We have previously shown that pharmacological blockade of the gastrin-releasing peptide receptor (GRPR) during the neonatal period in rats produces behavioral features of developmental neuropsychiatric disorders. Here, we show that social interaction deficits in this model are reversed by the atypical antipsychotic clozapine given in the adulthood. In addition, we analyzed the mRNA expression of three neuronal receptors potentially involved in the etiology of disorders of the autism spectrum. Rats were injected with the GRPR antagonist RC-3095 or saline (SAL) from postnatal days 1-10, and tested for social behavior and recognition memory in the adulthood. One hour prior to the behavioral testing, rats were given a systemic injection of clozapine or saline. The mRNA expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor, the epidermal growth factor receptor (EGFR), and GRPR was measured in the hippocampus and cortex of a separate set of rats given RC-3095 or SAL neonatally. Rats given neonatal RC-3095 showed decreased social interaction and impaired object recognition memory. Clozapine rescued the social interaction impairment. Neonatal treatment with RC-3095 also resulted in dose-dependent decreases in the expression of GRPR, NR1, and EGFR in the cortex, whereas all three receptor mRNAs were increased in the hippocampus in rats treated with the lower dose of RC-3095. The results contribute to further validate the novel rat model of neurodevelopmental disorders induced by GRPR blockade, and shows alterations in the expression of neuronal receptors in this model.     

Early life stress decreases hippocampal BDNF content and exacerbates recognition memory deficits induced by repeated D-amphetamine exposure

Adverse experiences early in life may have profound influences on brain development, for example, determining alterations in response to psychostimulant drugs, an increased risk of developing a substance abuse disorder, and individual differences in the vulnerability to neuropsychiatric disorders later in life. Here, we investigated the effects of exposure to an early adverse life event, maternal deprivation, combined with repeated d-amphetamine (AMPH) administration in adulthood, on recognition memory and brain-derived neurotrophic factor (BDNF) levels in rats’ brain and serum. Rats were exposed to one of the following maternal rearing conditions from postnatal days 1 to 14: non-deprived (ND) or deprived (D). In adulthood, both groups received injections of saline (SAL) or AMPH (2.0 mg/kg, i.p.) for 7 days. In Experiment I (performed 24 h after the last AMPH injection), AMPH induced long-term memory (LTM) impairments in ND and D groups. The D + AMPH group also presented short-term memory (STM) impairments, indicating that the effects of AMPH on memory were more pronounced when the animals where maternally deprived. The group exposed to D + SAL (SAL) showed only LTM impairments. In Experiment II (performed 8 days after the last injection), AMPH detrimental effects on memory persisted in ND and D groups. BDNF levels were decreased in the hippocampus of D + SAL rats. In conclusion, AMPH produces severe and persistent recognition memory impairments that were more pronounced when the animals were maternally deprived, suggesting that an early adverse life event may increase the vulnerability of cognitive function to exposure to a psychostimulant later in life.     

Folic acid administration prevents ouabain‐induced hyperlocomotion and alterations in oxidative stress markers in the rat brain

Brocardo PS, Budni J, Pavesi E, Franco JL, Uliano‐Silva M, Trevisan R, Terenzi MG, Dafre AL, Rodrigues ALS. Folic acid administration prevents ouabain‐induced hyperlocomotion and alterations in oxidative stress markers in the rat brain.
Bipolar Disord 2010: 12: 414–424. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objective: Bipolar disorder (BD) is a chronic, prevalent, and highly debilitating psychiatric illness. Folic acid has been shown to have antidepressant‐like effects in preclinical and clinical studies and has also been suggested to play a role in BD. The present work investigates the therapeutic value of folic acid supplementation in a preclinical animal model of mania induced by ouabain. Methods: Male Wistar rats were treated twice daily for seven days with folic acid (10, 50, and 100 mg/kg, p.o.) or the mood stabilizer lithium chloride (LiCl) (45 mg/kg, p.o.). One day after the last dose was given, the animals received an i.c.v. injection of ouabain (10 μM), a Na⁺,K⁺‐ATPase‐inhibiting compound. Locomotor activity was assessed in the open‐field test. Thiobarbituric acid‐reactive substance (TBARS) levels, glutathione peroxidase (GPx), and glutathione reductase (GR) activities were measured in the cerebral cortex and hippocampus. Results: Ouabain (10 μM, i.c.v.) significantly increased motor activity in the open‐field test, and seven days of pretreatment with folic acid (50 mg/kg, p.o.) or LiCl (45 mg/kg, p.o.) completely prevented this effect. Ouabain treatment elicited lipid peroxidation (increased TBARS levels) and reduced GPx activity in the hippocampus. GR activity was decreased in the cerebral cortex and hippocampus. These effects were prevented by pretreatment with folic acid and LiCl. Conclusions: Our results show that folic acid, similarly to LiCl, produces a clear antimanic action and prevents the neurochemical alterations indicative of oxidative stress in an animal model of mania.     

Effects of alpha‐lipoic acid in an animal model of mania induced by d‐amphetamine

Macêdo DS, Medeiros CD, Cordeiro RC, Sousa FC, Santos JV, Morais TA, Hyphantis TN, McIntyre RS, Quevedo J, Carvalho AF. Effects of alpha‐lipoic acid in an animal model of mania induced by d ‐amphetamine. Bipolar Disord 2012: 14: 707–718. © 2012 The Authors.
Journal compilation © 2012 John Wiley & Sons A/S Objectives: Oxidative stress and neurotrophic factors are involved in the pathophysiology of bipolar disorder (BD). Alpha‐lipoic acid (ALA) is a naturally occurring compound with strong antioxidant properties. The present study investigated ALA effects in an amphetamine‐induced model of mania. Methods: In the reversal protocol, adult mice were first given d ‐amphetamine (AMPH) 2 mg/kg, intraperitoneally (i.p.) or saline for 14 days. Between days 8 and 14, the animals received ALA 50 or 100 mg/kg orally, lithium (Li) 47.5 mg/kg i.p., or saline. In the prevention paradigm, mice were pretreated with ALA, Li, or saline prior to AMPH. Locomotor activity was assessed in the open‐field task. Superoxide dismutase (SOD) activity, reduced glutathione (GSH), and thiobarbituric acid‐reactive substance (TBARS) levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC), and striatum (ST). Brain‐derived neurotrophic factor (BDNF) levels were measured in the HC. Results: ALA and Li prevented and reversed the AMPH‐induced increase in locomotor activity. Prevention model: ALA and Li co‐administration with AMPH prevented the decrease in SOD activity induced by AMPH in the HC and ST, respectively; ALA and Li prevented GSH alteration in the HC and TBARS formation in all brain areas studied. Reversal model: ALA reversed the decrease in SOD activity in the ST. TBARS formation was reversed by ALA and Li in all brain areas. Furthermore, ALA reversed AMPH‐induced decreases in BDNF and GSH in the HC. Conclusions: Our findings showed that ALA, similarly to Li, is effective in reversing and preventing AMPH‐induced behavioral and neurochemical alterations, providing a rationale for the design of clinical trials investigating ALA’s possible antimanic effect.     

Oxidative stress in the brain following intraventricular administration of ethylcholine aziridinium (AF64A)

AF64A is a toxic analog of choline that disrupts high affinity choline transport and produces a persistent presynaptic cholinergic hypofunction. The observed neuroprotectant effects of Vitamin E in the AF64A model suggested that oxidative stress contributed to the cholinotoxicity of AF64A. The studies presented here examined whether intraventricular injection of AF64A produces oxidative stress in the brain of male Wistar rats. Indices of oxidative stress including thiobarbituric acid reactive species TBARS), free radical generation using hydrogen peroxide-induced, luminol-dependent chemiluminescence (CL) and superoxide scavenging/generating activity were measured in cerebral cortex, hippocampus and the rest of the brain, without cerebellum, 1, 3 or 5 days after bilateral intraventricular injection of 3 nmol of AF64A or artificial CSF (sham surgery). The sham operation itself induced oxidative stress throughout the brain (increased TBARS, CL and superoxide generation). In addition to the oxidative stress of the sham surgery AF64A increased basal TBARS on day 1 and Fe/ascorbate-induced TBARS on days 3 and 5 throughout the brain. AF64A produced compensatory ‘antioxidative’ changes as well with increased superoxide scavenging activity observed on day 3 and decreased basal TBARS on day 5. AF64A also induced specific changes in the hippocampus including a decrease of CL and an increase of superoxide scavenging activity on day 5. The increased superoxide scavenging activity persisted up to 126 days. The results of the present study provide the first direct evidence that AF64A induces oxidative stress following intraventricular injection.     

Early biochemical effects after unilateral hypoxia–ischemia in the immature rat brain

Perinatal hypoxia–ischemia (HI) gives rise to inadequate substrate supply to the brain tissue, resulting in damage to neural cells. Previous studies at different time points of development, and with different animal species, suggest that the HI insult causes oxidative damage and changes Na⁺, K⁺–ATPase activity, which is known to be very susceptible to free radical-related lipid peroxidation. The aim of the present study was to establish the onset of the oxidative damage response in neonatal Wistar rats subjected to brain HI, evaluating parameters of oxidative stress, namely nitric oxide production, lipoperoxidation by thiobarbituric acid reactive substances (TBA-RS) production and malondialdehyde (MDA) levels, reactive species production by DCFH oxidation, antioxidant enzymatic activities of catalase, glutathione peroxidase, superoxide dismutase as well as Na⁺, K⁺–ATPase activity in hippocampus and cerebral cortex. Rat pups were subjected to right common carotid ligation followed by exposure to a hypoxic atmosphere (8% oxygen and 92% nitrogen) for 90 min. Animals were sacrificed by decapitation 0, 1 and 2 h after HI and both hippocampus and cerebral cortex from the right hemisphere (ipsilateral to the carotid occlusion) were dissected out for further experimentation. Results show an early decrease of Na⁺, K⁺–ATPase activity (at 0 and 1 h), as well as a late increase in MDA levels (2 h) and superoxide dismutase activity (1 and 2 h after HI) in the hippocampus. There was a late increase in both MDA levels and DCFH oxidation (1 and 2 h) and an increase in superoxide dismutase activity (2 h after HI) in cortex; however Na⁺, K⁺–ATPase activity remained unchanged. We suggest that neonatal HI induces oxidative damage to both hippocampus and cortex, in addition to a decrease in Na⁺, K⁺–ATPase activity in hippocampus early after the insult. These events might contribute to the later morphological damage in the brain and indicate that it would be essential to pursue neuroprotective strategies, aimed to counteract oxidative stress, as early as possible after the HI insult.     

Protective effect of Melissa officinalis aqueous extract against Mn-induced oxidative stress in chronically exposed mice

Manganese (Mn) is an essential element for biological systems; however occupational exposure to high levels of this metal may lead to neurodegenerative disorders, resembling Parkinson's disease (PD). While its mechanisms of neurotoxicity have yet to be fully understood, oxidative stress plays a critical role. Thus, the main goal of this study was to investigate the efficacy of aqueous extract of Melissa officinalis in attenuating Mn-induced brain oxidative stress in mice. Sixteen male mice were randomly divided into two groups and treated for 3 months: the first group consumed tap water (control group) and the second group was treated with Mn (50 mg/kg/day for habituation during the first 15 days followed by 100 mg/kg/day for additional 75 days) in the drinking water. After 3 months both groups were sub divided (n = 4 per group) and treated for additional 3 months with Mn and/or M. officinalis in the drinking water. The first group (control) was treated with water and served as control; the second group (M. officinalis) was treated with M. officinalis (100 mg/kg/day); the third group was treated with Mn (100 mg/kg/day); the fourth group (Mn + M. officinalis) was treated with both Mn and M. officinalis (100 mg/kg/day each). Mn-treated mice showed a significant increase in thiobarbituric acid reactive species (TBARS) levels (a marker of oxidative stress) in both the hippocampus and striatum. These changes were accompanied by a decrease in total thiol content in the hippocampus and a significant increase in antioxidant enzyme activity (superoxide dismutase and catalase) in the hippocampus, striatum, cortex and cerebellum. Co-treatment with M. officinalis aqueous extract in Mn-treated mice significantly inhibited the antioxidant enzyme activities and attenuated the oxidative damage (TBARS and decreased total thiol levels). These results establish that M. officinalis aqueous extract possesses potent antioxidative properties, validating its efficacy in attenuating Mn-induced oxidative stress in the mouse brain.     

Protective effects of guanosine against sepsis-induced damage in rat brain and cognitive impairment

The development of cognitive impairment in sepsis is associated with neurotoxic effects caused by oxidative stress. We have assessed the effects of acute and extended administration of guanosine (GUA) on brain oxidative stress parameters and cognitive impairment in rats submitted to sepsis by cecal ligation and perforation (CLP). To achieve this goal, male Wistar rats underwent either sham operation or CLP with GUA. Rats subjected to CLP were treated with intraperitoneal injection of GUA (8 mg/kg after CLP) or vehicle. Twelve and 24 h after CLP, the rats were sacrificed, and samples from brain (hippocampus, striatum, cerebellum, prefrontal cortex and cortex) were obtained and assayed for thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. On the 10th day, another group of rats was submitted to the behavioral tasks. GUA administration reduced TBARS and carbonyl levels in some brain regions between 12 and 24 h after CLP, and ameliorated cognitive impairment evaluated 10 days after CLP. Our data provide the first experimental demonstration that GUA was able to reduce the consequences of CLP-induced sepsis in rats, by decreasing oxidative stress parameters in the brain and recovering the memory impairment.     

Antipsychotic-induced oxidative stress in Rat Brain

Typical and atypical antipsychotic drugs have been shown to have different clinical and behavioral profiles. Haloperidol (HAL) is a typical neuroleptic that acts primarily as a D(2) dopamine receptor antagonist. It has been proposed that reactive oxygen species play a causative role in neurotoxic effects induced by HAL. We evaluated oxidative damage in rat brain induced by chronic (28 days) HAL, clozapine (CLO), olanzapine (OLZ) or aripiprazole (ARI) administration. Adult male Wistar rats received daily injections of HAL (1.5 mg/kg), CLO (25 mg/kg), OLZ (2.5, 5 or 10 mg/kg) or ARI (2, 10 or 20 mg/kg); control animals received vehicle (Tween 1% solution). Thiobarbituric acid reactive substances (TBARS) and protein carbonylation were measured in the prefrontal cortex, hippocampus, striatum and cerebral cortex. The results showed that TBARS were increased in the striatum after HAL treatment. On the other hand, TBARS were diminished in the prefrontal cortex by OLZ and ARI. Our results also showed that all drugs tested in this work decreased TBARS levels in the cerebral cortex. In hippocampus, TBARS levels were not altered by any drug. Protein carbonyl content after HAL and CLO treatment was increased in the hippocampus. Moreover, OLZ and ARI did not alter protein carbonyl content when compared to control group. ARI chronic administration (20 mg/kg) also increased mitochondrial superoxide in the prefrontal cortex and striatum. ARI did not alter mitochondrial superoxide in the hippocampus and cerebral cortex. Moreover, HAL, OLZ and CLO did not cause significant alterations in mitochondrial superoxide in rat brain. Our findings demonstrate that OLZ and ARI do not induce oxidative damage in rat brain as observed after HAL and CLO treatment.     

<Emphasis Type="Italic">Valeriana officinalis</Emphasis> ameliorates vacuous chewing movements induced by reserpine in rats

Oral movements are associated with important neuropathologies as Parkinson’s disease and tardive dyskinesia. However, until this time, there has been no known efficacious treatment, without side effects, for these disorders. Thus, the aim of the present study was to investigate the possible preventive effects of V. officinalis, a phytotherapic that has GABAergic and antioxidant properties, in vacuous chewing movements (VCMs) induced by reserpine in rats. Adult male rats were treated with reserpine (1 mg/kg, s.c.) and/or with V. officinalis (in the drinking water, starting 15 days before the administration of the reserpine). VCMs, locomotor activity and oxidative stress measurements were evaluated. Furthermore, we carried out the identification of valeric acid and gallic acid by HPLC in the V. officinalis tincture. Our findings demonstrated that reserpine caused a marked increase on VCMs and the co-treatment with V. officinalis was able to reduce the intensity of VCM. Reserpine did not induce oxidative stress in cerebral structures (cortex, hippocampus, striatum and substantia nigra). However, a significant positive correlation between DCF-oxidation (an estimation of oxidative stress) in the cortex and VCMs (p < 0.05) was observed. Moreover, a negative correlation between Na⁺K⁺-ATPase activity in substantia nigra and the number of VCMs was observed (p < 0.05). In conclusion, V. officinalis had behavioral protective effect against reserpine-induced VCMs in rats; however, the exact mechanisms that contributed to this effect have not been completely understood.     

The effects of oxidative stress on in vivo brain GSH turnover in young and mature mice

Glutathione (GSH) synthetase activities and GSH turnover rates were examined during severe oxidative stress in the mouse brain as induced byt-butylhydroperoxide (t-BuOOH). Brain GSH synthetase activities in 8-mo-old mice in the cortex, striatum, thalamus, hippocampus, midbrain, and cerebellum were found to increase followingt-BuOOH treatment. The effect of GSH synthesis on brain GSH turnover rates for 2- and 8-mo-old mice were determined after intracerebroventricular (icv) injection of [³⁵S]cysteine. Rate constants for GSH turnover were determined by least-squares iterative minimization from the specific activity data from 20 min to 108 h after [³⁵S]cysteine administration. GSH and glutathione disulfide (GSSG) specific activities were determined after separation by high-pressure liquid chromatography (HPLC). The half-life of GSH in the 2-mo-old mouse was 59.5 h and in the 8-mo-old mouse was 79.1 h. In summary, defense mechanisms against oxidative stress in the brain differ with age. Young mice can increase the cellular availability of GSH, whereas mature mice can increase GSH synthetase activity during oxidative stress. These differences make mature mice more susceptible to brain oxidative damage.     

Intracerebroventricular ouabain administration induces oxidative stress in the rat brain

Intracerebroventricular (ICV) injection of ouabain (a potent Na⁺/K⁺-ATPase inhibitor) in rats resulted in manic-like effects. There is an emerging body of data indicating that major neuropsychiatric disorders, such as bipolar disorder and schizophrenia, are associated with increased oxidative stress. In this study, we investigated the effects of ICV ouabain injection on oxidative stress parameters in total tissue of rat brain. Our findings demonstrated that ICV injection increased thiobarbituric acid reactive species levels and protein carbonyl generation in the prefrontal cortex and hippocampus of rats. Moreover, the activity of the antioxidants enzymes catalase and superoxide dismutase was altered in several areas of the rat brain and cerebrospinal fluid of ICV ouabain-subjected rats. These results showed that Na⁺/K⁺-ATPase inhibition can lead to oxidative stress in the brain of rats.     

Increased oxidative stress after repeated amphetamine exposure: possible relevance as a model of mania

BACKGROUND: Acute mania can be modeled in animals using D-amphetamine (AMPH). Acute AMPH injections are associated with monoamine depletion, loss of neurofilaments and neurite degeneration. However, the precise mechanisms underlying AMPH-induced neurotoxicity are still unclear. Several studies have demonstrated that oxidative stress may play a role in the behavioral and neurochemical changes observed after AMPH administration. METHODS: The effects of a single and repeated injections (seven daily injections) of AMPH administered intraperitonially on locomotion and the production of lipid and protein oxidative markers in rat cortex, striatum and hippocampus were assessed. Locomotion was assessed in an open-field task and markers of oxidative stress were assessed in brain tissue. RESULTS: Both single and repeated injections of AMPH increased protein carbonyl formation in rat brain. Repeated exposure to AMPH induced an additional increase in thiobarbituric acid reactive species in brain tissue. CONCLUSIONS: Longer periods of exposure to AMPH were associated with increased oxidative stress in rat brain. This adds to the notion that repeated manic episodes may be associated with greater brain damage and, therefore, poorer outcomes.     

Increased oxidative stress in submitochondrial particles after chronic amphetamine exposure

Previous studies have suggested that reactive oxygen species (ROS) production may play a role in the pathophysiology of many neuropsychiatric disorders, such as bipolar disorder (BD) and schizophrenia (SCZ). In addition, there is an emerging body of data indicating that BD and SCZ may be associated with mitochondrial dysfunction. We studied the effects of acute and chronic d-amphetamine on ROS production in submitochondrial particles of rat brain. Male Wistar rats were divided in two experimental groups: acute and chronic treatment. In the acute treatment, rats received one single IP injection of d-amphetamine (1, 2 or 4 mg/kg) or saline (control group). In the chronic treatment, rats received one daily IP injection of d-amphetamine (1, 2 or 4 mg/kg) or saline for 7 days. Locomotor activity was assessed with the open field task, and thiobarbituric acid reactive substances (TBARS) and superoxide production were measured in submitochondrial particles of the prefrontal cortex and hippocampus. Both acute and chronic amphetamine treatment increased locomotor behavior. Chronic amphetamine exposure induced a 3- to 6-fold increase of TBARS and a 1.5- to 2-fold increase of superoxide production in submitochondrial particles of prefrontal cortex and hippocampus (P < 0.05). No effects on superoxide or TBARS were observed with acute treatment. These findings suggest that amphetamine-induced mitochondrial ROS generation may be a useful model to investigate the hypothesis of altered brain energy metabolism associated with BD and SCZ. Further studies assessing the effects of mood stabilizers and antipsychotics in preventing mitochondrial oxidative stress are necessary.     

Transient disruption of fear-related memory by post-retrieval inactivation of gastrin-releasing peptide or N-methyl-D-aspartate receptors in the hippocampus

Molecular accounts of memory consolidation suggest that new learning generates persistent synaptic modifications through activation of an extensive set of neuronal receptors and intracellular signal transduction pathways, accompanied by RNA and protein synthesis. This traditional cellular consolidation theory has been challenged by evidence that reactivation of a previously consolidated memory might render this memory again susceptible to disruption by amnesic treatments, a process generally referred to as reconsolidation. Current evidence indicates that reconsolidation can be disrupted by administration of a variety of pharmacological agents after memory reactivation. Previous studies have indicated that the gastrin-releasing preferring type of bombesin receptor (GRPR) and the N-methyl-D-aspartate glutamate receptor (NMDAR) in the rat hippocampus are involved in consolidation of inhibitory avoidance (IA), a fear-related memory task. We show here that blockade of hippocampal GRPRs or NMDARs after memory reactivation temporarily disrupts memory retention. Post-retrieval intra-hippocampal infusion of the GRPR antagonist RC-3095 or the NMDAR antagonist aminophosphonopentanoic acid (AP5) produced an impairment of IA performance tested 2 days after training in rats. However, this impairment was transient and recovered to levels of control rats in a subsequent test 3 days after training. The drug effects were only present after memory reactivation and not in its absence. These findings provide evidence that GRPR or NMDAR inactivation after retrieval can impair fear memory.     

Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment

Microdialysis in behaving animals was used to characterize the hippocampus (HP) and prefrontal cortex (PFC) norepinephrine (NE) responses to amphetamine (AMPH) and cocaine (COC). NE exhibited regionally similar dose- and time-dependent increases to each drug. However, peak NE concentrations were 2-fold greater at behaviorally similar doses of AMPH compared with COC. To examine the role of noradrenergic impulse flow in the mechanism(s) by which these stimulants enhance extracellular NE, groups of animals were pretreated with the α₂ autoreceptor agonist, clonidine (CLON), prior to stimulant administration. CLON (50 μg/kg) administration completely blocked the NE response to both 20 and 30 mg/kg COC. By contrast, CLON decreased the NE response to 0.5 mg/kg AMPH by 75%, but became progressively less effective on the response as the dose was increased to 1.75 and 5.0 mg/kg. CLON also had no effect on the caudate dopamine responses to either AMPH or COC, consistent with the presumed specificity of this drug for α₂ receptors and suggesting the absence of any significant pharmacokinetic interactions. These results indicate that COC acts as an uptake blocker at NE-containing neurons and suggest that AMPH increases extracellular NE through two consequences of its interaction with the neuronal transport carrier: (1) reuptake blockade which predominates at lower doses; (2) release which becomes more prevalent at higher doses. Behavioral analyses revealed effects of CLON which varied as a function of stimulant and dose.     

Evaluation of oxidative status and depression-like responses in Brown Norway rats with acute myeloid leukemia

It has been proved that oxidative stress increases when leukemia is accompanied by depression. This fact may indicate the role of oxidative stress in the development of depression in cancer patients. The aim of this study was to determine whether the acute myeloid leukemia of Brown Norway rats, which is accompanied by oxidative stress, evoked behavioral and receptor changes resembling alterations characteristic of rat models of depression. The rats were divided into two groups: leukemic rats and healthy control. Leukemia was induced through intraperitoneal injection of 10⁷ promyelocytic leukemia cells to the Brown Norway rats. Depression-like behavior was evaluated in the forced swim test at 30 or 34 days after leukemic cells injection. The rats were killed after the evaluation and the spleen, brain cortex and hippocampus were excised. The red–ox state was assessed in homogenates of tissues by measuring total glutathione (GSH) content, the ferric ion reducing ability of plasma (FRAP) level, expression of heme oxygenase-1 (HO-1), biliverdin reductase (BvR) and ferritin mRNA, superoxide dismutase (SOD) activity, as well as malondialdehyde (MDA) concentration. Radioligand binding assay was used to assess of the effect of leukemia on cortical receptors. Leukemic cells were identified using RM-124 antibody by FACS Calibur flow cytometry. Leukemia influenced locomotory activity as well as forced swim test behavior in a 34-day series of experiments. Signs of oxidative stress in leukemic rats were observed in each examined stage of leukemia development. The FRAP values and glutathione contents, were significantly lowered whereas HO-1 mRNA expression, and malonodialdehyde concentrations were significantly increased in the spleen and brain structures of leukemic rats in comparison with the healthy controls. A significant increase in the potency of glycine to displace [³H]L-689,560 from the strychnine-insensitive glycine site of the N-methyl-D-aspartic (NMDA) receptors receptor complex in cortical homogenates of the leukemic rats in 30- and 34-day experimental series was observed in comparison with the control. Upregulation of 5-HT_2A receptors was observed in rat cortex after 30 days of leukemia development but not in 34-days series compared with the control. It is concluded that disturbances in antioxidant system in brain cortex were accompanied by an activation of glycine sites of the NMDA receptor complex, regardless of stage of leukemia development, which are characteristic of model of depression. Findings of our study demonstrate the link between glutamatergic activity, oxidative stress and leukemia.     

The effects of n-acetylcysteine and/or deferoxamine on manic-like behavior and brain oxidative damage in mice submitted to the paradoxal sleep deprivation model of mania

Bipolar disorder (BD) is a severe psychiatric disorder associated with social and functional impairment. Some studies have strongly suggested the involvement of oxidative stress in the pathophysiology of BD. Paradoxal sleep deprivation (PSD) in mice has been considered a good animal model of mania because it induces similar manic-like behavior, as well as producing the neurochemical alterations which have been observed in bipolar patients. Thus, the objective of the present study was to evaluate the effects of the antioxidant agent's n-acetylcysteine (Nac) and/or deferoxamine (DFX) on behavior and the oxidative stress parameters in the brains of mice submitted to the animal model of mania induced by PSD. The mice were treated for a period of seven days with saline solution (SAL), Nac, DFX or Nac plus DFX. The animals were subject to the PSD protocol for 36 h. Locomotor activity was then evaluated using the open-field test, and the oxidative stress parameters were subsequently evaluated in the hippocampus and frontal cortex of mice. The results showed PSD induced hyperactivity in mice, which is considered a manic-like behavior. In addition to this, PSD increased lipid peroxidation and oxidative damage to proteins, as well as causing alterations to antioxidant enzymes in the frontal cortex and hippocampus of mice. The Nac plus DFX adjunctive treatment prevented both the manic-like behavior and oxidative damage induced by PSD. Improving our understanding relating to oxidative damage in biomolecules, and the antioxidant mechanisms presented in the animal models of mania are important in helping to improve our knowledge concerning the pathophysiology and development of new therapeutical treatments for BD.     

Area-specific modification of acetylcholinesterase activity following 3-mercaptopropionic acid-induced seizures

Acetylcholinesterase activity (AChE) was assayed in rat CNS membrane fractions after administration of the convulsant 3-mercaptopropionic acid (150 mg/kg, ip). In comparison with saline-injected controls, total AChE activity decreased 12–20% in striatum and cerebellum during seizure and postseizure but failed, to change in cerebral cortex. Specific AChE activity, assayed in the presence of 10^?4 M ethopropazine (a butyrylcholinesterase inhibitor) decreased 15–25% in striatum and cerebellum, increased 20–45% in hippocampus, but remained unchanged in cerebral cortex. Saline injection alone increased AChE activity in striatum (68%) and cerebellum (36%) but failed to modify enzyme activity in hippocampus and cerebral cortex. To conclude, AChE sensitivity to convulsant, and saline administration is tissue-specific and not restricted to cholinergic areas.