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1.
Mol Vis ; 26: 409-422, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32565669

RESUMO

Purpose: Glaucoma is a group of chronic optic neuropathies characterized by the degeneration of retinal ganglion cells (RGCs) and their axons, and they ultimately cause blindness. Because neuroprotection using neurotrophic factors against RGC loss has been proven a beneficial strategy, extensive attempts have been made to perform gene transfer of neurotrophic proteins. This study used the inner retinal injury mouse model to evaluate the neuroprotective effect of tyrosine triple mutated and self-complementary adeno-associated virus (AAV) encoding brain-derived neurotrophic factor (BDNF; tm-scAAV2-BDNF). Methods: C57BL/6J mice were intravitreally injected with 1 µl of tm-scAAV2-BDNF and its control AAV at a titer of 6.6 E+13 genome copies/ml. Three weeks later, 1 µl of 2 mM N-methyl-D-aspartate (NMDA) was administered in the same way as the viral injection. Six days after the NMDA injection, we assessed the dark-adapted electroretinography (ERG). Mice were sacrificed at one week after the NMDA injection, followed by RNA quantification, protein detection, and histopathological analysis. Results: The RNA expression of BDNF in retinas treated with tm-scAAV2-BDNF was about 300-fold higher than that of its control AAV. Meanwhile, the expression of recombinant BDNF protein increased in retinas treated with tm-scAAV2-BDNF. In addition, histological analysis revealed that tm-scAAV2-BDNF prevented thinning of the inner retina. Furthermore, b-wave amplitudes of the tm-scAAV2-BDNF group were significantly higher than those of the control vector group. Histopathological and electrophysiological evaluations showed that tm-scAAV2-BDNF treatment offered significant protection against NMDA toxicity. Conclusions: Results showed that tm-scAAV2-BDNF-treated retinas were resistant to NMDA injury, while retinas treated with the control AAV exhibited histopathological and functional changes after the administration of NMDA. These results suggest that tm-scAAV2-BDNF is potentially effective against inner retinal injury, including normal tension glaucoma.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Terapia Genética/métodos , N-Metilaspartato/toxicidade , Doenças Retinianas/terapia , Animais , Dependovirus/genética , Modelos Animais de Doenças , Eletrorretinografia , Expressão Gênica , Vetores Genéticos , Imuno-Histoquímica , Injeções Intravítreas , Camundongos , Camundongos Endogâmicos C57BL , N-Metilaspartato/administração & dosagem , Proteínas Recombinantes , Doenças Retinianas/genética , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia
2.
Neurosci Lett ; 705: 33-38, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-31004707

RESUMO

Noradrenergic projections from the nucleus tractus solitarius (NTS) to the hypothalamic paraventricular nucleus (PVN) are involved in nicotine (Nic) dependence. Nic induces hypothalamic norepinephrine (NE) release through N-methyl-d-aspartate receptors (NMDARs) and nitric oxide in the NTS. However, acupuncture attenuates Nic withdrawal-induced anxiety. Therefore, this study investigated the effects of acupuncture on Nic-induced hypothalamic NE release. Rats received an intravenous infusion of Nic (90 µg/kg, over 60 s) and extracellular NE levels in the PVN were determined by in vivo microdialysis. Immediately after Nic administration, the rats were bilaterally treated with acupuncture at acupoint HT7 (Shen-Men) or PC6 (Nei-Guan), or a non-acupoint (tail) for 60 s. Acupuncture at HT7, but not at PC6 or the tail, significantly reduced Nic-induced NE release. However, this was abolished by a post-acupuncture infusion of either NMDA or sodium nitroprusside into the NTS. Additionally, acupuncture at HT7, but not the control points, prevented Nic-induced plasma corticosterone secretion and inhibited Nic-induced increases in the phosphorylation of neuronal nitric oxide synthase (nNOS) and endothelial NOS in the NTS. These findings suggest that acupuncture at HT7 reduces Nic-induced NE release in the PVN via inhibition of the solitary NMDAR/NOS pathway.


Assuntos
Terapia por Acupuntura , Nicotina/farmacologia , Óxido Nítrico Sintase Tipo I/metabolismo , Norepinefrina/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Corticosterona/sangue , Infusões Intravenosas , Masculino , Microdiálise , N-Metilaspartato/administração & dosagem , N-Metilaspartato/farmacologia , Nicotina/administração & dosagem , Nicotina/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Nitroprussiato/administração & dosagem , Nitroprussiato/farmacologia , Fosforilação/efeitos dos fármacos , Ratos
3.
Neuropharmacology ; 111: 78-91, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27569994

RESUMO

Positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (α7nAChRs) exhibit pro-cognitive effects in animal models of schizophrenia and are targets for the discovery of cognition-enhancing drugs. However, little is known about their in vivo mechanism of action because such studies have been performed in vitro. Here we test the hypothesis that PAMs' potentiation of glutamate release in prefrontal cortex depends upon the level of endogenous cholinergic activity. NMDA stimulation of the nucleus accumbens shell (0.05-0.30 µg in 0.5 µL) increased extracellular choline (0.87 ± 0.15 - 1.73 ± 0.31 µM) and glutamate (0.15 µg, 3.79 ± 0.87 µM) in medial prefrontal cortex, and the glutamate release was prevented by local infusions of MLA (6.75 µg, 0.19 ± 0.06 µM). The lower dose (1 mg/kg) of AVL3288 (type I) potentiated the glutamate release to a greater degree after the high dose of NMDA (0.30 µg; 84.7% increase vs AVL vehicle) versus the low dose of NMDA (0.05 µg; 24.2% increase), whereas glutamate release was inhibited when the high dose of NMDA was combined with the high dose of AVL3288 (64.2% decrease). In contrast, PNU120596 (type II) only potentiated glutamate release when the high dose (9 mg/kg) was combined with the low dose of NMDA (0.05 µg; 211% increase from PNU vehicle). Collectively, the results suggest a potential in vivo mechanism for the pro-cognitive effects of PAMs and provide the proof-of-concept for the continued focus on allosteric modulation of cortical α7nAChRs for cognition-enhancing drug development.


Assuntos
Anilidas/administração & dosagem , Anilidas/farmacologia , Colina/metabolismo , Ácido Glutâmico/metabolismo , Isoxazóis/administração & dosagem , Isoxazóis/farmacologia , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Masculino , N-Metilaspartato/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Compostos de Fenilureia/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar
4.
J Agric Food Chem ; 62(6): 1310-23, 2014 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-24428171

RESUMO

We investigated the effects of an ethanol extract of C. denticulatum (EECD) in a mouse model of glaucoma established by optic nerve crush (ONC), and found that EECD significantly protected against retinal ganglion cell (RGC) death caused by ONC. Furthermore, EECD effectively protected against N-methyl-d-aspartate-induced damage to the rat retinas. In vitro, EECD attenuated transformed retinal ganglion cell (RGC-5) death and significantly blunted the up-regulation of apoptotic proteins and mRNA level induced by 1-buthionine-(S,R)-sulfoximine combined with glutamate, reduced reactive oxygen species production by radical species, and inhibited lipid peroxidation. The major EECD components were found to be chicoric acid and 3,5-dicaffeoylquinic acid (3,5-DCQA) that have shown beneficial effects on retinal degeneration both in vitro and in vivo studies. Thus, EECD could be used as a natural neuroprotective agent for glaucoma, and chicoric acid and 3,5-DCQA as mark compounds for the development of functional food.


Assuntos
Asteraceae/química , Ácidos Cumáricos/administração & dosagem , Ácidos Cumáricos/análise , Estresse Oxidativo , Doenças Retinianas/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Ácidos Cafeicos/administração & dosagem , Ácidos Cafeicos/análise , Ácido Clorogênico/administração & dosagem , Ácido Clorogênico/análogos & derivados , Ácido Clorogênico/análise , Modelos Animais de Doenças , Glaucoma/etiologia , Glaucoma/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , N-Metilaspartato/administração & dosagem , Compressão Nervosa , Fármacos Neuroprotetores , Nervo Óptico , Extratos Vegetais/administração & dosagem , Ratos , Ratos Sprague-Dawley , Doenças Retinianas/etiologia , Succinatos/administração & dosagem , Succinatos/análise
5.
Hippocampus ; 22(5): 1096-106, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21618640

RESUMO

Fear can be extinguished by repeated exposure to a cue that signals threat. However, extinction does not erase fear, as an extinguished cue presented in a context distinct from that of extinction results in renewed fear of that cue. The hippocampus, which is involved in the formation of contextual representations, is a natural candidate structure for investigations into the neural circuitry underlying fear renewal. Thus far, studies examining the necessity of the hippocampus for fear renewal have produced mixed results. We isolated the conditions under which the hippocampus may be required for renewal. Rats received lesions of the dorsal hippocampus either prior to tone fear conditioning or following extinction. Fear renewal was measured using discrete tone presentations or a long, continuous tone. The topography of fear responding at test was assessed by comparing "early" and "sustained" renewal, where early fear was determined by freezing to the first discrete tone or the equivalent initial segment of a continuous tone and sustained fear was determined by freezing averaged across all discrete tones or the entire continuous tone. We found that following pretraining damage of the hippocampus, early renewal remained intact regardless of lesion condition. However, sustained renewal only persisted in discrete, but not continuous, tone-tested animals. A more extensive analysis of the topography of fear responding revealed that the disruption of renewal was generated when the tone duration at test began to violate that used during extinction, suggesting that the hippocampus is sensitive to mismatches in CS-duration. Postextinction lesions resulted in an overall reduction of fear renewal. This pattern of results is consistent with those observed for contextual fear conditioning, wherein animals display a resistance to anterograde amnesia despite the presence of a strong retrograde amnesia for the same contextual information. Furthermore, the data support a role for the hippocampus in sustaining renewal when the CS duration at test does not match that used during extinction.


Assuntos
Condicionamento Psicológico/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Reação de Congelamento Cataléptica/fisiologia , Hipocampo/fisiologia , Estimulação Acústica , Amnésia Anterógrada/fisiopatologia , Amnésia Retrógrada/fisiopatologia , Análise de Variância , Animais , Sinais (Psicologia) , Hipocampo/cirurgia , Masculino , Microinjeções , N-Metilaspartato/administração & dosagem , Ratos , Ratos Long-Evans , Fatores de Tempo
6.
BMC Neurosci ; 10: 123, 2009 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-19785755

RESUMO

BACKGROUND: Chronic N-Methyl-d-aspartate (NMDA) administration to rats is reported to increase arachidonic acid signaling and upregulate neuroinflammatory markers in rat brain. These changes may damage brain cells. In this study, we determined if chronic NMDA administration (25 mg/kg i.p., 21 days) to rats would alter expression of pro- and anti-apoptotic factors in frontal cortex, compared with vehicle control. RESULTS: Using real time RT-PCR and Western blotting, chronic NMDA administration was shown to decrease mRNA and protein levels of anti-apoptotic markers Bcl-2 and BDNF, and of their transcription factor phospho-CREB in the cortex. Expression of pro-apoptotic Bax, Bad, and 14-3-3zeta was increased, as well as Fluoro-Jade B (FJB) staining, a marker of neuronal loss. CONCLUSION: This alteration in the balance between pro- and anti-apoptotic factors by chronic NMDA receptor activation in this animal model may contribute to neuronal loss, and further suggests that the model can be used to examine multiple processes involved in excitotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Lobo Frontal/metabolismo , N-Metilaspartato/administração & dosagem , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Animais , Western Blotting , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Lobo Frontal/efeitos dos fármacos , Injeções Intraperitoneais , Masculino , Fosforilação/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Frações Subcelulares
7.
J Neurosci ; 29(25): 8087-93, 2009 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-19553448

RESUMO

Trace conditioning is considered a model of higher cognitive involvement in simple associative tasks. Studies of trace conditioning have shown that cortical areas and the hippocampal formation are required to associate events that occur at different times. However, the mechanisms that bridge the trace interval during the acquisition of trace conditioning remain unknown. In four experiments with fear conditioning in rats, we explored the involvement of the entorhinal cortex (EC) in the acquisition of fear under a trace-30 s protocol. We first determined that pretraining neurotoxic lesions of the EC selectively impaired trace-, but not delay-conditioned fear as evaluated by freezing behavior. A local cholinergic deafferentation of the EC using 192-IgG-saporin did not replicate this deficit, presumably because cholinergic interneurons were spared by the toxin. However, pretraining local blockade of EC muscarinic receptors with the M1 antagonist pirenzepine yielded a specific and dose-dependent deficit in trace-conditioned responses. The same microinjections performed after conditioning were without effect on trace fear responses. These effects of blocking M1 receptors are consistent with the notion that conditioned stimulus (CS)-elicited, acetylcholine-dependent persistent activities in the EC are needed to maintain a representation of a tone CS across the trace interval during the acquisition of trace conditioning. This function of the EC is consistent with recent views of this region as a short-term stimulus buffer.


Assuntos
Acetilcolina/metabolismo , Aprendizagem por Associação/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Córtex Entorrinal/fisiopatologia , Medo , Antagonistas Muscarínicos/farmacologia , Pirenzepina/farmacologia , Estimulação Acústica/métodos , Animais , Relação Dose-Resposta a Droga , Eletrochoque/métodos , Córtex Entorrinal/efeitos dos fármacos , Córtex Entorrinal/patologia , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Agonistas de Aminoácidos Excitatórios/toxicidade , Imuno-Histoquímica , Imunotoxinas/administração & dosagem , Imunotoxinas/toxicidade , Masculino , Microinjeções , Antagonistas Muscarínicos/administração & dosagem , N-Metilaspartato/administração & dosagem , N-Metilaspartato/toxicidade , Pirenzepina/administração & dosagem , Ratos , Ratos Long-Evans , Tempo de Reação/efeitos dos fármacos , Receptor Muscarínico M1/antagonistas & inibidores , Reflexo de Sobressalto/efeitos dos fármacos , Proteínas Inativadoras de Ribossomos Tipo 1/administração & dosagem , Proteínas Inativadoras de Ribossomos Tipo 1/toxicidade , Saporinas
8.
J Physiol ; 587(Pt 6): 1201-15, 2009 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19171660

RESUMO

Stimulation of neurons in the lateral/dorsolateral periaqueductal grey (l/dlPAG) produces increases in heart rate (HR) and mean arterial pressure (MAP) that are, according to traditional views, mediated through projections to medullary autonomic centres and independent of forebrain mechanisms. Recent studies in rats suggest that neurons in the l/dlPAG are downstream effectors responsible for responses evoked from the dorsomedial hypothalamus (DMH) from which similar cardiovascular changes and increase in core body temperature (T(co)) can be elicited. We hypothesized that, instead, autonomic effects evoked from the l/dlPAG depend on neuronal activity in the DMH. Thus, we examined the effect of microinjection of the neuronal inhibitor muscimol into the DMH on increases in HR, MAP and T(co) produced by microinjection of N-methyl-D-aspartate (NMDA) into the l/dlPAG in conscious rats. Microinjection of muscimol alone modestly decreased baseline HR and MAP but failed to alter T(co). Microinjection of NMDA into the l/dlPAG caused marked increases in all three variables, and these were virtually abolished by prior injection of muscimol into the DMH. Similar microinjection of glutamate receptor antagonists into the DMH also suppressed increases in HR and abolished increases in T(co) evoked from the PAG. In contrast, microinjection of muscimol into the hypothalamic paraventricular nucleus failed to reduce changes evoked from the PAG and actually enhanced the increase in T(co). Thus, our data suggest that increases in HR, MAP and T(co) evoked from the l/dlPAG require neuronal activity in the DMH, challenging traditional views of the place of the PAG in central autonomic neural circuitry.


Assuntos
Pressão Sanguínea/fisiologia , Regulação da Temperatura Corporal/fisiologia , Frequência Cardíaca/fisiologia , Hipotálamo/fisiologia , Vias Neurais/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Regulação da Temperatura Corporal/efeitos dos fármacos , Núcleo Hipotalâmico Dorsomedial/efeitos dos fármacos , Núcleo Hipotalâmico Dorsomedial/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Muscimol/administração & dosagem , Muscimol/farmacologia , N-Metilaspartato/administração & dosagem , N-Metilaspartato/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/fisiologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley
9.
Neurochem Res ; 33(11): 2318-23, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18500552

RESUMO

Chronic N-Methyl-D: -aspartate (NMDA) administration, a model of excitotoxicity, and chronic intracerebroventricular lipopolysaccharide infusion, a model of neuroinflammation, are reported to upregulate arachidonic acid incorporation and turnover in rat brain phospholipids as well as enzymes involved in arachidonic acid metabolism. This suggests cross-talk between signaling pathways of excitotoxicity and of neuroinflammation, involving arachidonic acid. To test whether chronic NMDA administrations to rats can upregulate brain markers of neuroinflammation, NMDA (25 mg/kg i.p.) or vehicle (1 ml saline/kg i.p.) was administered daily to adult male rats for 21 days. Protein and mRNA levels of cytokines and other inflammatory markers were measured in the frontal cortex using immunoblot and real-time PCR. Compared with chronic vehicle, chronic NMDA significantly increased protein and mRNA levels of interleukin-1beta, tumor necrosis factor alpha, glial fibrillary acidic protein and inducible nitric oxide synthase. Chronic NMDA receptor overactivation results in increased levels of neuroinflammatory markers in the rat frontal cortex, consistent with cross-talk between excitotoxicity and neuroinflammation. As both processes have been reported in a number of human brain diseases, NMDA receptor inhibitors might be of use in treating neuroinflammation in these diseases.


Assuntos
Biomarcadores/metabolismo , Citocinas/metabolismo , Lobo Frontal/efeitos dos fármacos , Inflamação/metabolismo , N-Metilaspartato/administração & dosagem , Animais , Western Blotting , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Masculino , N-Metilaspartato/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais
10.
Br J Pharmacol ; 153(4): 769-74, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17700719

RESUMO

BACKGROUND AND PURPOSE: The most common preclinical models of neuropathic pain involve surgical ligation of sensory nerves, which is especially difficult in mice. Transient models of chemically sensitized allodynia are potentially useful for rapidly characterizing the analgesic profile of compounds and conducting mechanistic studies. EXPERIMENTAL APPROACH: Increasing doses of NMDA, sulprostone (an EP1/EP3 prostaglandin receptor agonist) or phenylephrine (an alpha (1) adrenoceptor agonist) were injected intrathecally (i.t.) or i.p., and animals were subsequently assessed for allodynia. The effects of receptor antagonists and analgesic compounds on allodynia were also assessed. KEY RESULTS: A comparison of total body doses that cause allodynia following spinal or systemic administration indicated that NMDA induces allodynia in the spinal cord while sulprostone and phenylephrine act through a peripheral mechanism. Inhibition of the allodynia with receptor antagonists indicated that each agent induces allodynia by a distinct mechanism. The three models were benchmarked using compounds known to be active in neuropathic pain patients and nerve injury animal models, including gabapentin, amitriptyline and clonidine. CONCLUSIONS AND IMPLICATIONS: These transient allodynia models are a useful addition to the toolbox of preclinical pain models. They are simple, rapid and reproducible, and will be especially useful for characterizing the pain phenotype of knockout mice.


Assuntos
Analgésicos/farmacologia , Dinoprostona/análogos & derivados , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Hiperalgesia/induzido quimicamente , N-Metilaspartato/administração & dosagem , Dor/induzido quimicamente , Antagonistas Adrenérgicos alfa/farmacologia , Aminas/farmacologia , Amitriptilina/farmacologia , Analgésicos/uso terapêutico , Animais , Clonidina/farmacologia , Ácidos Cicloexanocarboxílicos/farmacologia , Dinoprostona/administração & dosagem , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Gabapentina , Hiperalgesia/metabolismo , Hiperalgesia/prevenção & controle , Injeções Intraperitoneais , Injeções Espinhais , Masculino , Memantina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Dor/metabolismo , Dor/prevenção & controle , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/metabolismo , Fenilefrina/administração & dosagem , Piperazinas/farmacologia , Antagonistas de Prostaglandina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de Prostaglandina E/efeitos dos fármacos , Receptores de Prostaglandina E/metabolismo , Receptores de Prostaglandina E Subtipo EP1 , Reprodutibilidade dos Testes , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Nervos Espinhais/cirurgia , Fatores de Tempo , Ácido gama-Aminobutírico/farmacologia
11.
Neuropharmacology ; 51(7-8): 1156-62, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16934300

RESUMO

Hippocampal damage produces spatial memory impairment and hyperactivity in animals, while reductions in hippocampal size have been associated with memory deficits in humans. There are no known treatments for the behavioral changes specifically related to reduced hippocampal size. The purpose of this study was to determine if risperidone, an atypical antipsychotic drug that has shown cognitive-enhancing properties in animals and humans, could alleviate the behavioral disturbances produced by hippocampal damage in rats. Young adult male Sprague-Dawley rats received either sham stereotaxic surgery or direct stereotaxic infusions of N-methyl-d-aspartate (NMDA) into the dorsal hippocampus to produce hippocampal damage. One week later, animals in each group received daily subcutaneous injections of either saline or risperidone (0.2mg/kg) until the end of the experiment. Three weeks after surgery, locomotor activity was tested in all animals. During the fourth and fifth post-surgical weeks, animals were tested in a discrete-trial, delayed rewarded alternation memory paradigm. Risperidone reversed lesion-induced hyperactivity; however it also decreased activity in the sham control rats. In the delayed alternation task, there were significant drug and lesion effects irrespective of the day of testing, but there was no drugxlesion interaction. Hippocampal lesions impaired performance in the delayed alternation task in saline and risperidone-treated rats. However, risperidone modestly improved performance in lesioned and sham controls in comparison to saline-treated lesioned and sham controls. Risperidone also slowed choice time in the alternation task. These data indicate that risperidone does not specifically correct the neurobiological consequences of hippocampal damage, but that animals with hippocampal damage nonetheless maintain a significant degree of sensitivity to the beneficial effects of risperidone.


Assuntos
Hipocampo/fisiopatologia , Hipercinese/tratamento farmacológico , Locomoção/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Nootrópicos/farmacologia , Risperidona/farmacologia , Comportamento Espacial/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos , Hipocampo/efeitos dos fármacos , Hipercinese/induzido quimicamente , Hipercinese/fisiopatologia , Injeções , Locomoção/fisiologia , Masculino , Memória/fisiologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/fisiopatologia , Atividade Motora/fisiologia , N-Metilaspartato/administração & dosagem , N-Metilaspartato/toxicidade , Neurotoxinas/administração & dosagem , Neurotoxinas/toxicidade , Nootrópicos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Risperidona/uso terapêutico , Comportamento Espacial/fisiologia
12.
Brain Res Bull ; 66(1): 59-69, 2005 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-15925145

RESUMO

This study aimed to investigate the roles of glutamate (Glu) receptors in the anteroventral third ventricular region (AV3V), a pivotal area for water, cardiovascular and neuroendocrine regulations, in causing vasopressin (AVP) secretion and other phenomena in response to bleeding. The effects of intracerebral infusions of MK-801 [a N-methyl-D-aspartate (NMDA) receptor antagonist] or a metabotropic Glu receptor antagonist (MCPG) on plasma levels of AVP, electrolytes, osmolality and glucose, heart rate and arterial pressure following AV3V administration with NMDA or bleeding stimuli were analyzed in conscious rats. NMDA provoked prominent rises of plasma AVP, osmolality, glucose and arterial pressure, without changing plasma electrolytes or heart rate significantly. All the effects of NMDA were blocked by pre-administration of MK-801 into the same loci. Removal through a femoral arterial line of 10 ml blood per kg body weight did not affect arterial pressure or other variables significantly, although plasma AVP and angiotensin II (ANG II) tended to increase. When bleeding was repeated after 10 min (B2), arterial pressure dropped promptly, and plasma AVP, ANG II, osmolality and glucose augmented remarkably. MK-801 applied 35 min preceding B2, to loci such as the median preoptic nucleus, periventricular nucleus and medial preoptic area inhibited the response of plasma AVP significantly, without exerting any effects on other variables. When MK-801 was administered intracerebroventricularly, or when MCPG was infused into the AV3V, significant alterations did not occur in B2-evoked responses of plasma AVP nor in those of the other variables. In rats given sham bleeding after AV3V infusions of MK-801 or MCPG or intracerebroventricular applications of MK-801, all monitored variables roughly remained at stable levels throughout the experiments. We conclude that NMDA receptors in AV3V, but not metabotropic Glu receptors, may facilitate AVP secretion in hypotensive hypovolemia.


Assuntos
Glicina/análogos & derivados , Hemorragia/metabolismo , Receptores de Glutamato Metabotrópico/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Terceiro Ventrículo/metabolismo , Vasopressinas/metabolismo , Análise de Variância , Angiotensina II/sangue , Animais , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Interações Medicamentosas , Eletrólitos/sangue , Antagonistas de Aminoácidos Excitatórios/farmacologia , Glicina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Injeções Intraventriculares/métodos , Masculino , N-Metilaspartato/administração & dosagem , Concentração Osmolar , Ratos , Ratos Wistar , Terceiro Ventrículo/efeitos dos fármacos , Fatores de Tempo , Vasopressinas/administração & dosagem , Vasopressinas/sangue , Vigília
13.
Brain Res ; 1031(2): 151-63, 2005 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-15649440

RESUMO

Freezing and escape responses induced by gradual increases in the intensity of the electrical current applied to dorsal regions of the periaqueductal gray (dPAG) cause a distinct pattern of Fos distribution in the brain. From these studies, it has been suggested that a pathway involving the dPAG itself, dorsomedial hypothalamus and the cuneiform nucleus (CnF) would mediate responses to immediate danger and another one involving the amygdala and ventrolateral periaqueductal gray (vlPAG) would mediate cue-elicited responses. As electrical stimulation activates body cells and fibers of passage the need of studies with chemical stimulation of only post-synaptic fibers of the dPAG is obvious. To examine further this issue we measured Fos protein expression in brain areas activated by stimulation of the dPAG with glutamate (5 nmol/0.2 microL) and N-methyl-D-aspartate (NMDA) at doses that provoke either freezing (4 nmol/0.2 microL) or escape (7 nmol/0.2 microL) responses, respectively. The results showed that glutamate-induced freezing caused a selective increase in Fos expression in the superior and inferior colliculi as well as in the laterodorsal nucleus of the thalamus. On the other hand, NMDA-induced escape led to widespread increases in Fos labeling in almost all structures studied. Differently from glutamate, NMDA at doses provoking freezing caused significant increase of Fos labeling in the dPAG and CnF. Therefore, the present data support the notion that freezing behavior induced by activation of either non-NMDA or NMDA receptors in the dorsolateral periaqueductal gray (dlPAG) is neurally segregated: glutamate activates only structures that are mainly involved in the sensorial processing and NMDA-induced freezing structures involved in the motor output of defensive behavior. Therefore, the freezing elicited by the activation of non-NMDA receptors seem to be related to the acquisition of aversive information, whereas that resulting from the activation of NMDA receptors could serve as a preparatory response for flight.


Assuntos
Reação de Fuga/fisiologia , Reação de Congelamento Cataléptica/fisiologia , Vias Neurais/metabolismo , Neurônios/metabolismo , Substância Cinzenta Periaquedutal/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores de Glutamato/metabolismo , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/metabolismo , Animais , Relação Dose-Resposta a Droga , Ácido Glutâmico/administração & dosagem , Ácido Glutâmico/fisiologia , Hipotálamo/citologia , Hipotálamo/metabolismo , Masculino , Microinjeções , Atividade Motora/fisiologia , N-Metilaspartato/administração & dosagem , N-Metilaspartato/fisiologia , Vias Neurais/citologia , Neurônios/efeitos dos fármacos , Percepção/fisiologia , Substância Cinzenta Periaquedutal/citologia , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Glutamato/efeitos dos fármacos , Formação Reticular/citologia , Formação Reticular/metabolismo , Estimulação Química , Distribuição Tecidual
14.
Toxicol Appl Pharmacol ; 200(1): 48-53, 2004 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-15451307

RESUMO

To investigate the role of tissue plasminogen activator (tPA) in retinal damage, tPA-deficient and wild-type mice were employed. Two different retinal neuron insult models were used in the present study. One is an excitotoxin-treated retinal model, created by direct intravitreal injection of glutamate analogs, NMDA or kainic acid (KA), and the other is an ischemia-reperfusion model induced by transient elevation of intraocular pressure. TdT-dUTP terminal nick-end labeling (TUNEL) method was used to examine the retinal cell nuclear damage. The number of TUNEL-positive cells in ganglion cell layer (GCL) and inner nuclear layer (INL) in tPA-deficient mice after low-, but not high-dose NMDA was significantly less compared to wild type. In contrast, neither intravitreal KA or transient ischemia produced significant difference in retinal damage in tPA vs. wild-type mice. These data show that tPA-deficient mice are resistant to retinal damage by intravitreal injection of NMDA, and indicate that tPA plays a role in the retinal cell damage induced by excitotoxins, especially NMDA.


Assuntos
Agonistas de Aminoácidos Excitatórios/farmacologia , N-Metilaspartato/toxicidade , Inativadores de Plasminogênio/fisiologia , Doenças Retinianas/induzido quimicamente , Animais , Contagem de Células , Fragmentação do DNA , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Glutamatos/administração & dosagem , Glutamatos/farmacologia , Marcação In Situ das Extremidades Cortadas , Injeções , Ácido Caínico/administração & dosagem , Ácido Caínico/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Metilaspartato/administração & dosagem , Neurônios/efeitos dos fármacos , Inativadores de Plasminogênio/deficiência , Proteínas Recombinantes/farmacologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle , Retina , Doenças Retinianas/patologia , Células Ganglionares da Retina/efeitos dos fármacos
15.
Electrophoresis ; 24(18): 3266-72, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14518055

RESUMO

An effective microseparation system integrated with ring-disc electrodes and two microfluidic devices was fabricated for in vivo determination using a microdialysis pump. The major interference of ascorbic acid (AA) was excluded by direct oxidation with ascorbate oxidase. Glucose, glutamate, and choline were successfully determined simultaneously through the biosensors modified with a bilayer of osmium-poly(4-vinylpyridine)gel-horseradish peroxidase (Os-gel-HRP)/glucose oxidase (GOD), glutamate oxidase (GlutaOD) or choline oxidase (ChOD). To stabilize the biosensors, 0.2% polyethylenimine (PEI) was mixed with the oxidases. The cathodic currents of glucose, glutamate, and choline biosensors started to increase after the standard solutions were injected into the microseparation system. The on-line biosensors show a wide calibration range (10(-7)-10(-5) mol/L) with a detection limit of 10(-8) mol/L at the working potential of -50 mV. The variations of glucose, glutamate, and choline were determined simultaneously in a free moving rat when we perfused the medial frontal cortex with 100 micro mol/L N-methyl-D-aspartate (NMDA) solution, which is the agonist of the NMDA receptor.


Assuntos
Técnicas Biossensoriais , Colina/análise , Eletroquímica/métodos , Glucose/análise , Ácido Glutâmico/análise , Oxirredutases do Álcool/metabolismo , Animais , Ascorbato Oxidase/metabolismo , Técnicas Biossensoriais/instrumentação , Eletroquímica/instrumentação , Eletrodos , Lobo Frontal/química , Lobo Frontal/metabolismo , Glucose Oxidase/metabolismo , Peroxidase do Rábano Silvestre/metabolismo , Microdiálise/métodos , Miniaturização , N-Metilaspartato/administração & dosagem , Ratos
16.
Pol J Pharmacol ; 55(5): 727-33, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14704468

RESUMO

Loreclezole (5 mg/kg) exerted a significant protective action in amygdala-kindled rats, reducing both seizure and afterdischarge durations. The combinations of loreclezole (2.5 mg/kg) with valproate, clonazepam, or carbamazepine (applied at their subprotective doses) also exhibited antiseizure effect in this test. However, only two first combinations occurred to be of pharmacodynamic nature. Among several chemoconvulsants, bicuculline, N-methyl-D-aspartic acid and BAY k-8644 (the opener of L-type calcium channels) reversed the protective activity of loreclezole alone and its combination with valproate. On the other hand, bicuculline, aminophylline and BAY k-8644 inhibited the anticonvulsive action of loreclezole combined with clonazepam. The results support the hypothesis that the protective activity of loreclezole and its combinations with other antiepileptics may involve potentiation of GABAergic neurotransmission and blockade of L-type of calcium channels.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Convulsivantes/efeitos adversos , Combinação de Medicamentos , Excitação Neurológica/efeitos dos fármacos , Triazóis/antagonistas & inibidores , Triazóis/uso terapêutico , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Aminofilina/administração & dosagem , Aminofilina/efeitos adversos , Aminofilina/farmacocinética , Tonsila do Cerebelo/fisiopatologia , Tonsila do Cerebelo/cirurgia , Animais , Bicuculina/administração & dosagem , Bicuculina/efeitos adversos , Bicuculina/farmacocinética , Carbamazepina/farmacologia , Clonazepam/antagonistas & inibidores , Clonazepam/farmacologia , Convulsivantes/administração & dosagem , Convulsivantes/antagonistas & inibidores , Modelos Animais de Doenças , Interações Medicamentosas , Eletrodos Implantados , Injeções Intraperitoneais , Ácido Caínico/administração & dosagem , Ácido Caínico/farmacocinética , Masculino , N-Metilaspartato/administração & dosagem , N-Metilaspartato/efeitos adversos , N-Metilaspartato/farmacocinética , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Convulsões/prevenção & controle , Técnicas Estereotáxicas , Estricnina/administração & dosagem , Estricnina/efeitos adversos , Estricnina/farmacocinética , Fatores de Tempo , Triazóis/administração & dosagem , Ácido Valproico/administração & dosagem , Ácido Valproico/antagonistas & inibidores , Ácido Valproico/farmacocinética
17.
Hear Res ; 168(1-2): 208-22, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12117522

RESUMO

The main goal of this article is to review the key role that the inferior colliculus plays in the expression of acoustic-motor and acoustic-limbic integration involved, respectively, in acute and chronic audiogenic seizures. In order to put this in context, we will review the behavioral characterization of acute and chronic audiogenic seizures, neuroanatomical substrates, neurochemistry, neuropharmacology, electrophysiology, as well as the cellular and molecular mechanisms involved in their expression. Secondly, we will also correlate our results, collected from audiogenic seizures susceptible rats, before and after the genetic selection of our own audiogenic susceptible strain, and from those sensitized by lesions or drug microinjections, with those pertinent from the international literature. In brief, genetic or sensitized animals express acute audiogenic seizures as a wild running behavior preceding the onset of tonic-clonic seizures. The latter can have several presentations including opistotonus and fore- and hindlimb tonic hyperextensions, followed by clonic convulsions of fore- and hindlimbs. Chronic (kindled) audiogenic seizures change this behavioral expression, with similar patterns such as those present in temporal lobe epileptic seizures, intermingled with the original audiogenic seizure pattern, which is known to be dependent on brainstem networks.


Assuntos
Epilepsia Reflexa/fisiopatologia , Colículos Inferiores/fisiopatologia , Estimulação Acústica , Doença Aguda , Animais , Bicuculina/administração & dosagem , Epilepsia Reflexa/etiologia , Epilepsia Reflexa/patologia , Colículos Inferiores/efeitos dos fármacos , Colículos Inferiores/patologia , Excitação Neurológica , Sistema Límbico/fisiopatologia , Neurônios Motores/fisiologia , N-Metilaspartato/administração & dosagem , N-Metilaspartato/fisiologia , Neurônios Aferentes/fisiologia , Ratos , Ratos Wistar , Reflexo de Sobressalto/fisiologia , Substância Negra/fisiopatologia , Zumbido/fisiopatologia , Ácido gama-Aminobutírico/fisiologia
18.
Pharmacology ; 61(4): 257-62, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11093078

RESUMO

The nuclei of hypothalamus and amygdala have been shown to be involved in the central cardiovascular homeostasis. Recent studies suggest that glutamate-containing neurons have an important role in the regulation of the central cardiovascular function. In this study, we demonstrate the roles of the central nucleus of the amygdala and the paraventricular nucleus of the amygdala and the paraventricular nucleus or the dorsomedial nucleus of the hypothalamus in N-methyl-D-aspartate (NMDA) induced blood pressure and heart rate changes in conscious Sprague-Dawley rats. Intracerebroventricular or parenchymal injections of NMDA evoke increases in arterial pressure. The NMDA-induced elevations in blood pressure are more prominent when NMDA is administered into the dorsomedial nucleus of the hypothalamus. Microinjections of NMDA into the dorsomedial hypothalamus exert significant heart rate increases, whereas NMDA when administered into the paraventricular nucleus of the hypothalamus or into the central nucleus of the amygdala has no significant effect on the heart rate. The dorsomedial nucleus of the hypothalamus is found to be the most effective site in this respect. The present study provides strong evidence for the tonic glutamatergic influence on blood pressure and heart rate via NMDA receptors located within the dorsomedial nucleus and to a lesser extent via those located within the paraventricular nucleus of the hypothalamus.


Assuntos
Tonsila do Cerebelo/fisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Hemodinâmica/efeitos dos fármacos , Hipotálamo/fisiologia , N-Metilaspartato/farmacologia , Tonsila do Cerebelo/anatomia & histologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Núcleo Hipotalâmico Dorsomedial/fisiologia , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hipotálamo/anatomia & histologia , Injeções , Injeções Intraventriculares , Masculino , N-Metilaspartato/administração & dosagem , Núcleo Hipotalâmico Paraventricular/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Fatores de Tempo
19.
Exp Neurol ; 164(2): 396-406, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10915578

RESUMO

The role of glutamate receptors in the inferior colliculus (IC) in audiogenic and audiogenic-like seizures was investigated in adult rats with transient neonatal hypothyroidism by 0.02% propylthiouracil (PTU) treatment through mother's milk (PTU rats) and in naive rats treated intracisternally with N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA), or cyclothiazide, an inhibitor of rapid AMPA receptor desensitization. All rats showed audiogenic or audiogenic-like seizures characterized by running fit (RF) and generalized tonic-clonic seizures (GTCS). While systemically administered MK-801 inhibited GTCS, intracisternally administered NBQX inhibited RF and GTCS in both audiogenic and audiogenic-like seizures. Auditory stimulation shortened the latency to GTCS induced by AMPA, but not NMDA, at a subclinical dose and further elongated the shortened duration of RF, but not GTCS, induced by MK-801 pretreatment. Furthermore, Northern blot analysis was used to evaluate the expression of the immediate-early gene c-fos in the IC following induction of audiogenic or audiogenic-like seizures. The significant induction of c-fos mRNA by audiogenic seizures in PTU rats or by AMPA- or cyclothiazide-induced seizures in naive rats was prominent in the IC. MK-801 suppressed c-fos mRNA expression in the IC induced by audiogenic seizures in PTU rats or by AMPA-induced seizures in naive rats. NBQX suppressed the expression of c-fos mRNA in the IC induced by AMPA-induced seizures but did not suppress c-fos mRNA in PTU rats or rats with cyclothiazide-induced seizures. Auditory stimuli failed to affect c-fos mRNA induction by AMPA. The present study suggests that audiogenic-like seizures can be reproduced by glutamate receptor agonists in which AMPA receptors are primarily linked to the initiation of audiogenic seizures (RF) while NMDA receptors presumably located within the IC are involved in the propagation of GTCS in audiogenic seizures.


Assuntos
Hipotireoidismo/metabolismo , Colículos Inferiores/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/metabolismo , Estimulação Acústica , Animais , Animais Lactentes , Benzotiadiazinas/administração & dosagem , Maleato de Dizocilpina/administração & dosagem , Vias de Administração de Medicamentos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/fisiopatologia , Colículos Inferiores/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Exposição Materna , N-Metilaspartato/administração & dosagem , Propiltiouracila , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Quinoxalinas/administração & dosagem , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Receptores de AMPA/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/administração & dosagem
20.
Srp Arh Celok Lek ; 128(9-10): 316-21, 2000.
Artigo em Sérvio | MEDLINE | ID: mdl-11255685

RESUMO

INTRODUCTION: Audiogenic seizures (AGS) are induced by high intensity sound stimulation in genetically susceptible rats or in animals subjected to chemical or electrical manipulation. Epileptic seizure may result from an impaired balance between excitation and inhibition in the CNS. The effect of NMDA (N-methyl-D-aspartic acid) on metaphit 1-(1(3-isothiocyanatophenyl-ciclohexyl)-piperidine) induced audiogenic seizures was evaluated in rats. METHODS: Male Wistar albino rats were divided into 4 groups: 1) saline; 2) metaphit (10 mg/kg); 3) metaphit + NMDA; 4) NMDA (70 mg/kg). Animals were injected with metaphit intraperitoneally (i.p.) and exposed to sound stimulation (100 +/- 3 dB, 60 s) at hourly intervals. The incidence and severity (running, clonus and tonus) of seizures were analyzed. NMDA alone was administered i.p. to 6 rats. In group metaphit + NMDA only animals which did not exhibit any seizure during 8 hours were injected with NMDA i.p. after the 8th audiogenic testing. For electroencephalograph (EEG) recordings three gold-plated screws were used. Convulsive behaviour was assessed by incidence of motor seizure and by seizure severity grade, determined by use of a descriptive rating scale with range of 0-3; 0-no response; 1-wild running only; 2-wild running followed by clonic seizures of all four limbs with body rollover; 3-wild running progressing to generalized clonic convulsions and then a tonic extension of the fore and hind limbs and tail. Sound onset, seizure events, and sound offset, along with the animals behaviour (convulsive or other) were recorded as the correlates to the respective EEG responses. RESULTS: In most animals the administration of metaphit (10 mg/kg) resulted in electrographic abnormalities, elicited epileptiform activity in the form of spikes, polyspikes and spikewave complexes (Fig. 1.). Maximum incidence and severity of metaphit convulsions occurred 8 h after the injection (9/12, 75%) (Fig. 2, 3.), then abated gradually and disappeared 30 h later. NMDA (70 mg/kg) alone induced no seizure response but isolated spiking activity, and sporadic slow-wave complexes were recorded (Fig. 4). NMDA induced stereotyped behaviour in the form of asymmetric posture, loss of righting reflex and tonic hindlimb extension, which lasted for 60-90 min. Subconvulsive dose of NMDA potentiated the metaphit-induced audiogenic seizures in rats. Two hours after NMDA administration 3 of 17 metaphit-treated rats convulsed, which in 8 previous testings never displayed seizures. Maximum incidence was 8 of 17 (53%), 5-6 h after NMDA administration and seizures lasted for 9 hours. DISCUSSION: Several authors reported that metaphit dose of 10 mg/kg accompanied by some REM sleep deprivation (REM-D) procedures [4], or subconvulsive doses of NMDA [25] provoked seizures of higher intensity and incidence. Metaphit treatment (10 mg/kg) followed 24 h later by NMDA dose of 50 mg/kg provoked no spontaneous convulsions, while metaphit in combination with a higher NMDA dose of 70 mg/kg resulted in spontaneous and AGS-induced seizures only in one time point [25]. It was found that the incidence and severity of convulsive responses were highest 8-12 h after metaphit injection (10 mg/kg) [23, 24]. Although about 8 h after metaphit administration the power spectra increased and were more intense in the period of sound onset and seizure events. CONCLUSION: The results of the present study strongly suggest that treatment of adult rats with the combination of metaphit and NMDA in the doses employed here followed by AGS provides a suitable animal model for examinations of epileptic seizures.


Assuntos
Estimulação Acústica , Modelos Animais de Doenças , Eletroencefalografia/efeitos dos fármacos , Epilepsia Reflexa/fisiopatologia , Agonistas de Aminoácidos Excitatórios/administração & dosagem , N-Metilaspartato/administração & dosagem , Fenciclidina/análogos & derivados , Fenciclidina/administração & dosagem , Animais , Epilepsia Reflexa/induzido quimicamente , Masculino , Ratos , Ratos Wistar
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