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1.
Pharmacol Rep ; 76(4): 887-894, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38789891

RESUMO

BACKGROUND: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated. METHODS: Pregnant Sprague-Dawley rats were treated with MAM (22 mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6 mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed. RESULTS: A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats. CONCLUSIONS: The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.


Assuntos
Ácido Cinurênico , Acetato de Metilazoximetanol , Córtex Pré-Frontal , Efeitos Tardios da Exposição Pré-Natal , Ratos Sprague-Dawley , Esquizofrenia , Animais , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Feminino , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ácido Cinurênico/metabolismo , Ratos , Masculino , Esquizofrenia/metabolismo , Esquizofrenia/tratamento farmacológico , Acetato de Metilazoximetanol/análogos & derivados , Haloperidol/farmacologia , Piperidinas/farmacologia , Modelos Animais de Doenças , Antipsicóticos/farmacologia , Pirazóis/farmacologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Receptor CB1 de Canabinoide/metabolismo
2.
Proc Natl Acad Sci U S A ; 121(17): e2319607121, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38635635

RESUMO

The development of seizures in epilepsy syndromes associated with malformations of cortical development (MCDs) has traditionally been attributed to intrinsic cortical alterations resulting from abnormal network excitability. However, recent analyses at single-cell resolution of human brain samples from MCD patients have indicated the possible involvement of adaptive immunity in the pathogenesis of these disorders. By exploiting the MethylAzoxyMethanol (MAM)/pilocarpine (MP) rat model of drug-resistant epilepsy associated with MCD, we show here that the occurrence of status epilepticus and subsequent spontaneous recurrent seizures in the malformed, but not in the normal brain, are associated with the outbreak of a destructive autoimmune response with encephalitis-like features, involving components of both cell-mediated and humoral immune responses. The MP brain is characterized by blood-brain barrier dysfunction, marked and persisting CD8+ T cell invasion of the brain parenchyma, meningeal B cell accumulation, and complement-dependent cytotoxicity mediated by antineuronal antibodies. Furthermore, the therapeutic treatment of MP rats with the immunomodulatory drug fingolimod promotes both antiepileptogenic and neuroprotective effects. Collectively, these data show that the MP rat could serve as a translational model of epileptogenic cortical malformations associated with a central nervous system autoimmune response. This work indicates that a preexisting brain maldevelopment predisposes to a secondary autoimmune response, which acts as a precipitating factor for epilepsy and suggests immune intervention as a therapeutic option to be further explored in epileptic syndromes associated with MCDs.


Assuntos
Epilepsia , Acetato de Metilazoximetanol/análogos & derivados , Pilocarpina , Ratos , Humanos , Animais , Autoimunidade , Epilepsia/induzido quimicamente , Epilepsia/patologia , Convulsões/patologia , Encéfalo/patologia , Modelos Animais de Doenças
3.
Exp Neurol ; 376: 114759, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38519010

RESUMO

Malformations of cortical development (MCDs) are caused by abnormal neuronal migration processes during the fetal period and are a major cause of intractable epilepsy in infancy. However, the timing of hyperexcitability or epileptogenesis in MCDs remains unclear. To identify the early developmental changes in the brain of the MCD rat model, which exhibits increased seizure susceptibility during infancy (P12-15), we analyzed the pathological changes in the brains of MCD model rats during the neonatal period and tested NMDA-induced seizure susceptibility. Pregnant rats were injected with two doses of methylazoxymethanol acetate (MAM, 15 mg/kg, i.p.) to induce MCD, while controls were administered normal saline. The cortical development of the offspring was measured by performing magnetic resonance imaging (MRI) on postnatal days (P) 1, 5, and 8. At P8, some rats were sacrificed for immunofluorescence, Golgi staining, and Western analysis. In another set of rats, the number and latency to onset of spasms were monitored for 90 min after the NMDA (5 mg/kg i.p.) injection at P8. In MCD rats, in vivo MR imaging showed smaller brain volume and thinner cortex from day 1 after birth (p < 0.001). Golgi staining and immunofluorescence revealed abnormal neuronal migration, with a reduced number of neuronal cell populations and less dendritic arborization at P8. Furthermore, MCD rats exhibited a significant reduction in the expression of NMDA receptors and AMPAR4, along with an increase in AMPAR3 expression (p < 0.05). Although there was no difference in the latency to seizure onset between MCD rats and controls, the MCD rats survived significantly longer than the controls. These results provide insights into the early developmental changes in the cortex of a MCD rat model and suggest that delayed and abnormal neuronal development in the immature brain is associated with a blunted response to NMDA-induced excitotoxic injury. These developmental changes may be involved in the sudden onset of epilepsy in patients with MCD or prenatal brain injury.


Assuntos
Movimento Celular , Modelos Animais de Doenças , Malformações do Desenvolvimento Cortical , N-Metilaspartato , Neurônios , Ratos Sprague-Dawley , Animais , Ratos , N-Metilaspartato/toxicidade , Feminino , Gravidez , Movimento Celular/efeitos dos fármacos , Neurônios/patologia , Neurônios/efeitos dos fármacos , Malformações do Desenvolvimento Cortical/induzido quimicamente , Malformações do Desenvolvimento Cortical/patologia , Animais Recém-Nascidos , Acetato de Metilazoximetanol/toxicidade , Acetato de Metilazoximetanol/análogos & derivados , Córtex Cerebral/patologia , Córtex Cerebral/efeitos dos fármacos , Masculino , Imageamento por Ressonância Magnética
4.
CNS Neurosci Ther ; 30(2): e14565, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38421095

RESUMO

AIM: Widely used second-generation antipsychotics are associated with adverse metabolic effects, contributing to increased cardiovascular mortality. To develop strategies to prevent or treat adverse metabolic effects, preclinical models have a clear role in uncovering underlying molecular mechanisms. However, with few exceptions, preclinical studies have been performed in healthy animals, neglecting the contribution of dysmetabolic features inherent to psychotic disorders. METHODS: In this study, methylazoxymethanol acetate (MAM) was prenatally administered to pregnant Sprague-Dawley rats at gestational day 17 to induce a well-validated neurodevelopmental model of schizophrenia mimicking its assumed pathogenesis with persistent phenotype. Against this background, the dysmetabolic effects of acute treatment with olanzapine and haloperidol were examined in female rats. RESULTS: Prenatally MAM-exposed animals exhibited several metabolic features, including lipid disturbances. Half of the MAM rats exposed to olanzapine had pronounced serum lipid profile alteration compared to non-MAM controls, interpreted as a reflection of a delicate MAM-induced metabolic balance disrupted by olanzapine. In accordance with the drugs' clinical metabolic profiles, olanzapine-associated dysmetabolic effects were more pronounced than haloperidol-associated dysmetabolic effects in non-MAM rats and rats exposed to MAM. CONCLUSION: Our results demonstrate metabolic vulnerability in female prenatally MAM-exposed rats, indicating that findings from healthy animals likely provide an underestimated impression of metabolic dysfunction associated with antipsychotics. In the context of metabolic disturbances, neurodevelopmental models possess a relevant background, and the search for adequate animal models should receive more attention within the field of experimental psychopharmacology.


Assuntos
Antipsicóticos , Haloperidol , Acetato de Metilazoximetanol/análogos & derivados , Gravidez , Ratos , Feminino , Animais , Haloperidol/toxicidade , Acetato de Metilazoximetanol/toxicidade , Olanzapina/toxicidade , Ratos Sprague-Dawley , Antipsicóticos/uso terapêutico , Lipídeos , Modelos Animais de Doenças
6.
Neurosci Bull ; 40(6): 683-694, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38141109

RESUMO

Early-onset mental disorders are associated with disrupted neurodevelopmental processes during adolescence. The methylazoxymethanol acetate (MAM) animal model, in which disruption in neurodevelopmental processes is induced, mimics the abnormal neurodevelopment associated with early-onset mental disorders from an etiological perspective. We conducted longitudinal structural magnetic resonance imaging (MRI) scans during childhood, adolescence, and adulthood in MAM rats to identify specific brain regions and critical windows for intervention. Then, the effect of repetitive transcranial magnetic stimulation (rTMS) intervention on the target brain region during the critical window was investigated. In addition, the efficacy of this intervention paradigm was tested in a group of adolescent patients with early-onset mental disorders (diagnosed with major depressive disorder or bipolar disorder) to evaluate its clinical translational potential. The results demonstrated that, compared to the control group, the MAM rats exhibited significantly lower striatal volume from childhood to adulthood (all P <0.001). In contrast, the volume of the hippocampus did not show significant differences during childhood (P >0.05) but was significantly lower than the control group from adolescence to adulthood (both P <0.001). Subsequently, rTMS was applied to the occipital cortex, which is anatomically connected to the hippocampus, in the MAM models during adolescence. The MAM-rTMS group showed a significant increase in hippocampal volume compared to the MAM-sham group (P <0.01), while the volume of the striatum remained unchanged (P >0.05). In the clinical trial, adolescents with early-onset mental disorders showed a significant increase in hippocampal volume after rTMS treatment compared to baseline (P <0.01), and these volumetric changes were associated with improvement in depressive symptoms (r = - 0.524, P = 0.018). These findings highlight the potential of targeting aberrant hippocampal development during adolescence as a viable intervention for early-onset mental disorders with neurodevelopmental etiology as well as the promise of rTMS as a therapeutic approach for mitigating aberrant neurodevelopmental processes and alleviating clinical symptoms.


Assuntos
Modelos Animais de Doenças , Hipocampo , Imageamento por Ressonância Magnética , Acetato de Metilazoximetanol , Estimulação Magnética Transcraniana , Animais , Hipocampo/patologia , Estimulação Magnética Transcraniana/métodos , Masculino , Adolescente , Feminino , Ratos , Humanos , Acetato de Metilazoximetanol/análogos & derivados , Transtorno Depressivo Maior/terapia , Transtornos Mentais/terapia , Pesquisa Translacional Biomédica , Ratos Sprague-Dawley , Transtorno Bipolar/terapia
7.
Brain Behav ; 12(2): e2466, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35025141

RESUMO

INTRODUCTION: Synaptic N-methyl-d-aspartate receptor subtype 2B(NR2B) is significantly reduced in prefrontal cortex (PFC) in the neurodevelopmental methylazoxymethanol (MAM) model of schizophrenia (SCZ). Recent research has shown that LY395756 can effectively restore NR2B levels and improve cognitive performance in juvenile MAM mice model. However, the underlying mechanisms of these beneficial effects remain unclear. MATERIALS AND METHODS: Juvenile MAM mice model of SCZ is used in our study. Synaptic membrane protein levels were examined by western blotting under different treatment conditions. Interaction of cAMP-response element binding protein (CREB) and the promoter of NR2B was detected by the chromatin immunoprecipitation (ChIP) assay. Further examination of signaling pathway that mediates NR2B expression was also investigated by western blotting. RESULTS: In the PFC of the juvenile MAM mice schizophrenia model, CREB was found to directly bind with the promoter of NR2B. LY395756 activated the phosphorylation of AKT. Phosphorylated AKT subsequently induced the phosphorylation of CREB, and the activated CREB promoted the expression of NR2B. Subsequent experiments showed that the dephosphorylation of CREB induced by protein phosphatase 1 (PP1) can inhibit NR2B levels. Taken together, these findings support that the AKT/CREB signaling pathway is essential for the promoting effect of LY395756 on synaptic NR2B in PFC in juvenile MAM mice SCZ model. CONCLUSIONS: Our investigation has identified a novel mechanism by which LY395756 increases NR2B expression in juvenile MAM mice SCZ model. The AKT/CREB signaling pathway warrants further research as a potential direction for clinical treatment of SCZ.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Esquizofrenia , Aminoácidos Dicarboxílicos , Animais , Compostos Bicíclicos com Pontes , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Acetato de Metilazoximetanol/análogos & derivados , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/induzido quimicamente , Transdução de Sinais
8.
Int J Neuropsychopharmacol ; 24(12): 979-987, 2021 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-34622270

RESUMO

BACKGROUND: The present study utilized the methylazoxymethanol (MAM) neurodevelopmental rodent model of schizophrenia (SCZ) to evaluate the hypothesis that individuals with SCZ smoke in an attempt to "self-medicate" their symptoms through nicotine (NIC) intake. METHODS: To explore this question, we examined the effects of acute and chronic administration of NIC in 2 established behavioral tests known to be disrupted in the MAM model: prepulse inhibition of startle and novel object recognition. Additionally, we assessed the effects of acute and chronic NIC on 2 indices of the pathophysiology of SCZ modeled by MAM, elevated dopamine neuron population activity in the ventral tegmental area and neuronal activity in the ventral hippocampus, using in vivo electrophysiological recordings. RESULTS: Our findings demonstrated that both acute and chronic administration of NIC significantly improved deficits in prepulse inhibition of startle and novel object recognition among MAM rats and normalized elevated ventral tegmental area and ventral hippocampal neuronal activity in these animals. CONCLUSION: Together, these findings of NIC-induced improvement of deficits lend support for a "self-medication" hypothesis behind increased cigarette smoking in SCZ and illustrate the potential utility of nicotinic modulation in future pharmacotherapies for certain SCZ symptoms.


Assuntos
Acetato de Metilazoximetanol/análogos & derivados , Nicotina/administração & dosagem , Esquizofrenia/tratamento farmacológico , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Inibição Pré-Pulso/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Automedicação , Área Tegmentar Ventral/efeitos dos fármacos
9.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445411

RESUMO

BACKGROUND: The present study investigated the role of proteins from the bromodomain and extra-terminal (BET) family in schizophrenia-like abnormalities in a neurodevelopmental model of schizophrenia induced by prenatal methylazoxymethanol (MAM) administration (MAM-E17). METHODS: An inhibitor of BET proteins, JQ1, was administered during adolescence on postnatal days (P) 23-P29, and behavioural responses (sensorimotor gating, recognition memory) and prefrontal cortical (mPFC) function (long-term potentiation (LTP), molecular and proteomic analyses) studies were performed in adult males and females. RESULTS: Deficits in sensorimotor gating and recognition memory were observed only in MAM-treated males. However, adolescent JQ1 treatment affected animals of both sexes in the control but not MAM-treated groups and reduced behavioural responses in both sexes. An electrophysiological study showed LTP impairments only in male MAM-treated animals, and JQ1 did not affect LTP in the mPFC. In contrast, MAM did not affect activity-dependent gene expression, but JQ1 altered gene expression in both sexes. A proteomic study revealed alterations in MAM-treated groups mainly in males, while JQ1 affected both sexes. CONCLUSIONS: MAM-induced schizophrenia-like abnormalities were observed only in males, while adolescent JQ1 treatment affected memory recognition and altered the molecular and proteomic landscape in the mPFC of both sexes. Thus, transient adolescent inhibition of the BET family might prompt permanent alterations in the mPFC.


Assuntos
Azepinas/administração & dosagem , Acetato de Metilazoximetanol/análogos & derivados , Córtex Pré-Frontal/crescimento & desenvolvimento , Esquizofrenia/fisiopatologia , Triazóis/administração & dosagem , Adolescente , Desenvolvimento do Adolescente/efeitos dos fármacos , Animais , Azepinas/farmacologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Acetato de Metilazoximetanol/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Proteômica , Ratos , Reconhecimento Psicológico/efeitos dos fármacos , Esquizofrenia/induzido quimicamente , Esquizofrenia/metabolismo , Caracteres Sexuais , Triazóis/farmacologia
10.
Behav Brain Res ; 412: 113442, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34229023

RESUMO

Malformation of cortical developments (MCDs) is currently an incurable disease and is associated with significant neuropsychological problems, such as intellectual disability, epilepsy, and anxiety disorders from a young age. Development of a suitable animal model and pathophysiological study is therefore necessary to better understand and treat MCDs from being an incurable disease. The Y-maze, open field, and fear conditioning studies were performed at postnatal days 40-44 to validate the behavioral phenotypes of the existing rat model of MCD with prenatal methylazoxymethanol exposure at their developmental period. The study results show that juvenile rats with MCD spent significantly less time inside the novel arms in Y-maze and less time in the peripheral zones of the open field. Additionally, the rats with MCDs showed attenuated freezing behavior to sound and light cues as well as to context after fear conditioning. This comprehensive behavioral analysis of rats with MCDs at the juvenile period indicate a lack of spatial memory, decreased anxiety, and learning disability in these rats, which is compatible with the human behavioral phenotype of MCDs and can be used as the behavioral biomarkers for future translational research.


Assuntos
Malformações do Desenvolvimento Cortical/fisiopatologia , Memória de Curto Prazo/fisiologia , Comportamento de Redução do Risco , Afeto , Animais , Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Cognição/fisiologia , Sinais (Psicologia) , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Masculino , Malformações do Desenvolvimento Cortical/psicologia , Aprendizagem em Labirinto/fisiologia , Acetato de Metilazoximetanol/efeitos adversos , Acetato de Metilazoximetanol/análogos & derivados , Acetato de Metilazoximetanol/farmacologia , Atividade Motora/fisiologia , Neurogênese/fisiologia , Ratos , Ratos Sprague-Dawley , Assunção de Riscos , Memória Espacial/fisiologia
11.
Brain Res ; 1762: 147425, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33737065

RESUMO

The amygdala plays a crucial role in anxiety-related behavior and various neuropsychiatric disorders. The offspring of dams, administered methylazoxymethanol acetate (MAM) intraperitoneally at gestational day 15, exhibit micrencephaly and anxiety-related behavior, such as hyperactivity in rearing and crossing behavior, alongside a distinct Fos expression profile in the basolateral (BLA) and central amygdala. However, the histochemical underpinnings of these changes remain to be elucidated. To determine the histochemical alterations in MAM-induced model rats, we performed Nissl staining, immunohistochemistry for parvalbumin (PV) or calbindin (Calb), and immunohistochemistry for PV in conjunction with in situ hybridization for glutamate decarboxylase (GAD). We compared immunoreactivity in the BLA between normal and MAM-induced model rats and observed a significant decrease in the number of PV-positive neurons in MAM-induced model rats; however, no significant differences in the number of Nissl- and Calb-positive neurons were observed. We did not detect any significant between-group differences with regards to the effects of environmental enrichment on the number of PV-positive neurons in the BLA. Double-labeling for GAD and PV revealed that many PV-positive neurons colocalized with digoxigenin-GAD65/67 signals. In addition, GAD/PV double-positive neurons and the total number of GAD-positive neurons in the BLA were lower in the MAM-induced model rats. These results indicate that histochemical alterations observed in the BLA of the MAM-induced model rats may attribute to an aberrant GABAergic inhibitory system.


Assuntos
Complexo Nuclear Basolateral da Amígdala/metabolismo , Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Acetato de Metilazoximetanol/análogos & derivados , Microcefalia/metabolismo , Parvalbuminas/metabolismo , Animais , Complexo Nuclear Basolateral da Amígdala/química , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Carcinógenos/toxicidade , Feminino , Neurônios GABAérgicos/química , Neurônios GABAérgicos/efeitos dos fármacos , Interneurônios/química , Interneurônios/efeitos dos fármacos , Masculino , Acetato de Metilazoximetanol/toxicidade , Microcefalia/induzido quimicamente , Microcefalia/psicologia , Parvalbuminas/análise , Gravidez , Ratos , Ratos Sprague-Dawley
12.
Behav Brain Res ; 406: 113231, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33737089

RESUMO

Adolescent social isolation (SI) might change the trajectory of brain development. In the present study, we investigated the effect of short-term adolescent SI on fear memory, anxiety and protein levels in the adult medial prefrontal cortex of rats prenatally treated with methylazoxymethanol, MAM-E17 model of schizophrenia. The animals were maintained in standard housing (SH) or social isolation (P30-P40, SI) conditions. Behavioural tests (trace or delay fear conditioning, light/dark box) were performed in late adolescence and early adulthood. The results showed that MAM treatment did not alter fear memory, which was investigated with the use of either trace or delay fear conditioning, at any age, and SI decreased the fear response in adult control animals only under trace conditioning. Neither MAM nor SI influenced anxiety-related behaviour measured in the light/dark box. A proteomics study showed that both MAM and SI changed the protein levels related to synapse maturation and cytoskeletal organization, energy transfer and metabolic processes. Prenatal or adolescent environmental factors are able to change the expression of proteins that are correlated with behavioural impairments. Moreover, SI reversed some alterations in proteins induced by MAM. Thus, normally developing brains showed different responses to adolescent SI than those with altering courses of MAM administration.


Assuntos
Comportamento Animal/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Córtex Pré-Frontal , Efeitos Tardios da Exposição Pré-Natal , Esquizofrenia , Isolamento Social , Fatores Etários , Animais , Feminino , Masculino , Acetato de Metilazoximetanol/análogos & derivados , Acetato de Metilazoximetanol/farmacologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Proteoma , Ratos Wistar , Esquizofrenia/etiologia , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Teratogênicos/farmacologia
14.
Toxicol Appl Pharmacol ; 406: 115214, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32866524

RESUMO

Mortality in psychiatric patients with severe mental illnesses reaches a 2-3 times higher mortality rate compared to the general population, primarily due to somatic comorbidities. A high prevalence of cardiovascular morbidity can be attributed to the adverse metabolic effects of atypical antipsychotics (atypical APs), but also to metabolic dysregulation present in drug-naïve patients. The metabolic aspects of neurodevelopmental schizophrenia-like models are understudied. This study evaluated the metabolic phenotype of a methylazoxymethanol (MAM) schizophrenia-like model together with the metabolic effects of three APs [olanzapine (OLA), risperidone (RIS) and haloperidol (HAL)] administered via long-acting formulations for 8 weeks in female rats. Body weight, feed efficiency, serum lipid profile, gastrointestinal and adipose tissue-derived hormones (leptin, ghrelin, glucagon and glucagon-like peptide 1) were determined. The lipid profile was assessed in APs-naïve MAM and control cohorts of both sexes. Body weight was not altered by the MAM model, though cumulative food intake and feed efficiency was lowered in the MAM compared to CTR animals. The effect of the APs was also present; body weight gain was increased by OLA and RIS, while OLA induced lower weight gain in the MAM rats. Further, the MAM model showed lower abdominal adiposity, while OLA increased it. Serum lipid profile revealed MAM model-induced alterations in both sexes; total, HDL and LDL cholesterol levels were increased. The MAM model did not exert significant alterations in hormonal parameters except for elevation in leptin level. The results support intrinsic metabolic dysregulation in the MAM model in both sexes, but the MAM model did not manifest higher sensitivity to metabolic effects induced by antipsychotic treatment.


Assuntos
Modelos Animais de Doenças , Acetato de Metilazoximetanol/análogos & derivados , Esquizofrenia/induzido quimicamente , Esquizofrenia/metabolismo , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Feminino , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Metaboloma/efeitos dos fármacos , Olanzapina/farmacologia , Olanzapina/uso terapêutico , Ratos Sprague-Dawley , Risperidona/farmacologia , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico
15.
Neuropharmacology ; 153: 82-97, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047919

RESUMO

Glutamate receptors play a crucial pathogenic role in brain damage induced by status epilepticus (SE). SE may initiate NMDAR-dependent excitotoxicity through the production of oxidative damage mediated by the activation of a ternary complex formed by the NMDA receptor, the post-synaptic density scaffolding protein 95 (PSD95) and the neuronal NO synthase (nNOS). The inhibition of the protein-protein-interaction (PPI) of the NMDAR-PSD95-nNOS complex is one of the most intriguing challenges recently developed to reduce neuronal death in both animal models and in patients with cerebral ischemia. We took advantage of this promising approach to verify whether early administration of a neuroprotective NMDAR-PSD95-nNOS PPI inhibitor preserves the brain from SE-induced damage in a model of acquired cortical dysplasia, the methylazoxymethanol (MAM)/pilocarpine rat. Pilocarpine-induced SE rapidly determined neurodegenerative changes mediated by a NMDAR-downstream neurotoxic pathway in MAM rats. We demonstrated that SE rapidly induces NMDAR activation, nNOS membrane translocation, PSD95-nNOS molecular interaction associated with neuronal and glial peroxynitrite accumulation in the neocortex of MAM-pilocarpine rats. These changes were paralleled by rapid c-fos overexpression and by progressive spectrin proteolysis, suggestive of calpain activity and irreversible cytoskeletal damage. Early administration of a cell-penetrating Tat-N-dimer peptide inhibitor of NMDAR-PSD95-nNOS PPI during SE significantly rescued the MAM-pilocarpine rats from SE-induced mortality, reduced the number of degenerating neurons, decreased neuronal c-fos activation, peroxynitrite formation and cytoskeletal degradation and prevented astrogliosis. Our findings suggest an overall neuroprotective effect of blocking PSD95-nNOS protein-protein-interaction against SE insult.


Assuntos
Proteína 4 Homóloga a Disks-Large/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Óxido Nítrico Sintase Tipo I/metabolismo , Peptídeos/administração & dosagem , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Animais , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/antagonistas & inibidores , Feminino , Acetato de Metilazoximetanol/análogos & derivados , Acetato de Metilazoximetanol/toxicidade , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Pilocarpina/toxicidade , Gravidez , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/prevenção & controle
16.
Toxicon ; 155: 49-50, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30316979

RESUMO

Cycad-associated neurodegenerative disease is more strongly correlated with the gymnosperm's major neurotoxin cycasin (methylazoxymethanol glucoside) than with the minor neurotoxin ß-N-methylamino-L-alanine (L-BMAA).


Assuntos
Diamino Aminoácidos/toxicidade , Acetato de Metilazoximetanol/análogos & derivados , Doenças Neurodegenerativas/induzido quimicamente , Encéfalo/efeitos dos fármacos , Toxinas de Cianobactérias , Cycas/química , Humanos , Acetato de Metilazoximetanol/toxicidade , Neurotoxinas/toxicidade
17.
Neuropharmacology ; 140: 287-301, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30056124

RESUMO

Gestational and perinatal disruption of neural development increases the risk of developing schizophrenia (SCZ) later in life. Embryonic day 17 (E17) methylazoxymethanol (MAM) treatment leads to histological, physiological and behavioural abnormalities in post-puberty rats that model the neuropathological and cognitive deficits reported in SCZ patients. However, the validity of E17 MAM-exposed mice to model SCZ has not been explored. Here we treated E17 C57BL/6 mouse dams with various dosages of MAM. We found that this mouse strain was more vulnerable to MAM treatment than rats and there were gender differences in behavioural abnormalities, histological changes and prefrontal cortical gene expression profiles in MAM (7.5 mg/kg)-exposed mice. Both male and female MAM-exposed mice had deficits in prepulse inhibition. Female MAM-exposed mice exhibited mildly increased spontaneous locomotion activity and social recognition deficits, while male mice were normal. Consistently, only female MAM-exposed mice exhibited reduced brain weight, decreased size of prefrontal cortex (PFC) and enlarged lateral ventricles. Transcriptome analysis of the PFC revealed that there were more differentially expressed genes in female MAM-exposed mice than those in male mice. Moreover, expression of Pvalb, Arc and genes in their association networks were downregulated in the PFC of female MAM-exposed mice. These results indicate that E17 MAM-exposure in C57BL/6 mice leads to behavioural changes that model certain deficits reported in SCZ patients. MAM-exposed female mice may be used to study gene expression changes, inhibitory neural circuit dysfunction and glutamatergic synaptic plasticity deficits with a possible relation to those in the brains of SCZ patients.


Assuntos
Acetato de Metilazoximetanol/análogos & derivados , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Esquizofrenia/patologia , Psicologia do Esquizofrênico , Transcriptoma/efeitos dos fármacos , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Hipertrofia , Ventrículos Laterais/patologia , Masculino , Acetato de Metilazoximetanol/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Inibição Pré-Pulso/efeitos dos fármacos , Caracteres Sexuais , Comportamento Social
18.
Schizophr Res ; 201: 254-260, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29705007

RESUMO

Altered cannabinoid 1 receptor (CB1R) expression has been reported in the brain of subjects with schizophrenia, a developmental mental illness that usually emerges in late adolescence/early adulthood. However, the developmental period at which changes in the CB1R expression appear in schizophrenia is unknown. To gain insight into this factor, we assessed the postnatal developmental trajectory of CB1R expression in the methylazoxymethanol (MAM) model of schizophrenia. Using in situ hybridization with film and grain analyses, CB1R messenger RNA (mRNA) levels were quantified in multiple brain regions, including the medial prefrontal cortex (mPFC), secondary motor cortex, dorsomedial and dorsolateral striatum, dorsal subregions and ventral subiculum of the hippocampus, of MAM-treated rats and normal controls at three developmental periods [juvenile - postnatal day (PD) 30; adolescence - PD45; and adulthood - PD85]. In all brain regions studied, CB1R mRNA levels were highest in juveniles and then decreased progressively toward adolescent and adult levels in control and MAM-treated rats. However, in MAM-treated rats, CB1R mRNA levels were lower in the mPFC at PD85 and higher in the dorsolateral striatum at PD45 and PD85 relative to controls. Cellular analyses confirmed the changes in CB1R mRNA expression in MAM-treated rats. These findings are in accordance with previous studies showing a decrease in the CB1R mRNA expression from juvenile period to adolescence to adulthood in cortical, striatal, and hippocampal regions. Additionally, similar to most of the schizophrenia-like signs observed in the MAM model, embryonic exposure to MAM leads to schizophrenia-related changes in CB1R mRNA expression that only emerge later in development.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , RNA Mensageiro/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Esquizofrenia/metabolismo , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Hibridização In Situ , Masculino , Acetato de Metilazoximetanol/análogos & derivados , Distribuição Aleatória , Ratos Sprague-Dawley
19.
Int J Dev Neurosci ; 68: 1-9, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29605566

RESUMO

BACKGROUND: Melatonin, which is an antioxidant and neuroprotective agent, can be an effective treatment for neurological disorders. We assessed the effect of melatonin administration on histological changes, antioxidant enzyme levels, and behavioral changes in a neonate mouse model of cortical malformation. MATERIALS AND METHODS: Cortical malformation was induced by two injections of 15 mg/kg methylazoxymethanol (MAM) on gestational day 15 (E15). Pregnant Balb/c mice were randomly divided into the following six groups: Control (CO), Melatonin (MEL), Luzindole (LUZ), MAM, MEL + MAM1 (co-treatment), and MEL + MAM2 (pretreatment). Melatonin was intraperitoneally injected at a dose of 10 mg/kg daily (from E15 until delivery of from E6 for 20 days after delivery). On postnatal day 31, the activity and anxiety of mice were assessed by open field and elevated plus maze tests, respectively. Histopathological changes in the neonate cortex were studied using hematoxylin and eosin staining and neurofilament immunohistochemistry. Enzyme-linked immunosorbent assays were used to measure the activity of nitric oxide (NO), malondialdehyde (MDA), and antioxidant enzymes, including catalase (CAT), super oxide dismutase (SOD), and glutathione peroxidase (GPX). RESULTS: In the behavioral assessment of neonate mice, a significant increase in the crossing activity and decrease in anxiety were recorded in groups treated with MAM plus melatonin. In histological examination, heterotopic, dysmorphic, and ectopic cells, as well as dyslamination, were seen in the MAM and LUZ groups. However, these defects were attenuated in the MAM plus melatonin groups. Significant reductions were recorded in the SOD and GPX levels in the MAM and LUZ groups compared to the control, while the NO level was increased in these groups. Groups that received MAM plus melatonin showed significant increases in the levels of SOD and GPX and a significant decrease in the level of NO, compared to the MAM group. CONCLUSION: Melatonin increased the crossing activity and decreased the anxiety in the treated mice of the neonate mouse model of cortical malformation. Histologically, the administration of exogenous melatonin in pregnant mice and their neonates had a protective effect on the cerebral cortex of neonates. Also, this effect is elicited by decreasing NO and increasing antioxidative enzymes.


Assuntos
Antioxidantes/uso terapêutico , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/tratamento farmacológico , Melatonina/uso terapêutico , Animais , Animais Recém-Nascidos , Carcinógenos/toxicidade , Catalase/metabolismo , Modelos Animais de Doenças , Feminino , Glutationa Peroxidase/metabolismo , Filamentos Intermediários/metabolismo , Malformações do Desenvolvimento Cortical/induzido quimicamente , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Acetato de Metilazoximetanol/análogos & derivados , Acetato de Metilazoximetanol/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Nitroprussiato/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Superóxido Dismutase/metabolismo , Triptaminas/toxicidade
20.
Neurotox Res ; 34(2): 305-323, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29536265

RESUMO

Social isolation (SI) during adolescence may induce schizophrenia-like behavior. In the present study, we investigated whether adolescent SI might affect the development of schizophrenia-like behavior in the MAM-E17 neurodevelopmental model of schizophrenia. Rats were socially isolated for 10 days during adolescence (postnatal days (P) 30-40), followed by resocialization until late adolescence (P45-P48) or early adulthood (P70-P75); behavioral and neurochemical studies were performed at these ages. The behavioral studies analyzed locomotor activity, social interaction, recognition memory, and sensorimotor gating; GAD65 and GAD67 protein levels were measured in the prefrontal cortex. The results showed that SI did not affect locomotor activity, but it prevented the social interaction deficits induced by MAM administration at both of the analyzed age points. However, SI induced a deficit in recognition memory in the MAM group during adolescence, which was not observed in the MAM-treated, socially housed rats at this age. In adulthood, impairments in recognition memory were detected in both MAM groups. In contrast, SI did not accelerate the appearance of sensorimotor gating deficits in MAM animals during adolescence, and sensorimotor gating impairments were observed in both MAM groups during adulthood. Adolescent SI rearing did not affect any examined behavioral responses in the VEH-treated groups. SI altered the levels of GAD65 and GAD67 proteins during adolescence in both groups; however, the decrease in the level of GAD65 protein was observed only in the adult MAM-SI group. Thus, SI rearing during a defined period of adolescence might have specific effects on the emergence of schizophrenia-like abnormalities in MAM-treated animals.


Assuntos
Carcinógenos/toxicidade , Acetato de Metilazoximetanol/análogos & derivados , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Isolamento Social/psicologia , Fatores Etários , Animais , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Glutamato Descarboxilase/metabolismo , Relações Interpessoais , Locomoção , Acetato de Metilazoximetanol/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Wistar , Reconhecimento Psicológico , Filtro Sensorial , Estatísticas não Paramétricas
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