Effect of maternal immune activation on the kynurenine pathway in preadolescent rat offspring and on MK801-induced hyperlocomotion in adulthood: Amelioration by COX-2 inhibition

Infections during pregnancy and subsequent maternal immune activation (MIA) increase risk for schizophrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during gestation display brain and behavioural abnormalities but the underlying mechanisms are unknown. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly regulated by the immune system, we tested if KP changes occur in polyI:C offspring at preadolescence. We also tested whether MK801-induced hyperlocomotion, a behaviour characteristic of adult polyI:C offspring, is prevented by adolescent treatment with celecoxib, a COX-2 inhibitor that impacts the KP. Pregnant rats were treated with polyI:C (4 mg/kg, i.v.) or vehicle on gestational day 19. Serum levels of KP metabolites were measured in offspring of polyI:C or vehicle treated dams at postnatal day (PND) 31–33 using HPLC/GCMS. Additional polyI:C or vehicle exposed offspring were given celecoxib or vehicle between PND 35 and 46 and tested with MK801 (0.3 mg/kg) in adulthood (PND > 90). Prenatal polyI:C resulted in increases in the serum KP neurotoxic metabolite quinolinic acid at PND 31–33 (105%, p = 0.014). In contrast, the neuroprotective kynurenic acid and its precursor kynurenine were significantly decreased (28% p = 0.027, and 31% p = 0.033, respectively). Picolinic acid, another neuroprotective KP metabolite, was increased (31%, p = 0.014). Adolescent treatment with celecoxib (2.5 and 5 mg/kg/day, i.p.) prevented the development of MK801-induced hyperlocomotion in adult polyI:C offspring. Our study reveals the blood KP as a potential mechanism by which MIA interferes with postnatal brain maturation and associated behavioural disturbances and emphasises the preventative potential of inflammation targeting drugs.     

Berberine protects against memory impairment and anxiogenic-like behavior in rats submitted to sporadic Alzheimer’s-like dementia: Involvement of acetylcholinesterase and cell death

The present study aimed to investigate the effects of berberine (BRB) on spatial and learning memory, anxiety, acetylcholinesterase activity and cell death in an experimental model of intracerebroventricular streptozotocin (ICV-STZ) induced sporadic Alzheimer’s-like dementia. Sixty male Wistar rats were randomly divided into six groups: control (CTR), BRB 50 mg/kg (BRB 50), BRB 100 mg/kg (BRB 100), streptozotocin (STZ), streptozotocin plus BRB 50 mg/kg (STZ + BRB 50), and streptozotocin plus BRB 100 mg/kg (STZ + BRB 100). Rats were injected with ICV-STZ (3 mg/kg) or saline, and daily oral BRB treatment began on day 4 for a period of 21 days. Behavioral tests were carried out on day 17, and rats were euthanized on day 24. Cell death analysis and determination of acetylcholinesterase activity was performed on the cerebral cortex and hippocampus of the brain. Administration of BRB prevented the memory loss, anxiogenic behavior, increased acetylcholinesterase activity and cell death induced by ICV-STZ. This may be explained, in part, by a protective effect of BRB on ameliorating the progression of neurodegenerative diseases, including Alzheimer’s disease, and the results of this study provide a better understanding of the effect of BRB on the brain. Thus, BRB may act as a potential neuroprotective agent.     

Developmental exposure to manganese induces lasting motor and cognitive impairment in rats

Exposure to high manganese (Mn) levels may damage the basal ganglia, leading to a syndrome analogous to Parkinson's disease, with motor and cognitive impairments. The molecular mechanisms underlying Mn neurotoxicity, particularly during development, still deserve further investigation. Herein, we addressed whether early-life Mn exposure affects motor coordination and cognitive function in adulthood and potential underlying mechanisms. Male Wistar rats were exposed intraperitoneally to saline (control) or MnCl₂ (5, 10 or 20 mg/kg/day) from post-natal day (PND) 8–12. Behavioral tests were performed on PND 60–65 and biochemical analysis in the striatum and hippocampus were performed on PND14 or PND70. Rats exposed to Mn (10 and 20 mg/kg) performed significantly worse on the rotarod test than controls indicating motor coordination and balance impairments. The object and social recognition tasks were used to evaluate short-term memory. Rats exposed to the highest Mn dose failed to recognize a familiar object when replaced by a novel object as well as to recognize a familiar juvenile rat after a short period of time. However, Mn did not alter olfactory discrimination ability. In addition, Mn-treated rats displayed decreased levels of non-protein thiols (e.g. glutathione) and increased levels of glial fibrillary acidic protein (GFAP) in the striatum. Moreover, Mn significantly increased hippocampal glutathione peroxidase (GPx) activity. These findings demonstrate that acute low-level exposure to Mn during a critical neurodevelopmental period causes cognitive and motor dysfunctions that last into adulthood, that are accompanied by alterations in antioxidant defense system in both the hippocampus and striatum.     

Behavioral disturbances in adult mice following neonatal virus infection or kynurenine treatment – Role of brain kynurenic acid

Exposure to infections in early life is considered a risk-factor for developing schizophrenia. Recently we reported that a neonatal CNS infection with influenza A virus in mice resulted in a transient induction of the brain kynurenine pathway, and subsequent behavioral disturbances in immune-deficient adult mice. The aim of the present study was to investigate a potential role in this regard of kynurenic acid (KYNA), an endogenous antagonist at the glycine site of the N-methyl-d-aspartic acid (NMDA) receptor and at the cholinergic α7 nicotinic receptor. C57BL/6 mice were injected i.p. with neurotropic influenza A/WSN/33 virus (2400 plaque-forming units) at postnatal day (P) 3 or with l-kynurenine (2 × 200 mg/kg/day) at P7–16. In mice neonatally treated with l-kynurenine prepulse inhibition of the acoustic startle, anxiety, and learning and memory were also assessed. Neonatally infected mice showed enhanced sensitivity to d-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as adults. Neonatally l-kynurenine treated mice showed enhanced sensitivity to d-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as well as mild impairments in prepulse inhibition and memory. Also, d-amphetamine tended to potentiate dopamine release in the striatum in kynurenine-treated mice. These long-lasting behavioral and neurochemical alterations suggest that the kynurenine pathway can link early-life infection with the development of neuropsychiatric disturbances in adulthood.     

Cell proliferation and cell death are disturbed during prenatal and postnatal brain development after uranium exposure

The developing brain is more susceptible to neurotoxic compounds than adult brain. It is also well known that disturbances during brain development cause neurological disorders in adulthood. The brain is known to be a target organ of uranium (U) exposure and previous studies have noted that internal U contamination of adult rats induces behavioral disorders as well as affects neurochemistry and neurophysiological properties. In this study, we investigated whether depleted uranium (DU) exposure affects neurogenesis during prenatal and postnatal brain development. We examined the structural morphology of the brain, cell death and finally cell proliferation in animals exposed to DU during gestation and lactation compared to control animals. Our results showed that DU decreases cell death in the cortical neuroepithelium of gestational day (GD) 13 embryos exposed at 40 mg/L and 120 mg/L and of GD18 fetuses exposed at 120 mg/L without modification of the number of apoptotic cells. Cell proliferation analysis showed an increase of BrdU labeling in the dentate neuroepithelium of fetuses from GD18 at 120 mg/L. Postnatally, cell death is increased in the dentate gyrus of postnatal day (PND) 0 and PND5 exposed pups at 120 mg/L and is associated with an increase of apoptotic cell number only at PND5. Finally, a decrease in dividing cells is observed in the dentate gyrus of PND21 rats developmentally exposed to 120 mg/L DU, but not at PND0 and PND5. These results show that DU exposure during brain development causes opposite effects on cell proliferation and cell death processes between prenatal and postnatal development mainly at the highest dose. Although these modifications do not have a major impact in brain morphology, they could affect the next steps of neurogenesis and thus might disrupt the fine organization of the neuronal network.     

Role of nitric oxide in the anticonvulsive effect of progesterone

Described here is an investigation of the potential interaction of the nitric oxide signaling pathway with the anticonvulsant effects of progesterone. In ovariectomized Swiss mice, the threshold for seizures induced by intravenous infusion of pentylenetetrazole was determined after treatment with progesterone (25, 50, or 75 mg/kg, given subcutaneously 6 h before seizure testing) or vehicle. Progesterone induced significant anticonvulsive activity at moderate (50 mg/kg) and high (75 mg/kg) doses. This effect of progesterone was abolished by the NO precursor compound l-arginine (200 mg/kg). Moreover, when subeffective doses of progesterone (25 mg/kg) and the NO synthase inhibitor N^ω-nitro-l-arginine methyl ester (10 mg/kg) were injected, a strong anticonvulsant effect was observed. These findings suggest a potential role for NO signaling as an anticonvulsant target in females.     

Impairment of lithium chloride-induced conditioned gaping responses (anticipatory nausea) following immune system stimulation with lipopolysaccharide (LPS) occurs in both LPS tolerant and LPS non-tolerant rats

Anticipatory nausea is a classically conditioned response to a context that has been previously paired with toxin-induced nausea and/or vomiting. When injected with a nausea-inducing drug, such as lithium chloride (LiCl), rats will show a distinctive conditioned gaping response that has been suggested to be an index of nausea. Previous studies have found that immune system activation with an endotoxin, such as lipopolysaccharide (LPS), attenuates LiCl-induced conditioned gaping in rats. The present study examined the acquisition of LiCl-induced conditioned gaping in rats that were either LPS tolerant or LPS non-tolerant, as little is known about the effects of endotoxin tolerance on learning and memory. Male Long-Evan rats were given four systemic injections of LPS (200 μg/kg) or isotonic saline (NaCl) to induce LPS tolerance, indexed with 24 h changes in body weight following treatment. The animals were then given 4 acquisition trials in a LiCl-induced conditioned gaping paradigm. On conditioning days animals were treated with LPS (200 μg/kg) or saline followed 90 min later by injection of LiCl (127 mg/kg) or saline and then placed in a distinctive context for 30 min and their behavior video-recorded. On a drug free test day all animals were again placed in the distinctive context for 10 min and behavior was video-recorded. Gaping responses were scored for all acquisition days and the test day. Spleen and body weights were also obtained for all rats at the end of the experiment. Gaping responses were attenuated in rats treated with LPS in both the LPS tolerant and LPS non-tolerant groups. There were significant negative correlations between spleen weight as well as spleen/body weight ratios, and levels of conditioned gaping responses in LiCl treated rats, but not control rats. These results show that LPS interferes with learning/memory in the anticipatory nausea paradigm in rats that are both LPS tolerant and LPS non-tolerant.     

Early postnatal exposure to methylphenidate alters stress reactivity and increases hippocampal ectopic granule cells in adult rats

To mimic clinical treatment with methylphenidate (MPH; Ritalin) for attention deficit/hyperactivity disorder (ADHD), rat pups were injected with MPH (5 mg/kg, I.P.) or placebo twice daily during their nocturnal active phase from postnatal day (PND) 7–35. Thirty-nine days after the last MPH administration (PND 76), four litters of rats experienced stressful conditions during the 2003 New York City blackout. MPH-treated rats that endured the blackout lost more weight and regained it at a slower pace than controls (p < 0.05; N = 7–11 per group). Furthermore, MPH-treated rats had elevated systolic arterial blood pressure (from 115.6 ± 1.2 to 126 ± 1.8 mmHg; p < 0.05), assessed on PND 130 by tail cuff plethysmography. Immunocytochemical studies of transmitter systems in the brain demonstrated rearrangements of catecholamine and neuropeptide Y fibers in select brain regions at PND 135, which did not differ between blackout and control groups. However, MPH-treated rats that endured the blackout had more ectopic granule cells in the hilus of the dorsal hippocampal dentate gyrus compared to controls at PND 135 (p < 0.05; N = 6 per group). These findings indicate that early postnatal exposure to high therapeutic doses of MPH can have long lasting effects on the plasticity of select brain regions and can induce changes in the reactivity to stress that persist into adulthood.     

Physical exercise improves motor and short-term social memory deficits in reserpinized rats

Previous studies have shown that cognitive deficits precede the classical motor symptoms seen in Parkinson's disease (PD) and that physical exercise may exert beneficial effects on PD. We have recently verified that the monoamine-depleting drug reserpine – at doses that do not modify motor function – impairs memory processes in rats. Here, we evaluated the potential of physical exercise to improve cognitive and motor deficits induced by reserpine. Adult Wistar rats were assigned to six groups: (1) untrained-vehicle; (2) untrained-reserpine; (3) running wheel (RW)-vehicle; (4) RW-reserpine; (5) treadmill-vehicle; and (6) treadmill-reserpine. Exercise groups were given free nocturnal access to RW or continuous treadmill exercise (20–25 min/day) for 5 days/week over 4 weeks. The animals were injected subcutaneously with reserpine (1.0 or 5.0 mg/kg) or vehicle 48 h after the end of physical program, and 24 h later they were tested in a battery of behavioral paradigms. RW and treadmill improved the motor deficits induced by a high reserpine dose (5.0 mg/kg), as evaluated in the rotarod and open-field tests. Moreover, untrained rats treated with a low reserpine dose (1.0 mg/kg) presented short-term social memory deficits (without motor or olfactory disturbance) that were selectively improved by the exercise training. Our results reinforce the potential of low to moderate physical exercise as a useful tool in the prevention of motor and cognitive impairments associated to CNS monoaminergic depletion.     

The evaluation of antimuscarinic-induced convulsions in fasted rats after food intake

The present study was performed to evaluate convulsions after food intake in fasted rats pretreated with scopolamine or atropine and to determine whether these convulsions respond to drugs found effective in fasted mice. Scopolamine (2.4 mg/kg) and atropine (2.4 mg/kg) were given intraperitoneally (i.p.) to rats fasted for 52 h. Both drugs induced convulsions after animals were allowed to eat ad lib. Another group of fasted rats pretreated with saline, MK-801 (0.1 mg/kg), clonidine (0.1 mg/kg), chlorpromazine (2 and 4 mg/kg), valproate (200 mg/kg), diazepam (1.5 and 2 mg/kg) or gabapentin (50 mg/kg) were treated i.p. with saline or scopolamine (2.4 mg/kg) and were allowed to eat ad lib. Clonidine, MK-801, chlorpromazine (4 mg/kg) and diazepam (2 mg/kg) reduced the incidence of scopolamine-induced convulsions in fasted rats. Gabapentin could only prolong the onset of convulsions. Neither treatment was effective against myoclonus of hindlimbs. Present results showed that fasted rats also develop antimuscarinic-induced convulsions which do not completely respond to treatments found effective in convulsions of fasted mice.     

High dose versus low dose steroids in children with tuberculous meningitis

Guidelines for the best steroid dose in children with tuberculous meningitis (TBM) have not been established. We enrolled 63 children with TBM and divided them into three steroid dose groups: Group 1 (prednisolone 2 mg/kg/day over 4 weeks), Group 2 (prednisolone 4 mg/kg/day over 1 week and 2 mg/kg/day for the next 3 weeks) and Group 3 (prednisolone 4 mg/kg/day over 4 weeks). All patients received standard antituberculous therapy. Optic atrophy, tuberculoma, hydrocephalus, mental retardation, spasticity, hearing impairment, vasculitis and mortality outcomes were compared. Optic atrophy was higher in Group 3 compared to Group 1 (odds ratio [OR] = 2.8) and Group 2 (OR = 2.8), although Group 3 had a high incidence of optic atrophy at diagnosis. Tuberculomas were more frequent in Group 1 (OR = 2.4) and Group 3 (OR = 3.0) as compared to Group 2. Infarcts were more common in Group 3 than in Group 1 (OR = 1.9) and in Group 2 (OR = 3.5). Hearing loss was higher in Group 2 as compared to Group 1 (OR = 2.88) and Group 3 (OR = 4.8). Evolving hydrocephalus was higher in Group 3 as compared to Group 2 (OR = 2.8) and Group 1 (OR = 3.1). Mental retardation was higher in children in Group 3 (OR = 1.6) and in Group 2 (OR = 1.9) as compared to Group 1. Spasticity was higher in Group 3 (OR = 2.0) and in Group 2 (OR = 1.4) as compared to Group 1. There was no difference in mortality between the groups. We conclude that prednisolone at a dose of 4 mg/kg/day for 1 week followed by 2 mg/kg/day for 3 weeks is associated with fewer tuberculomas and infarcts but a higher incidence of hearing loss. A prolonged period of high dose steroids increases the risk of optic atrophy and hydrocephalus. Prednisolone at a dose of 2 mg/kg/day is associated with lower risk of mental retardation and spasticity.     

Rufinamide in children and adults with Lennox–Gastaut syndrome: First Italian multicenter experience

This is the first multicenter Italian experience with rufinamide as an adjunctive drug in children, adolescents and adults with Lennox–Gastaut syndrome.The patients were enrolled in a prospective, add-on, open-label treatment study from 11 Italian centers for children and adolescent epilepsy care. Forty-three patients (26 males, 17 females), aged between 4 and 34 years (mean 15.9 ± 7.3, median 15.0), were treated with rufinamide for a mean period of 12.3 months (range 3–21 months). Twenty patients were diagnosed as cryptogenic and 23 as symptomatic. Rufinamide was added to the baseline therapy at the starting dose of 10 mg/kg body weight, evenly divided in two daily doses and then increased by 10 mg/kg approximately every 3 days up to a maximum of 1000 mg/day in children aged ≥4 years with a body weight less than 30 kg. In patients more than 30 kg body weight, rufinamide could be titrated up to 3200 mg/day.After a mean follow-up period of 12.3 months (range 3–21 months), the final mean dose of rufinamide was 33.5 mg/kg/24 h (range 11.5–60) if combined to valproic acid, and of 54.5 mg/kg/24 h (range 21.8–85.6) without valproic acid. The response rate (≥50% decrease in countable seizures) was 60.5% (26 of 45 patients) in total; 51.1% experienced a 50–99% reduction in seizure frequency and complete seizure control was achieved in the last 4 weeks follow-up by 9.3% of patients. Two patients (4.7%) had a 25–50% seizure reduction, while seizure frequency remained unchanged in 13 (30.2%) and increased in 2 (4.7%). Reliable data for atypical absence seizures and myoclonic seizures were not available, as these are usually impossible to count.Ten patients (23.2%) reported adverse side effects, while taking rufinamide. They were generally mild and transient and most frequently included vomiting, drowsiness, irritalibility and loss of appetite.In conclusion, rufinamide as an adjunctive therapy reduced the number of drop attacks and major motor seizures in about 60% of patients with Lennox–Gastaut syndrome and produced only mild or moderate adverse side effects.     

Sex- and brain region- specific effects of prenatal stress and lead exposure on permissive and repressive post-translational histone modifications from embryonic development through adulthood

Developmental exposure to prenatal stress (PS) and lead (Pb) can affect brain development and adversely influence behavior and cognition. Epigenetic-based gene regulation is crucial for normal brain development and mis-regulation, in any form, can result in neurodevelopmental disorders. Post-translational histone modifications (PTHMs) are an integral and dynamic component of the epigenetic machinery involved in gene regulation. Exposures to Pb and/or PS may alter PTHM profiles, promoting lifelong alterations in brain function observed following Pb ± PS exposure. Here we examined the effects of Pb ± PS on global levels of activating marks H3K9Ac and H3K4Me3 and repressive marks H3K9Me2 and H3K27Me3 at different developmental stages: E18, PND0, PND6 and PND60. Dams were exposed to 0 or 100 ppm Pb beginning 2 months prior to breeding followed by no PS (NS) or PS resulting in 4 offspring treatment groups per sex: 0-NS (control), 0-PS, 100-NS and 100-PS. Global levels of PTHMs varied from E18 through adulthood even in control mice, and were influenced by sex and brain-region. The developmental trajectory of these PTHM levels was further modified by Pb ± PS in a sex-, brain region- and age-dependent manner. Females showed a preferential response to Pb alone in frontal cortex (FC) and differentially to PS alone and combined Pb + PS in hippocampus (HIPP). In males, PS-induced increases in PTHM levels in FC, whereas PS produced reductions in HIPP. Pb ± PS-based changes in PTHM levels continued to be observed in adulthood (PND60), demonstrating the lasting effect of these early life environmental events on these histone marks. These results indicate that epigenetic consequences of Pb ± PS and their contribution to mechanisms of toxicity are sex dependent. Additional studies will assist in understanding the functional significance of these changes in PTHM levels on expression of individual genes, functional pathways, and ultimately, their behavioral consequences.     

Chronic dietary chlorpyrifos causes long-term spatial memory impairment and thigmotaxic behavior

Little is known about the long-term effects of chronic exposure to low-level organophosphate (OP) pesticides, and the role of neurotransmitter systems, other than the cholinergic system, in mediating OP neurotoxicity. In this study, rats were administered 5 mg/kg/day of chlorpyrifos (CPF) for 6 months commencing at 3-months-of-age. The animals were examined 7 months later (at 16-months-of-age) for spatial learning and memory in the Morris water maze (MWM) and locomotor activity. In addition, we assessed the chronic effects of CPF on glutamatergic and gamma-aminobutyric acid (GABAergic) function using pharmacological challenges with dizocilpine (MK801) and diazepam. Impaired performance related to altered search patterns, including thigmotaxis and long-term spatial memory was noted in the MWM in animals exposed to CPF, pointing to dietary CPF-induced behavioral disturbances, such as anxiety. Twenty-four hours after the 31st session of repeated acquisition task, 0.1 mg/kg MK801, an N-methyl-d-aspartate (NMDA) antagonist was intraperitoneally (i.p.) injected for 4 consecutive days. Decreased latencies in the MWM in the control group were noted after two sessions with MK801 treatment. Once the MWM assessment was completed, animals were administered 0.1 or 0.2 mg/kg of MK801 and 1 or 3 mg/kg of diazepam i.p., and tested for locomotor activity. Both groups, the CPF dietary and control, displayed analogous performance in motor activity. In conclusion, our data point to a connection between the long-term spatial memory, thigmotaxic response and CPF long after the exposure ended.     

Spatial learning impairment in prepubertal guinea pigs prenatally exposed to the organophosphorus pesticide chlorpyrifos: Toxicological implications

Exposure of the developing brain to chlorpyrifos (CPF), an organophosphorus (OP) pesticide used extensively in agriculture worldwide, has been associated with increased prevalence of cognitive deficits in children, particularly boys. The present study was designed to test the hypothesis that cognitive deficits induced by prenatal exposure to sub-acute doses of CPF can be reproduced in precocial small species. To address this hypothesis, pregnant guinea pigs were injected daily with CPF (25 mg/kg, s.c.) or vehicle (peanut oil) for 10 days starting on presumed gestation day (GD) 53⿿55. Offspring were born around GD 65, weaned on postnatal day (PND) 20, and subjected to behavioral tests starting around PND 30. On the day of birth, butyrylcholinesterase (BuChE), an OP bioscavenger used as a biomarker of OP exposures, and acetylcholinesterase (AChE), a major molecular target of OP compounds, were significantly inhibited in the blood of CPF-exposed offspring. In their brains, BuChE, but not AChE, was significantly inhibited. Prenatal CPF exposure had no significant effect on locomotor activity or on locomotor habituation, a form of non-associative memory assessed in open fields. Spatial navigation in the Morris water maze (MWM) was found to be sexually dimorphic among guinea pigs, with males outperforming females. Prenatal CPF exposure impaired spatial learning more significantly among male than female guinea pigs and, consequently, reduced the sexual dimorphism of the task. The results presented here, which strongly support the test hypothesis, reveal that the guinea pig is a valuable animal model for preclinical assessment of the developmental neurotoxicity of OP pesticides. These findings are far reaching as they lay the groundwork for future studies aimed at identifying therapeutic interventions to treat and/or prevent the neurotoxic effects of CPF in the developing brain.     

Arginine vasopressin relates with spatial learning and memory in a mouse model of spinocerebellar ataxia type 3

Spinocerebellar ataxia is an inherited neurodegenerative disorder that the most prevalent type is type 3 (SCA3). Arginine vasopressin (AVP) is released within the lateral septum for controlling the learning and memory. This communication studied the effect of AVP on the spatial learning and memory of SCA3 mice. The spatial learning and memory were analyzed by Morris water maze test (MWM), and AVP concentration was measured by radioimmunoassay. The results showed that (Alves et al., 2010) the swimming velocity, distance traveled and latency to the platform of MWM in SCA3 mice were reduced slower than those in WT mice over 4 training days (p < 0.05, 0.01 or 0.001); (Antunes and Zimmerman, 1978) SCA3 mice showed a lower performance of spatial learning and memory of MWM during the fifth day (test day) compared to WT mice; (Bao et al., 2014) SCA3 mice had a decrease of AVP concentration in cerebral cortex (6.3 ± 0.6 pg/mg vs. 11.4 ± 1.0 pg/mg, p < 0.01), hypothalamus (6.1 ± 1.3 ng/mg vs. 10.3 ± 2.1 ng/mg, p < 0.05), hippocampus (3.2 ± 0.5 pg/mg vs. 5.2 ± 1.0 pg/mg, p < 0.01) and cerebellum (4.7 ± 0.9 pg/mg vs. 8.3 ± 1.1 pg/mg, p < 0.01), not in spinal cord, pituitary and serum; and (Barberies and Tribollet, 1996) intraventricular AVP could significantly quicken swimming velocity, cut down distance traveled and reduce latency to the platform of MWM in a dose-dependent manner, but intraventricular AVP receptor antagonist weakened the spatial learning and memory of MWM in SCA3 mice during the fifth day. The data suggested that AVP in the brain, not spinal cord and peripheral system of SCA3 mice related with the change of the spatial learning and memory of MWM.     

Social isolation rearing induces mitochondrial,immunological, neurochemical and behavioural deficits in rats,and is reversed by clozapine or N-acetyl cysteine

Apart from altered dopamine (DA) function, schizophrenia displays mitochondrial and immune-inflammatory abnormalities, evidenced by oxidative stress, altered kynurenine metabolism and cytokine release. N-acetyl cysteine (NAC), an antioxidant and glutamate modulator, is effective in the adjunctive treatment of schizophrenia. Social isolation rearing (SIR) in rats is a valid neurodevelopmental animal model of schizophrenia. This study evaluated whether SIR-induced behavioural deficits may be explained by altered plasma pro- and anti-inflammatory cytokines, kynurenine metabolism, and cortico-striatal DA and mitochondrial function (via adenosine triphosphate (ATP) release), and if clozapine or NAC (alone and in combination) reverses these changes. SIR induced pronounced deficits in social interactive behaviours, object recognition memory, and prepulse inhibition (PPI), while simultaneously increasing striatal but reducing frontal cortical accumulation of ATP as well as DA. SIR increased pro- vs. anti-inflammatory cytokine balance and altered kynurenine metabolism with a decrease in neuroprotective ratio. Clozapine (5 mg/kg/day × 14 days) as well as clozapine + NAC (5 mg/kg/day and 150 mg/kg/day × 14 days) reversed these changes, with NAC (150 mg/kg/day) alone significantly but partially effective in some parameters. Clozapine + NAC was more effective than clozapine alone in reversing SIR-induced PPI, mitochondrial, immune and DA changes. In conclusion, SIR induces mitochondrial and immune-inflammatory changes that underlie cortico-striatal DA perturbations and subsequent behavioural deficits, and responds to treatment with clozapine or NAC, with an additive effect following combination treatment. The data provides insight into the mechanisms that might underlie the utility of NAC as an adjunctive treatment in schizophrenia.     

Long-term effects of adolescent exposure to bisphenol A on neuron and glia number in the rat prefrontal cortex: Differences between the sexes and cell type

Bisphenol A (BPA), an endocrine disruptor used in a variety of consumer products, has been found to alter the number of neurons in multiple brain areas in rats following exposure in perinatal development. Both the number of neurons and glia also change in the medial prefrontal cortex (mPFC) during adolescence, and this process is known to be influenced by gonadal hormones which could be altered by BPA. In the current study, we examined Long-Evans male and female rats that were administered BPA (0, 4, 40, or 400 μg/kg/day) during adolescent development (postnatal days 27–46). In adulthood (postnatal day 150), the number of neurons and glia in the mPFC were stereologically assessed in methylene blue/azure II stained sections. There were no changes in the number of neurons, but there was a significant dose by sex interaction in number of glia in the mPFC. Pairwise comparisons between controls and each dose showed a significant increase in the number of glia between 0 and 40 μg/kg/day in females, and a significant decrease in the number of glia between 0 and 4 μg/kg/day in males. In order to determine the type of glial cells that were changing in these groups in response to adolescent BPA administration, adjacent sections were labelled with S100β (astrocytes) and IBA-1 (microglia) in the mPFC of the groups that differed. The number of microglia was significantly higher in females exposed to 40 μg/kg/day than controls and lower in males exposed to 4 μg/kg/day than controls. There were no significant effects of adolescent exposure to BPA on the number of astrocytes in male or females. Thus, adolescent exposure to BPA produced long-term alterations in the number of microglia in the mPFC of rats, the functional implications of which need to be explored.     

Anticonvulsant activity of the cyclooxygenase-2 (COX-2) inhibitor etoricoxib in pentylenetetrazole-kindled rats is associated with memory impairment

PurposeVarious selective and nonselective cyclooxygenase (COX) inhibitors are known to have effects on development and progression of seizures. In the present study, the effect of the selective COX-2 inhibitor etoricoxib on seizures, oxidative stress, and learning and memory was studied.MethodMale Wistar rats were kindled using subconvulsant dose of pentylenetetrazole (PTZ) (30 mg/kg, i.p.), on alternating days until animals were fully kindled. After a one-week PTZ-free period, kindled rats were challenged with PTZ 30 mg/kg, and the latency, duration, and severity of seizures were recorded. Etoricoxib was then administered intraperitoneally at 1 mg/kg and 10 mg/kg in kindled rats for nine days (days 6–14). On the ninth day of etoricoxib treatment, PTZ challenge (30 mg/kg) was given, and seizure parameters were noted. On day 15, behavioral assessment was carried out. The Morris water maze (MWM) apparatus and the passive avoidance (PA) apparatus were used for studying cognitive impairment. The rats were then sacrificed, and malondialdehyde (MDA) and glutathione (GSH), markers of oxidative stress, were estimated in the brain samples.ResultsEtoricoxib at lower dose (1 mg/kg) had an anticonvulsant effect which was reduced or reversed at higher dose (10 mg/kg). Etoricoxib also impaired the learning and memory in rats as tested by passive avoidance and Morris water maze tests.ConclusionThe results of the present study suggest that use of etoricoxib, especially at low dose, in patients with epilepsy may not be detrimental with regard to seizure control. However, attention should be paid to cognitive parameters.