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1.
Neurosci Lett ; 761: 136123, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34293418

RESUMO

BACKGROUND: Epilepsy is a disorder characterized by recurrent seizures that affects 1% of the population. However, the neurochemical alterations observed in epilepsy are not fully understood. There are different animal models of epilepsy, such as genetic or drug induced. In the present study, we utilize Wistar Audiogenic Rats (WAR), a murine strain that develops seizures in response to high intensity audio stimulation, in order to investigate abnormalities in glutamatergic and GABAergic systems. METHODS: Synaptosomes and glial plasmalemmal vesicles were prepared from hippocampus and cortex, respectively. Glutamate and GABA release and uptake were assayed by monitoring the fluorescence and using L-[3H]-radiolabeled compounds. Glutamate and calcium concentration in the synaptosomes were also measured. The expression of neuronal calcium sensor 1 (NCS-1) was determined by western blot. RESULTS: Glutamate and GABA release evoked by KCl was decreased in WAR compared to control Wistar rats. Calcium independent release was not considerably different in both groups. The total amount of glutamate of synaptosomes, as well as glutamate uptake by synaptosomes and GPV were also decreased in WAR in comparison with the controls. In addition, [Ca2+]i of hippocampal synaptosomes, as well as NCS-1 expression in the hippocampus, were increased in WAR in comparison with controls. CONCLUSION: In conclusion, our results suggest that WAR have important alterations in the glutamatergic and GABAergic pathways, as well as an increased expression of NCS-1 in the hippocampus and inferior colliculus. These alterations may be linked to the spreading of hyperexcitability and recruitment of various brain regions.


Assuntos
Hipocampo/metabolismo , Convulsões/metabolismo , Animais , Cálcio/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Proteínas Sensoras de Cálcio Neuronal/metabolismo , Neuropeptídeos/metabolismo , Ratos , Ratos Wistar , Sinaptossomos/metabolismo , Ácido gama-Aminobutírico/metabolismo
2.
Epilepsy Behav ; 121(Pt B): 106832, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-31839498

RESUMO

This review focuses on the possible roles of phytocannabinoids, synthetic cannabinoids, endocannabinoids, and "transient receptor potential cation channel, subfamily V, member 1" (TRPV1) channel blockers in epilepsy treatment. The phytocannabinoids are compounds produced by the herb Cannabis sativa, from which Δ9-tetrahydrocannabinol (Δ9-THC) is the main active compound. The therapeutic applications of Δ9-THC are limited, whereas cannabidiol (CBD), another phytocannabinoid, induces antiepileptic effects in experimental animals and in patients with refractory epilepsies. Synthetic CB1 agonists induce mixed effects, which hamper their therapeutic applications. A more promising strategy focuses on compounds that increase the brain levels of anandamide, an endocannabinoid produced on-demand to counteract hyperexcitability. Thus, anandamide hydrolysis inhibitors might represent a future class of antiepileptic drugs. Finally, compounds that block the TRPV1 ("vanilloid") channel, a possible anandamide target in the brain, have also been investigated. In conclusion, the therapeutic use of phytocannabinoids (CBD) is already in practice, although its mechanisms of action remain unclear. Endocannabinoid and TRPV1 mechanisms warrant further basic studies to support their potential clinical applications. This article is part of the Special Issue "NEWroscience 2018".


Assuntos
Canabidiol , Canabinoides , Cannabis , Epilepsia , Animais , Canabidiol/uso terapêutico , Canabinoides/uso terapêutico , Dronabinol , Epilepsia/tratamento farmacológico , Humanos
3.
Front Neurol ; 11: 586724, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33250852

RESUMO

Background: Clinical and experimental evidence indicates that olfactory stimulation modulates limbic seizures, either blocking or inducing ictal activity. Objective: We aim to evaluate the behavioral and electroencephalographic (EEGraphic) effects of dihydro-2,4,5-trimethylthiazoline (TMT) olfactory exposure on limbic seizures induced by amygdala rapid kindling (ARK). Materials and Methods: Wistar male rats (280-300 g) underwent stereotaxic surgery for electrode implantation in piriform cortex (PC), hippocampal formation (HIP), and amygdaloid complex (AMYG). Part of the animals was exposed to a saturated chamber with water or TMT, while others had ARK and olfactory exposure prior to the 21st stimulus. Behavioral responses were measured by traditional seizure severity scales (Racine and Pinel and Rovner) and/or by sequential analysis/neuroethology. The electrographic activity of epileptogenic limbic networks was quantified by the occurrence of the first and second EEG afterdischarges, comparing the 1st and 21st stimulus. The spectral analysis [Fast Fourier Transform (FFT)] of the first afterdischarge was performed at the 21st stimulus. Results: TMT olfactory exposure reduced the seizure severity in kindled rats, altering the displayed behavioral sequence. Moreover, TMT decreased the occurrence of first and second afterdischarges, at the 21st stimulus, and altered the spectral features. Conclusions: Both behavioral and EEGraphic evaluations indicated that TMT, a potent molecule with strong biological relevance, in fact, "predator odor," suppressed the epileptiform activity in limbic networks.

4.
Epilepsia ; 61(9): 1906-1918, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32761902

RESUMO

OBJECTIVE: Seizure detection is a major facet of electroencephalography (EEG) analysis in neurocritical care, epilepsy diagnosis and management, and the instantiation of novel therapies such as closed-loop stimulation or optogenetic control of seizures. It is also of increased importance in high-throughput, robust, and reproducible pre-clinical research. However, seizure detectors are not widely relied upon in either clinical or research settings due to limited validation. In this study, we create a high-performance seizure-detection approach, validated in multiple data sets, with the intention that such a system could be available to users for multiple purposes. METHODS: We introduce a generalized linear model trained on 141 EEG signal features for classification of seizures in continuous EEG for two data sets. In the first (Focal Epilepsy) data set consisting of 16 rats with focal epilepsy, we collected 1012 spontaneous seizures over 3 months of 24/7 recording. We trained a generalized linear model on the 141 features representing 20 feature classes, including univariate and multivariate, linear and nonlinear, time, and frequency domains. We tested performance on multiple hold-out test data sets. We then used the trained model in a second (Multifocal Epilepsy) data set consisting of 96 rats with 2883 spontaneous multifocal seizures. RESULTS: From the Focal Epilepsy data set, we built a pooled classifier with an Area Under the Receiver Operating Characteristic (AUROC) of 0.995 and leave-one-out classifiers with an AUROC of 0.962. We validated our method within the independently constructed Multifocal Epilepsy data set, resulting in a pooled AUROC of 0.963. We separately validated a model trained exclusively on the Focal Epilepsy data set and tested on the held-out Multifocal Epilepsy data set with an AUROC of 0.890. Latency to detection was under 5 seconds for over 80% of seizures and under 12 seconds for over 99% of seizures. SIGNIFICANCE: This method achieves the highest performance published for seizure detection on multiple independent data sets. This method of seizure detection can be applied to automated EEG analysis pipelines as well as closed loop interventional approaches, and can be especially useful in the setting of research using animals in which there is an increased need for standardization and high-throughput analysis of large number of seizures.


Assuntos
Eletrocorticografia/métodos , Epilepsias Parciais/diagnóstico , Aprendizado de Máquina , Convulsões/diagnóstico , Processamento de Sinais Assistido por Computador , Animais , Área Sob a Curva , Modelos Animais de Doenças , Eletroencefalografia , Epilepsias Parciais/fisiopatologia , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Caínico/toxicidade , Modelos Lineares , Curva ROC , Ratos , Reprodutibilidade dos Testes , Convulsões/induzido quimicamente , Convulsões/fisiopatologia
5.
Transl Psychiatry ; 10(1): 33, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-32066672

RESUMO

Although loneliness is a human experience, it can be estimated in laboratory animals deprived from physical contact with conspecifics. Rodents under social isolation (SI) tend to develop emotional distress and cognitive impairment. However, it is still to be determined whether those conditions present a common neural mechanism. Here, we conducted a series of behavioral, morphological, and neurochemical analyses in adult mice that underwent to 1 week of SI. We observed that SI mice display a depressive-like state that can be prevented by enriched environment, and the antidepressants fluoxetine (FLX) and desipramine (DES). Interestingly, chronic administration of FLX, but not DES, was able to counteract the deleterious effect of SI on social memory. We also analyzed cell proliferation, neurogenesis, and astrogenesis after the treatment with antidepressants. Our results showed that the olfactory bulb (OB) was the neurogenic niche with the highest increase in neurogenesis after the treatment with FLX. Considering that after FLX treatment social memory was rescued and depressive-like behavior decreased, we propose neurogenesis in the OB as a possible mechanism to unify the FLX ability to counteract the deleterious effect of SI.


Assuntos
Fluoxetina , Bulbo Olfatório , Animais , Antidepressivos/farmacologia , Fluoxetina/farmacologia , Memória , Camundongos , Neurogênese
6.
EBioMedicine ; 44: 516-529, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31130472

RESUMO

BACKGROUND: Zika virus (ZIKV) infection during pregnancy may cause major congenital defects, including microcephaly, ocular, articular and muscle abnormalities, which are collectively defined as Congenital Zika Syndrome. Here, we performed an in-depth characterization of the effects of congenital ZIKV infection (CZI) in immunocompetent mice. METHODS: Pregnant dams were inoculated with ZIKV on embryonic day 5.5 in the presence or absence of a sub-neutralizing dose of a pan-flavivirus monoclonal antibody (4G2) to evaluate the potential role of antibody-dependent enhancement phenomenon (ADE) during short and long outcomes of CZI. FINDINGS: ZIKV infection induced maternal immune activation (MIA), which was associated with occurrence of foetal abnormalities and death. Therapeutic administration of AH-D antiviral peptide during the early stages of pregnancy prevented ZIKV replication and death of offspring. In the post-natal period, CZI was associated with a decrease in whole brain volume, ophthalmologic abnormalities, changes in testicular morphology, and disruption in bone microarchitecture. Some alterations were enhanced in the presence of 4G2 antibody. INTERPRETATION: Our results reveal that early maternal ZIKV infection causes several birth defects in immunocompetent mice, which can be potentiated by ADE phenomenon and are associated with MIA. Additionally, antiviral treatment with AH-D peptide may be beneficial during early maternal ZIKV infection. FUND: This work was supported by the Brazilian National Science Council (CNPq, Brazil), Minas Gerais Foundation for Science (FAPEMIG), Funding Authority for Studies and Projects (FINEP), Coordination of Superior Level Staff Improvement (CAPES), National Research Foundation of Singapore and Centre for Precision Biology at Nanyang Technological University.


Assuntos
Anticorpos Facilitadores/imunologia , Interações Hospedeiro-Patógeno/imunologia , Complicações Infecciosas na Gravidez , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia , Zika virus/fisiologia , Animais , Anticorpos Antivirais/imunologia , Antivirais/farmacologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/virologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Peptídeos/farmacologia , Gravidez , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Baço/virologia , Síndrome , Resultado do Tratamento , Carga Viral , Infecção por Zika virus/diagnóstico , Infecção por Zika virus/tratamento farmacológico
7.
Sci Rep ; 9(1): 473, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679583

RESUMO

The absence of companion may jeopardize mental health in social animals. Here, we tested the hypothesis that social isolation impairs social recognition memory by altering the excitability and the dialog between the olfactory bulb (OB) and the dorsal hippocampus (dHIP). Adult male Swiss mice were kept grouped (GH) or isolated (SI) for 7 days. Social memory (LTM) was evaluated using social recognition test. SI increased glutamate release in the OB, while decreased in the dHIP. Blocking AMPA and NMDA receptors into the OB or activating AMPA into the dHIP rescued LTM in SI mice, suggesting a cause-effect relationship between glutamate levels and LTM impairment. Additionally, during memory retrieval, phase-amplitude coupling between OB and dHIP decreased in SI mice. Our results indicate that SI impaired the glutamatergic signaling and the normal communication between OB and HIP, compromising the persistence of social memory.


Assuntos
Ácido Glutâmico/metabolismo , Hipocampo/fisiologia , Memória , Bulbo Olfatório/fisiologia , Reconhecimento Psicológico , Isolamento Social , Animais , Fenômenos Eletrofisiológicos , Masculino , Camundongos , Modelos Animais
8.
Neurobiol Learn Mem ; 155: 92-103, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29964163

RESUMO

Although the functional role for newborn neurons in neural circuits is still matter of investigation, there is no doubt that neurogenesis modulates learning and memory in rodents. In general, boosting neurogenesis before learning, using genetic-target tools or drugs, improves hippocampus-dependent memories. However, inhibiting neurogenesis may yield contradictory results depending on the type of memory evaluated. Here we tested the hypothesis that inhibiting constitutive neurogenesis would compromise social recognition memory (SRM). Male Swiss mice were submitted to three distinct procedures to inhibit neurogenesis: (1) intra-cerebral infusion of Cystosine-ß-D-Arabinofuranoside (AraC); (2) intra-peritoneal injection of temozolomide (TMZ) and (3) cranial gamma irradiation. All three methods decreased cell proliferation and neurogenesis in the dentate gyrus of the dorsal (dDG) and ventral hippocampus (vDG), and the olfactory bulb (OB). However, the percentage inhibition diverged between methods and brain regions. Ara-C, TMZ and gamma irradiation impaired SRM, though only gamma irradiation did not cause side effects on weight gain, locomotor activity and anxiety. Finally, we examined the contribution of cell proliferation in vDG, dDG and OB to SRM. The percent of inhibition in the dDG correlates with SRM, independently of the method utilized. This correlation was observed for granular cell layer of OB and vDG, only when the inhibition was induced by gamma irradiation. Animal's performance was restrained by the inhibition of dDG cell proliferation, suggesting that cell proliferation in the dDG has a greater contribution to SRM. Altogether, our results demonstrate that SRM, similarly to other hippocampus-dependent memories, has its formation impaired by reducing constitutive neurogenesis.


Assuntos
Proliferação de Células/fisiologia , Hipocampo/fisiologia , Memória de Longo Prazo/fisiologia , Neurogênese/fisiologia , Bulbo Olfatório/fisiologia , Reconhecimento Psicológico/fisiologia , Percepção Social , Animais , Antineoplásicos Alquilantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Comportamento Animal/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Glicosídeo Hidrolases/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/efeitos da radiação , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Memória de Longo Prazo/efeitos da radiação , Camundongos , Neurogênese/efeitos dos fármacos , Neurogênese/efeitos da radiação , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/efeitos da radiação , Lesões Experimentais por Radiação , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/efeitos da radiação , Temozolomida/farmacologia
9.
Mol Neurobiol ; 54(9): 7063-7082, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-27796746

RESUMO

Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum infection, which can result in long-term cognitive and behavioral deficits despite successful anti-malarial therapy. Due to the substantial social and economic burden of CM, the development of adjuvant therapies is a scientific goal of highest priority. Apart from vascular and immune responses, changes in glutamate system have been reported in CM pathogenesis suggesting a potential therapeutic target. Based on that, we hypothesized that interventions in the glutamatergic system induced by blockage of N-methyl-D-aspartate (NMDA) receptors could attenuate experimental CM long-term cognitive and behavioral outcomes. Before the development of evident CM signs, susceptible mice infected with Plasmodium berghei ANKA (PbA) strain were initiated on treatment with dizocilpine maleate (MK801, 0.5 mg/kg), a noncompetitive NMDA receptor antagonist. On day 5 post-infection, mice were treated orally with a 10-day course chloroquine (CQ, 30 mg/kg). Control mice also received saline, CQ or MK801 + CQ therapy. After 10 days of cessation of CQ treatment, magnetic resonance images (MRI), behavioral and immunological assays were performed. Indeed, MK801 combined with CQ prevented long-term memory impairment and depressive-like behavior following successful PbA infection resolution. In addition, MK801 also modulated the immune system by promoting a balance of TH1/TH2 response and upregulating neurotrophic factors levels in the frontal cortex and hippocampus. Moreover, hippocampus abnormalities observed by MRI were partially prevented by MK801 treatment. Our results indicate that NMDA receptor antagonists can be neuroprotective in CM and could be a valuable adjuvant strategy for the management of the long-term impairment observed in CM.


Assuntos
Comportamento Animal , Cognição , Maleato de Dizocilpina/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Malária Cerebral/tratamento farmacológico , Malária Cerebral/fisiopatologia , Fármacos Neuroprotetores/uso terapêutico , Receptores de Glutamato/metabolismo , Animais , Ansiedade/complicações , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Citocinas/sangue , Citocinas/metabolismo , Depressão/complicações , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Leucócitos/metabolismo , Imageamento por Ressonância Magnética , Malária Cerebral/complicações , Malária Cerebral/patologia , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/metabolismo , Fármacos Neuroprotetores/farmacologia , Tamanho do Órgão , Parasitemia/sangue , Parasitemia/complicações , Parasitemia/patologia , Fenótipo , Plasmodium berghei/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Análise de Sobrevida , Regulação para Cima
10.
Toxicol Appl Pharmacol ; 286(3): 178-87, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25933444

RESUMO

Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity.


Assuntos
Cocaína/toxicidade , Endocanabinoides/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Benzamidas/farmacologia , Carbamatos/farmacologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Endocanabinoides/agonistas , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Receptor CB1 de Canabinoide/agonistas , Transdução de Sinais/fisiologia
11.
Psychoneuroendocrinology ; 57: 14-25, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25867995

RESUMO

It is well known that estradiol (E2) replacement therapy is effective on restoring memory deficits and mood disorders that may occur during natural menopause or after surgical ovarian removal (ovariectomy, OVX). However, it is still unknown the effectiveness of acute and localized E2 administration on the effects of chronic OVX. Here we tested the hypothesis that the intra-hippocampal E2 infusion, as well as specific agonists of estrogen receptors (ERs) alpha (ERα) and beta (ERß), are able to mend novel object recognition (NOR) memory deficit and depressive-like behavior caused by 12 weeks of OVX. We found that both ERα and ERß activation, at earlier stages of consolidation, recovered the NOR memory deficit caused by 12 w of OVX. Conversely, only the ERß activation was effective in decreasing the depressive-like behavior caused by 12 w of OVX. Furthermore, we investigated the effect of OVX on hippocampal volume and ERs expression. The structural MRI showed no alteration in the hippocampus volume of 12 w OVX animals. Interestingly, ERα expression in the hippocampus decreased after one week of OVX, but increased in 12 w OVX animals. Overall, we may conclude that the chronic estrogen deprivation, induced by 12 weeks of OVX, modulates the hippocampal ERα expression and induces NOR memory deficit and depressive-like behaviors. Nonetheless, it is noteworthy that the acute effects of E2 on NOR memory and depressive-like behavior are still apparent even after 12 weeks of OVX.


Assuntos
Depressão/etiologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Hipocampo/metabolismo , Transtornos da Memória/etiologia , Ovariectomia/efeitos adversos , Animais , Depressão/tratamento farmacológico , Depressão/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais
12.
Hippocampus ; 24(2): 239-48, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24123782

RESUMO

Social memory consists of the information necessary to identify and recognize cospecifics and is essential to many forms of social interaction. Social memory persistence is strongly modulated by the animal's experiences. We have shown in previous studies that social isolation (SI) in adulthood impairs social memory persistence and that an enriched environment (EE) prevents this impairment. However, the mechanisms involved in the effects of SI and EE on social memory persistence remain unknown. We hypothesized that the mechanism by which SI and EE affect social memory persistence is through their modulation of neurogenesis. To investigate this hypothesis, adult mice were submitted to 7 days of one of the following conditions: group-housing in a standard (GH) or enriched environment (GH+EE); social isolation in standard (SI) or enriched environment (SI+EE). We observed an increase in the number of newborn neurons in the dentate gyrus of the hippocampus (DG) and glomerular layer of the olfactory bulb (OB) in both GH+EE and SI+EE mice. However, this increase of newborn neurons in the granule cell layer of the OB was restricted to the GH+EE group. Furthermore, both SI and SI+EE groups showed less neurogenesis in the mitral layer of the OB. Interestingly, the performance of the SI mice in the buried food-finding task was inferior to that of the GH mice. To further analyze whether increased neurogenesis is in fact the mechanism by which the EE improves social memory persistence in SI mice, we administered the mitotic inhibitor AraC or saline directly into the lateral ventricles of the SI+EE mice. We found that the AraC treatment decreased cell proliferation in both the DG and OB, and impaired social memory persistence in the SI+EE mice. Taken together, our results strongly suggest that neurogenesis is what supports social memory persistence in socially isolated mice.


Assuntos
Meio Ambiente , Hipocampo/citologia , Neurogênese/fisiologia , Neurônios/fisiologia , Isolamento Social/psicologia , Fatores Etários , Animais , Bromodesoxiuridina , Proliferação de Células/efeitos dos fármacos , Citarabina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Imunossupressores/farmacologia , Masculino , Aprendizagem em Labirinto , Camundongos , Neurogênese/efeitos dos fármacos , Fosfopiruvato Hidratase/metabolismo , Reconhecimento Psicológico
13.
Neurosci Lett ; 543: 157-62, 2013 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-23523650

RESUMO

Many studies have shown that minocycline, an antibacterial tetracycline, suppresses experimental pain. While minocycline's positive effects on pain resolution suggest that clinical use of such drugs may prove beneficial, minocycline's antibiotic actions and divalent cation (Ca(2+); Mg(2+)) chelating effects detract from its potential utility. Thus, we tested the antiallodynic effect induced by a non-antibacterial, non-chelating minocycline derivative in a model of neuropathic pain and performed an initial investigation of its anti-inflammatory effects in vitro. Intraperitoneal minocycline (100mg/kg) and 12S-hydroxy-1,12-pyrazolinominocycline (PMIN; 23.75 mg/kg, 47.50mg/kg or 95.00 mg/kg) reduce the mechanical allodynia induced by chronic constriction injury of mouse sciatic nerve. PMIN reduces the LPS-induced production of PGE2 by primary microglial cell cultures. Human embryonic kidney cells were transfected to express human toll-like receptors 2 and 4, and the signaling via both receptors stimulated with PAM3CSK4 or LPS (respectively) was affected either by minocycline or PMIN. Importantly, these treatments did not affect the cell viability, as assessed by MTT test. Altogether, these results reinforce the evidence that the anti-inflammatory and experimental pain suppressive effects induced by tetracyclines are neither necessarily linked to antibacterial nor to Ca(2+) chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the management of neuropathic pain, as its lack of antibacterial and Ca(2+) chelating activities might confer greater safety over conventional tetracyclines.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Dinoprostona/biossíntese , Hiperalgesia/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Microglia/efeitos dos fármacos , Minociclina/farmacologia , Nervo Isquiático/lesões , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Células Cultivadas , Feminino , Humanos , Hiperalgesia/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Minociclina/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Estimulação Física , Ratos , Ratos Wistar , Nervo Isquiático/fisiopatologia , Transdução de Sinais , Tato
14.
Epilepsy Res ; 104(3): 195-202, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23352737

RESUMO

Cannabinoids and drugs that increase endocannabinoid levels inhibit neuronal excitability and restrain epileptic seizures through CB1 receptor activation. Nevertheless, the results have not been entirely consistent, since pro-convulsant effects have also been reported. The present study aimed to further investigate the effects of cannabinoid-related compounds on seizures induced by pentylenetetrazole (PTZ) in rats. Video-EEG recordings were used to determine both electrographic and behavioral thresholds to ictal activity. The animals received injections of WIN-55,212-2 (0.3-3 mg/kg, non-selective) or ACEA (1-4 mg/kg, CB1-selective), two synthetic cannabinoids, or URB-597 (0.3-3 mg/kg), an anandamide-hydrolysis inhibitor (FAAH enzyme inhibitor), followed by PTZ. Both WIN-55,212-2 (1 mg/kg) and ACEA (1-4 mg/kg) reduced the threshold for myoclonic seizures and enhanced epileptiform EEG activity, typical pro-convulsive effects. On the contrary, URB-597 (1 mg/kg) had an anti-convulsive effect, as it increased the threshold for the occurrence of minimal seizures and reduced EEG epileptiform activity. None of the drugs tested altered the tonic-clonic maximal seizure threshold. These data suggest that the effects of CB1 signaling upon seizure activity may depend on how this receptor is activated. Contrary to direct agonists, drugs that increase anandamide levels seem to promote an optimal tonus and represent a promising strategy for treating myoclonic seizures.


Assuntos
Benzamidas/uso terapêutico , Canabinoides/uso terapêutico , Carbamatos/uso terapêutico , Endocanabinoides/uso terapêutico , Convulsões/tratamento farmacológico , Animais , Benzoxazinas/uso terapêutico , Convulsivantes/antagonistas & inibidores , Modelos Animais de Doenças , Eletroencefalografia/métodos , Hidrólise , Masculino , Morfolinas/uso terapêutico , Naftalenos/uso terapêutico , Pentilenotetrazol , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/fisiopatologia
15.
Neurobiol Learn Mem ; 101: 19-25, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23298786

RESUMO

The critical window hypothesis predicts that estrogen replacement therapy (ERT) must be administered early on the menopause or ovariectomy (OVX) to positively affect cognition. However, the neural substrates, underling the time dependent efficacy of ERT, are still not completely known. In order to address this issue, we submitted female mice to 12 weeks of OVX followed by 5 weeks of chronic ERT (OVX(E2)). Within the first 12 weeks, the OVX animals showed a progressive compromised performance in the object recognition memory (ORM) task. After ERT, OVXE2 mice, but not the control group (OVXoil), were able to recognize the new object in the test session. Further, we evaluated the c-Fos expression in hippocampus, perirhinal cortex (PC) and central amygdala (CeA) of OVXoil and OVX(E2) mice, after context exposure (CTX) or object exploration (OBJ). We observed that ERT increased c-Fos expression unspecifically for CTX and OBJ. In addition, only the OVX(E2) group showed significantly higher c-Fos expression in the PC and CeA after object exploration. Thus, our results showed that delayed chronic ERT improves ORM (compromised by OVX) and increases constitutive c-Fos expression in temporal lobe regions. Furthermore, we showed for the first time that PC and CeA, but not the hippocampus, present a distinct pattern of activation in response to object exploration in ovariectomized females that underwent delayed-ERT.


Assuntos
Encéfalo/efeitos dos fármacos , Estradiol/farmacologia , Terapia de Reposição de Estrogênios/métodos , Estrogênios/farmacologia , Menopausa/fisiologia , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Menopausa/efeitos dos fármacos , Menopausa/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/metabolismo , Fatores de Tempo
16.
J Neurochem ; 123(2): 317-24, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22913494

RESUMO

Although it is well known that regular exercise may promote neuroprotection, the mechanisms underlying this effect are still not fully understood. We investigated if swim training promotes neuroprotection by potentiating antioxidant pathways, thereby decreasing the effects of oxidative stress on glutamate and nitric oxide release. Male Wistar rats (n=36) were evenly randomized into a trained group (TRA) (5 days/week, 8 weeks, 30 min) and a sedentary group (SED). Forty-eight hours after the last session of exercise, animals were killed and brain was collected for in vitro ischemia. Cortical slices were divided into two groups: a group in which oxidative stress was induced by oxygen and glucose deprivation (OGD), and a group of non-deprived controls (nOGD). Interestingly, exercise by itself increased superoxide dismutase activity (nOGD, SED vs. TRA animals) with no effect on pro-oxidative markers. In fact, TRA-OGD slices showed lowered levels of lactate dehydrogenase when compared with SED-OGD controls, reinforcing the idea that exercise affords a neuroprotective effect. We also demonstrated that exercise decreased glutamate and nitrite release as well as lipid membrane damage in the OGD cortical slices. Our data suggest that under conditions of metabolic stress, swim training prevents oxidative damage caused by glutamate and nitric oxide release.


Assuntos
Córtex Cerebral/metabolismo , Glucose/metabolismo , Estresse Oxidativo/fisiologia , Oxigênio/metabolismo , Condicionamento Físico Animal/fisiologia , Natação/fisiologia , Animais , Hipóxia Celular/fisiologia , Córtex Cerebral/patologia , Glucose/deficiência , Masculino , Técnicas de Cultura de Órgãos , Condicionamento Físico Animal/métodos , Ratos , Ratos Wistar
17.
Behav Brain Res ; 228(2): 440-6, 2012 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-22226622

RESUMO

Prolonged permanence of animals under social isolation (SI) arouses a variety of psychological symptoms like aggression, stress, anxiety and depression. However, short-term SI is commonly used to evaluate social memory. Interestingly, the social memory cannot be accessed with delays higher than 30min in SI mice. Our hypothesis is that SI with intermediate duration, like one week (1w), impairs the long-term storage of new social information (S-LTM), without affecting anxiety or other types of memories, because the SI compromises the olfactory function of the animal. Our results demonstrated that SI impaired S-LTM, without affecting other kinds of memory or anxiety. In addition, the SI increased the latency in the buried-food finding task, but did not affect the habituation or the discrimination of odors. Next, we postulated that if continuous input to the olfactory system is fundamental for the maintenance of the olfactory function and social memory persistence, isolated mice under odor-enriched environment (OEE) should behave like group-housed (GH) animals. In fact, the OEE prevented the S-LTM deficit imposed by the SI. However, OEE did not restore the SI mice olfaction to the GH mice level. Our results suggest that SI modulates olfaction and social memory persistence, probably, by independent mechanisms. We also showed for the first time that OEE rescued S-LTM in SI mice through a mechanism not necessarily involved with olfaction.


Assuntos
Meio Ambiente , Memória de Longo Prazo/fisiologia , Odorantes , Olfato/fisiologia , Isolamento Social/psicologia , Análise de Variância , Animais , Animais Recém-Nascidos , Aprendizagem da Esquiva , Discriminação Psicológica , Comportamento Exploratório , Habituação Psicofisiológica , Inibição Psicológica , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Reconhecimento Psicológico , Comportamento Social
18.
Naunyn Schmiedebergs Arch Pharmacol ; 385(3): 225-41, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22282331

RESUMO

Tetracyclines are natural or semi-synthetic bacteriostatic agents which have been used since late 1940s against a wide range of gram-positive and gram-negative bacteria and atypical organisms such as chlamydia, mycoplasmas, rickettsia, and protozoan parasites. After the discovery of the first tetracyclines, a second generation of compounds was sought in order to improve water solubility for parenteral administration or to enhance bioavailability after oral administration. This approach resulted in the development of doxycycline and minocycline in the 1970s. Doxycycline was included in the World Health Organization Model List of Essential Medicines either as antibacterial or to prevent malaria or to treat patients with this disease. Additional development led to the third generation of tetracyclines, being tigecycline the only medicine of this class to date. Besides antibacterial activities, the anti-inflammatory, antihypernociceptive and neuroprotective activities of tetracyclines began to be widely studied in the late 1990s. Indeed, there has been an increasing interest in investigating the effects induced by minocycline as this liposoluble derivative is known to cross the blood-brain barrier to the greatest extent. Minocycline induces antihypernociceptive effects in a wide range of animal models of nociceptive, inflammatory and neuropathic pain. In this study, we discuss the antihypernociceptive activity of tetracyclines and summarise its underlying cellular and molecular mechanisms.


Assuntos
Analgésicos/uso terapêutico , Dor/tratamento farmacológico , Tetraciclinas/uso terapêutico , Animais , Humanos , Dor/metabolismo , Dor/fisiopatologia
19.
Neurosci Lett ; 510(1): 20-3, 2012 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-22240103

RESUMO

Although neuroimmune interactions associated with the development of pain sensitization in models of neuropathic pain have been widely studied, there are some aspects that require further investigation. Thus, we aimed to evaluate whether the local intraneural or perineural injections of dexamethasone, an efficacious anti-inflammatory and immunosuppressant drug, delays the development of both thermal hyperalgesia and mechanical allodynia in an experimental model of neuropathic pain in rats. Hargreaves and electronic von Frey tests were applied. The chronic constriction injury (CCI) of right sciatic nerve was performed. Single intraneural dexamethasone administration at the moment of constriction delayed the development of sensitization for thermal hyperalgesia and mechanical allodynia. However, perineural administration of dexamethasone, at the highest dose, did not delay experimental pain development. These results show that inflammation/immune response at the site of nerve lesion is an essential trigger for the pathological changes that lead to both hyperalgesia and allodynia. In conclusion, this approach opens new opportunities to study cellular and molecular neuroimmune interactions associated with the development of pain derived from peripheral neuropathies.


Assuntos
Dexametasona/administração & dosagem , Dexametasona/farmacologia , Hiperalgesia/prevenção & controle , Neuralgia/prevenção & controle , Nervo Isquiático/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/biossíntese , Hiperalgesia/complicações , Hiperalgesia/imunologia , Hiperalgesia/patologia , Inflamação/complicações , Inflamação/imunologia , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Neuralgia/complicações , Neuralgia/imunologia , Neuralgia/patologia , Ratos , Ratos Wistar , Nervo Isquiático/lesões
20.
Neurobiol Learn Mem ; 97(1): 113-23, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22067210

RESUMO

It has been shown that the brain has its own intrinsic renin-angiotensin system (RAS) and angiotensin-(1-7) (Ang-(1-7)) is particularly interesting, because it appears to counterbalance most of the Ang II effects. Ang-(1-7) exerts its biological function through activation of the G-protein-coupled receptor Mas. Interestingly, hippocampus is one of the regions with higher expression of Mas. However, the role of Ang-(1-7)/Mas axis in hippocampus-dependent memories is still poorly understood. Here we demonstrated that Mas ablation, as well as the blockade of Mas in the CA1-hippocampus, impaired object recognition memory (ORM). We also demonstrated that the blockade of Ang II receptors AT1, but not AT2, recovers ORM impairment of Mas-deficient mice. Considering that high concentrations of Ang-(1-7) may activate AT1 receptors, nonspecifically, we evaluate the levels of Ang-(1-7) and its main precursors Ang I and Ang II in the hippocampus of Mas-deficient mice. The Ang I and Ang II levels are unaltered in the whole hipocampus of MasKo. However, Ang-(1-7) concentration is increased in the whole hippocampus of MasKo mice, as well as in the CA1 area. Taken together, our findings suggest that the functionality of the Ang-(1-7)/Mas axis is essential for normal ORM processing.


Assuntos
Angiotensina I/metabolismo , Hipocampo/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Reconhecimento Psicológico/fisiologia , Angiotensina I/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Hipocampo/efeitos dos fármacos , Imidazóis/farmacologia , Losartan/farmacologia , Camundongos , Camundongos Knockout , Fragmentos de Peptídeos/genética , Proteínas Proto-Oncogênicas/genética , Piridinas/farmacologia , Receptores de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/genética , Reconhecimento Psicológico/efeitos dos fármacos
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