RESUMO
To investigate the effectiveness of nasal delivery of levetiracetam (LEV) on the distributions of synaptic vesicle protein 2 isoform A (SV2A) in epileptic rats with injection of kainic acid (KA) into amygdala. A total of 138 rats were randomly divided into four groups, including the Sham surgery group, the epilepsy group (EP), and the LEV oral administration (LPO) and nasal delivery (LND) groups. The rat intra-amygdala KA model of epilepsy was constructed. Pathological changes of rat brain tissue after status epilepticus (SE) were detected using haematoxylin and eosin staining. Expression of SV2A in rat hippocampus after SE was evaluated using the western blotting analysis. Expression and distribution of SV2A in rat hippocampus after SE were detected based on immunofluorescence staining. The EP group showed evident cell loss and tissue necrosis in the CA3 area of hippocampus, whereas the tissue damage in both LPO and LND groups was significantly reduced. Western blotting analysis showed that the expressions of SV2A in the hippocampus of both EP and LND groups were significantly decreased 1 week after SE, increased to the similar levels of the Sham group in 2 weeks, and continuously increased 4 weeks after SE to the level significantly higher than that of the Sham group. Results of immunofluorescence revealed largely the same expression patterns of SV2A in the CA3 area of hippocampus as those in the entire hippocampus. Our study revealed the same antiepileptic and neuronal protective effects by the nasal and oral administrations of LEV, without changing the expression level of SV2A.
Assuntos
Epilepsia , Estado Epiléptico , Ratos , Animais , Levetiracetam/farmacologia , Ácido Caínico/metabolismo , Ácido Caínico/farmacologia , Ácido Caínico/uso terapêutico , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Epilepsia/metabolismo , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/metabolismo , Hipocampo/metabolismoRESUMO
BACKGROUND: Excitotoxicity-induced in vivo injury models are vital to reflect the pathophysiological features of acute spinal cord injury (SCI) in humans. The duration and concentration of chemical treatment controls the extent of neuronal cell damage. The extent of injury is explained in relation to locomotor and behavioural activity. Several SCI in vivo methods have been reported and studied extensively, particularly contusion, compression, and transection models. These models depict similar pathophysiology to that in humans but are extremely expensive (contusion) and require expertise (compression). Chemical excitotoxicity-induced SCI models are simple and easy while producing similar clinical manifestations. The kainic acid (KA) excitotoxicity model is a convenient, low-cost, and highly reproducible animal model of SCI in the laboratory. The basic impactor approximately cost between 10,000 and 20,000 USD, while the kainic acid only cost between 300 and 500 USD, which is quite cheap as compared to traditional SCI method. METHODS: In this study, 0.05 mM KA was administered at dose of 10 µL/100 g body weight, at a rate of 10 µL/min, to induce spinal injury by intra-spinal injection between the T12 and T13 thoracic vertebrae. In this protocol, detailed description of a dorsal laminectomy was explained to expose the spinal cord, following intra-spinal kainic acid administration at desired location. The dose, rate and technique to administer kainic acid were explained extensively to reflect a successful paraplegia and spinal cord injury in rats. The postoperative care and complication post injury of paraplegic laboratory animals were also explained, and necessary requirements to overcome these complications were also described to help researcher. RESULTS: This injury model produced impaired hind limb locomotor function with mild seizure. Hence this protocol will help researchers to induce spinal cord injury in laboratories at extremely low cost and also will help to determine the necessary supplies, methods for producing SCI in rats and treatments designed to mitigate post-injury impairment. CONCLUSIONS: Kainic acid intra-spinal injection at the concentration of 0.05 mM, and rate 10 µL/min, is an effective method create spinal injury in rats, however more potent concentrations of kainic acid need to be studied in order to create severe spinal injuries.
Assuntos
Traumatismos da Medula Espinal , Traumatismos da Coluna Vertebral , Humanos , Ratos , Animais , Ratos Sprague-Dawley , Ácido Caínico/uso terapêutico , Paraplegia/complicações , Traumatismos da Coluna Vertebral/complicações , Modelos Animais de DoençasRESUMO
BACKGROUND: Inflammation is often considered to play a crucial role in epilepsy by affecting iron status and metabolism. In this study, we investigated the curative effect of auricular acupuncture and somatic acupuncture on kainic acid- (KA-) induced epilepsy in rats. METHODS: We established an epileptic seizure model in rats by KA (12 mg, ip). The 2 Hz electroacupuncture (EA) was applied at auricular and applied at Zusanli and Shangjuxu (ST36-ST37) acupoints for 20 min for 3 days/week for 6 weeks beginning on the day following the KA injection. RESULTS: The electrophysiological results indicated that neuron overexcitation occurred in the KA-treated rats. This phenomenon could be reversed among either the auricular EA or ST36-ST37 EA treatment, but not in the sham-control rats. The Western blot results revealed that TRPA1, but not TRPV4, was upregulated by injecting KA and could be attenuated by administering auricular or ST36-ST37 EA, but not in the sham group. In addition, potentiation of TRPA1 was accompanied by increased PKCα and reduced PKCε. Furthermore, pERK1/2, which is indicated in inflammation, was also increased by KA. Furthermore, the aforementioned mechanisms could be reversed by administering auricular EA and could be partially reversed by ST36-ST37 EA. CONCLUSIONS: These results indicate a novel mechanism for treating inflammation-associated epilepsy and can be translated into clinical therapy.
Assuntos
Eletroacupuntura , Epilepsia/tratamento farmacológico , Epilepsia/terapia , Ácido Caínico/uso terapêutico , Proteína Quinase C-alfa/metabolismo , Proteína Quinase C-épsilon/metabolismo , Canais de Cátion TRPC/metabolismo , Animais , Inflamação , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Canal de Cátion TRPA1RESUMO
This article describes current experimental models of status epilepticus (SE) and neuronal injury for use in the screening of new therapeutic agents. Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. SE is an emergency condition associated with continuous seizures lasting more than 30 min. It causes significant mortality and morbidity. SE can cause devastating damage to the brain leading to cognitive impairment and increased risk of epilepsy. Benzodiazepines are the first-line drugs for the treatment of SE, however, many people exhibit partial or complete resistance due to a breakdown of GABA inhibition. Therefore, new drugs with neuroprotective effects against the SE-induced neuronal injury and degeneration are desirable. Animal models are used to study the pathophysiology of SE and for the discovery of newer anticonvulsants. In SE paradigms, seizures are induced in rodents by chemical agents or by electrical stimulation of brain structures. Electrical stimulation includes perforant path and self-sustaining stimulation models. Pharmacological models include kainic acid, pilocarpine, flurothyl, organophosphates and other convulsants that induce SE in rodents. Neuronal injury occurs within the initial SE episode, and animals exhibit cognitive dysfunction and spontaneous seizures several weeks after this precipitating event. Current SE models have potential applications but have some limitations. In general, the experimental SE model should be analogous to the human seizure state and it should share very similar neuropathological mechanisms. The pilocarpine and diisopropylfluorophosphate models are associated with prolonged, diazepam-insensitive seizures and neurodegeneration and therefore represent paradigms of refractory SE. Novel mechanism-based or clinically relevant models are essential to identify new therapies for SE and neuroprotective interventions.
Assuntos
Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/terapia , Animais , Convulsivantes/uso terapêutico , Terapia por Estimulação Elétrica , Flurotila/uso terapêutico , Humanos , Ácido Caínico/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/terapia , Via Perfurante/efeitos dos fármacos , Pilocarpina/uso terapêuticoRESUMO
Temporal lobe epilepsy (TLE) is presented the most common form of focal epilepsy with involvement of oxidative stress and neuroinflammation as important factors in its development. About one third of epileptic patients are intractable to currently available medications. Paeonol isolated from some herbs with traditional and medicinal uses has shown anti-oxidative and anti-inflammatory effects in different models of neurological disorders. In this research, we tried to evaluate the possible protective effect of paeonol in intrahippocampal kainate murine model of TLE. To induce TLE, kainate was microinjected into CA3 area of the hippocampus and paeonol was administered at two doses of 30 or 50 mg/kg. The results of this study showed that paeonol at the higher dose significantly reduces incidence of status epilepticus, hippocampal aberrant mossy fiber sprouting and also preserves neuronal density. Beneficial protective effect of paeonol was in parallel with partial reversal of some hippocampal oxidative stress markers (reactive oxygen species and malondialdehyde), caspase 1, glial fibrillary acidic protein, heme oxygenase 1, DNA fragmentation, and inflammation-associated factors (nuclear factor-kappa B, toll-like receptor 4, and tumor necrosis factor α). Our obtained data indicated anticonvulsant and neuroprotective effects of paeonol which is somewhat attributed to its anti-oxidative and anti-inflammation properties besides its attenuation of apoptosis, pyroptosis, and astrocyte activity.
Assuntos
Epilepsia do Lobo Temporal , Ácido Caínico , Acetofenonas/metabolismo , Acetofenonas/farmacologia , Acetofenonas/uso terapêutico , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/metabolismo , Hipocampo/metabolismo , Humanos , Ácido Caínico/metabolismo , Ácido Caínico/farmacologia , Ácido Caínico/uso terapêutico , CamundongosRESUMO
A neuroprotected state can be acquired by preconditioning brain with a stimulus that is subthreshold for damage (tolerance). Acquisition of tolerance involves coordinate, bi-directional changes to gene expression levels and the re-programmed phenotype is determined by the preconditioning stimulus. While best studied in ischemic brain there is evidence brief seizures can confer tolerance against prolonged seizures (status epilepticus). Presently, we developed a model of epileptic preconditioning in mice and used microarrays to gain insight into the transcriptional phenotype within the target hippocampus at the time tolerance had been acquired. Epileptic tolerance was induced by an episode of non-damaging seizures in adult C57Bl/6 mice using a systemic injection of kainic acid. Neuron and DNA damage-positive cell counts 24 h after status epilepticus induced by intraamygdala microinjection of kainic acid revealed preconditioning given 24 h prior reduced CA3 neuronal death by approximately 45% compared with non-tolerant seizure mice. Microarray analysis of over 39,000 transcripts (Affymetrix 430 2.0 chip) from microdissected CA3 subfields was undertaken at the point at which tolerance was acquired. Results revealed a unique profile of small numbers of equivalently up- and down-regulated genes with biological functions that included transport and localization, ubiquitin metabolism, apoptosis and cell cycle control. Select microarray findings were validated post hoc by real-time polymerase chain reaction and Western blotting. The present study defines a paradigm for inducing epileptic preconditioning in mice and first insight into the global transcriptome of the seizure-damage refractory brain.
Assuntos
Dano Encefálico Crônico/fisiopatologia , Dano Encefálico Crônico/terapia , Epilepsia/fisiopatologia , Expressão Gênica/fisiologia , Hipocampo/fisiopatologia , Animais , Dano Encefálico Crônico/etiologia , Convulsivantes/uso terapêutico , Modelos Animais de Doenças , Regulação para Baixo/genética , Epilepsia/complicações , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Perfilação da Expressão Gênica/métodos , Hipocampo/metabolismo , Precondicionamento Isquêmico/métodos , Ácido Caínico/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Neural/etiologia , Degeneração Neural/fisiopatologia , Degeneração Neural/terapia , Proteínas do Tecido Nervoso/genética , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Estado Epiléptico/fisiopatologia , Estado Epiléptico/prevenção & controle , Estado Epiléptico/terapia , Resultado do Tratamento , Regulação para Cima/genéticaRESUMO
In spite of prominent progress in basic pain research, neuropathic pain remains a significant medical problem, because it is often poorly relieved by conventional analgesics. Thus this situation encourages us to make more sophisticated efforts toward the discovery of new analgesics. We previously showed that i.t. administration of acromelic acid-A (ACRO-A), a Japanese mushroom poison, provoked prominent tactile pain (allodynia) at an extremely low dose of 1 fg/mouse. In the present study we synthesized ACRO-A analogues (2S,3R,4R)-3-carboxymethyl-4-phenoxypyrrolidine-2-carboxylic acid (POPA-2) and (2S,3R,4R)-3-carboxymethyl-4-(phenylthio)pyrrolidine-2-carboxylic acid (PSPA-1) chemically and examined their ability to induce allodynia in conscious mice. Whereas POPA-2 induced allodynia at extremely low doses from 1 to 100 fg/mouse, similar to ACRO-A, PSPA-1 did not induce allodynia; rather, it inhibited the ACRO-A-induced allodynia with an ID(50) value (95% confidence limits) of 2.19 fg/mouse (0.04-31.8 fg/mouse). Furthermore, PSPA-1 relieved neuropathic pain produced by L5 spinal nerve transection on day 7 after the operation in a dose-dependent manner from 1 to 100 pg/mouse. In contrast, it did not affect thermal or mechanical nociception or inflammatory pain. PSPA-1 reduced the increase in neuronal nitric oxide synthase activity in the spinal cord of neuropathic pain mice assessed by NADPH-diaphorase histochemistry and blocked the allodynia induced by N-methyl-d-aspartate. These results demonstrate that PSPA-1 may represent a novel class of anti-allodynic agents for neuropathic pain acting by blocking the glutamate-nitric oxide pathway.
Assuntos
Analgésicos/uso terapêutico , Ácido Caínico/análogos & derivados , Mononeuropatias/tratamento farmacológico , Dor/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ácido Glutâmico/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Imuno-Histoquímica , Inflamação/tratamento farmacológico , Inflamação/patologia , Ácido Caínico/síntese química , Ácido Caínico/farmacologia , Ácido Caínico/uso terapêutico , Camundongos , Mononeuropatias/patologia , N-Metilaspartato/farmacologia , NADPH Desidrogenase/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Nociceptores/metabolismo , Dor/patologia , Medula Espinal/enzimologia , Fatores de TempoRESUMO
BACKGROUND: Excitotoxicity-induced in vivo injury models are vital to reflect the pathophysiological features of acute spinal cord injury (SCI) in humans. The duration and concentration of chemical treatment controls the extent of neuronal cell damage. The extent of injury is explained in relation to locomotor and behavioural activity. Several SCI in vivo methods have been reported and studied extensively, particularly contusion, compression, and transection models. These models depict similar pathophysiology to that in humans but are extremely expensive (contusion) and require expertise (compression). Chemical excitotoxicity-induced SCI models are simple and easy while producing similar clinical manifestations. The kainic acid (KA) excitotoxicity model is a convenient, low-cost, and highly reproducible animal model of SCI in the laboratory. The basic impactor approximately cost between 10,000 and 20,000 USD, while the kainic acid only cost between 300 and 500 USD, which is quite cheap as compared to traditional SCI method. METHODS: In this study, 0.05 mM KA was administered at dose of 10 µL/100 g body weight, at a rate of 10 µL/min, to induce spinal injury by intra-spinal injection between the T12 and T13 thoracic vertebrae. In this protocol, detailed description of a dorsal laminectomy was explained to expose the spinal cord, following intra-spinal kainic acid administration at desired location. The dose, rate and technique to administer kainic acid were explained extensively to reflect a successful paraplegia and spinal cord injury in rats. The postoperative care and complication post injury of paraplegic laboratory animals were also explained, and necessary requirements to overcome these complications were also described to help researcher. RESULTS: This injury model produced impaired hind limb locomotor function with mild seizure. Hence this protocol will help researchers to induce spinal cord injury in laboratories at extremely low cost and also will help to determine the necessary supplies, methods for producing SCI in rats and treatments designed to mitigate post-injury impairment. CONCLUSIONS: Kainic acid intra-spinal injection at the concentration of 0.05 mM, and rate 10 µL/min, is an effective method create spinal injury in rats, however more potent concentrations of kainic acid need to be studied in order to create severe spinal injuries.
Assuntos
Humanos , Animais , Ratos , Traumatismos da Medula Espinal , Traumatismos da Coluna Vertebral/complicações , Paraplegia/complicações , Ratos Sprague-Dawley , Modelos Animais de Doenças , Ácido Caínico/uso terapêuticoRESUMO
First, existing commercially available open-loop and closed-loop implantable neurostimulators are reviewed and compared in terms of their targeted application, physical size, system-level features, and performance as a medical device. Next, signal processing algorithms as the primary strength point of the closed-loop neurostimulators are reviewed, and various design and implementation requirements and trade-offs are discussed in details along with quantitative examples. The review results in a set of guidelines for algorithm selection and evaluation. Second, the implementation of an inductively-powered seizure-predicting microsystem for monitoring and treatment of intractable epilepsy is presented. The miniaturized system is comprised of two miniboards and a power receiver coil. The first board hosts a 24-channel neurostimulator system on chip fabricated in a [Formula: see text] CMOS technology and performs neural recording, on-chip digital signal processing, and electrical stimulation. The second board communicates recorded brain signals as well as signal processing results wirelessly. The multilayer flexible coil receives inductively-transmitted power. The system is sized at 2 × 2 × 0.7 [Formula: see text] and weighs 6 g. The approach is validated in the control of chronic seizures in vivo in freely moving rats.
Assuntos
Antinematódeos/uso terapêutico , Epilepsia Resistente a Medicamentos/terapia , Eletroencefalografia/métodos , Neuroestimuladores Implantáveis , Algoritmos , Animais , Encéfalo/fisiologia , Epilepsia Resistente a Medicamentos/veterinária , Estimulação Elétrica , Eletroencefalografia/instrumentação , Desenho de Equipamento , Ácido Caínico/uso terapêutico , Microeletrodos , Ratos , Convulsões/diagnóstico , Convulsões/veterinária , Tecnologia sem FioRESUMO
Neurons in the parapyramidal region of the ventral medulla project to the dorsal vagal complex and intermediolateral column. Kainic acid (0.5-5.0 ng) microinjected unilaterally into the parapyramidal region reduced 45% ethanol-induced gastric lesions by 50-60% in urethane anesthetized rats. Microinjections at sites nearby, but outside of the parapyramidal region, had no effect. These results provide the first evidence that the activation of parapyramidal region neurons influences gastric function and suggests a possible role of this ventral medulla region in gastric regulation.
Assuntos
Ácido Caínico/uso terapêutico , Bulbo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Gastropatias/prevenção & controle , Análise de Variância , Animais , Etanol , Masculino , Bulbo/fisiologia , Ratos , Ratos Sprague-Dawley , Estômago/efeitos dos fármacos , Estômago/fisiologia , Gastropatias/induzido quimicamenteRESUMO
Intracerebroventricular (i.c.v.) infusion in mice of the selective metabotropic excitatory amino acid receptor agonist 1S,3R-1- aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) (0.6-575 nmol/min) dose dependently induced face washing and scratching. In contrast, the subtype-specific ionotropic excitatory amino acid receptor agonists N-methyl-D-aspartate (NMDA), kainate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) (0.3-3.0 nmol/min) dose dependently induced clonic convulsions. I.c.v. infusion of the non-selective metabotropic receptor agonists ibotenate (6 nmol/min) or quisqualate (30 nmol/min) induced clonic convulsions. However, when ionotropic receptors were blocked with (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine maleate (MK-801, dizoclipine) (3 nmol/min) or 2,3-dihydroxy-6-nitro-7- sulfamoyl-benzo(f)-quinoxaline (NBQX) (9 nmol/min), respectively, face washing and scratching behavior emerged. Neither MK-801 or NBQX (ED50 value > 100 nmol/min), nor the putative metabotropic receptor antagonist L-amino-3-phosphoro-propionic acid (L-AP3) (> 176 nmol/min); nor the dopamine receptor antagonists SCH 23390 (> 74 nmol/min), metoclopramide (> 89 nmol/min) and haloperidol (> 27 nmol/min) antagonized 1S,3R-ACPD-induced scratching (144 nmol/min). These results suggest that the behavioral consequences of i.c.v. infusion of 1S,3R-ACPD in mice reflect a selective activation of metabotropic receptors that differs from the behavioral changes observed with i.c.v. infusion of ionotropic receptor agonists.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cicloleucina/análogos & derivados , Ácido Caínico/farmacologia , N-Metilaspartato/farmacologia , Receptores de Glutamato/efeitos dos fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia , Animais , Cicloleucina/administração & dosagem , Cicloleucina/farmacologia , Cicloleucina/uso terapêutico , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Ácido Ibotênico/farmacologia , Ácido Caínico/administração & dosagem , Ácido Caínico/uso terapêutico , Masculino , Camundongos , N-Metilaspartato/administração & dosagem , N-Metilaspartato/uso terapêutico , Quinoxalinas/farmacologia , Ácido Quisquálico/farmacologia , Receptores de Glutamato/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/administração & dosagem , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/uso terapêuticoRESUMO
OBJECT: Symptoms from Parkinson's disease improve after surgical ablation of the medial globus pallidus (GPm). Although, in theory, selective chemical ablation of neurons in the GPm could preserve vital structures jeopardized by surgery, the potential of this approach is limited when using traditional techniques of drug delivery. The authors examined the feasibility of convection-enhanced distribution of a neurotoxin by high-flow microinfusion to ablate the neurons of the GPm selectively and reverse experimental Parkinson's disease (akinesia, tremor, and rigidity). METHODS: Initially, to test the feasibility of this approach, the GPms of two naive rhesus macaques were infused with kainic acid or ibotenic acid through two cannulas that had been placed using the magnetic resonance imaging-guided stereotactic technique. Two weeks later the animals were killed and their brains were examined histologically to determine the presence of neurons in the GPm and the integrity of the optic tract and the internal capsule. To examine the therapeutic potential of this paradigm, unilateral experimental Parkinson's disease was induced in six macaques by intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and their behavior was studied for 12 weeks after chemopallidotomy was performed using kainic acid (three animals) or control infusion (three animals). CONCLUSIONS: Chemopallidotomy using kainic acid permanently reversed the stigmata of MPTP-induced parkinsonism. By contrast, the control animals exhibited a transient recovery following intrapallidal infusion and then relapsed back to their baseline state. The use of high-flow microinfusion of selectively active toxins has the potential for treatment of Parkinson's disease and, by expanding the range of approachable targets to include large nuclei, for broad applications in clinical and experimental neuroscience.
Assuntos
Globo Pálido/efeitos dos fármacos , Ácido Ibotênico/uso terapêutico , Ácido Caínico/uso terapêutico , Intoxicação por MPTP , Doença de Parkinson Secundária/tratamento farmacológico , Animais , Avaliação Pré-Clínica de Medicamentos , Estudos de Viabilidade , Infusões Intra-Arteriais , Infusões Parenterais , Macaca mulatta , Doença de Parkinson Secundária/induzido quimicamente , Técnicas EstereotáxicasRESUMO
OBJECT: The long-term antiseizure effects of local convection-enhanced infusion of the excitotoxin ibotenate were examined in a rat model of temporal lobe epilepsy. METHODS: A single injection of kainate, an epileptogenic excitatory amino acid, into the left amygdala elicited chronic spontaneous recurrent seizure activity for at least 36 days after the injection. Two weeks after the injection, infusion of ibotenate, a nonepileptogenic excitatory amino acid that is an axon-sparing neuronal cell toxin, into the left amygdala and piriform lobe induced immediate and permanent extinction of electrical and behavioral seizure activity. CONCLUSIONS: Lesioning of an epileptic focus by convective distribution of ibotenate can produce an enduring suppression of seizure activity, indicating a chemical neurosurgical approach for epilepsy therapy.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiopatologia , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/fisiopatologia , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Ácido Ibotênico/administração & dosagem , Ácido Ibotênico/uso terapêutico , Neurotoxinas/administração & dosagem , Neurotoxinas/uso terapêutico , Animais , Modelos Animais de Doenças , Eletroencefalografia , Injeções , Ácido Caínico/administração & dosagem , Ácido Caínico/uso terapêutico , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
The immature central nervous system (CNS) is more susceptible to the development of seizures than its adult counterpart. Developmental studies of experimental seizures have suggested that young animals have unique behavioural seizure patterns, including the presence of bilateral, though asymmetric, convulsions. There are differences in the mechanisms responsible for the generation of seizures, propagation patterns and seizure arrest and recurrences. These differences are due to local factors as well as factors that affect neural systems consisting of long neuronal circuits. The substantia nigra, a site involved in the control of seizures, will be used as an example to demonstrate how evolving neurobiological processes modulates the suppression or exacerbation of seizures with age. Evidence will also be presented indicating that early in life, seizures may not produce hippocampal damage. An understanding of the age-related differences is important for the development of rational approaches to treating seizures and their consequences.
Assuntos
Epilepsia/fisiopatologia , Fatores Etários , Animais , Baclofeno/uso terapêutico , Criança , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Hipocampo/fisiopatologia , Humanos , Recém-Nascido , Ácido Caínico/uso terapêutico , Excitação Neurológica/fisiologia , Fenitoína/uso terapêutico , Ratos , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
It has been established that hippocampus, enthorhinal cortex, amygdala and substantia nigra (pars reticulata) lesions before head injury lead to a decrease of kainic acid-induced behavioral and electrographic seizure expressions. It can be concluded that after head injury the activation of limbic structures excitability due to excitation of "inputs" to these formations takes place. The obtained data indicate the significant role of nucleus caudatus in activation of posttraumatic brain excitatory mechanisms.
Assuntos
Corpo Estriado/efeitos dos fármacos , Ácido Caínico/uso terapêutico , Sistema Límbico/efeitos dos fármacos , Convulsões/prevenção & controle , Animais , Lesões Encefálicas/complicações , Ácido Caínico/farmacologia , Masculino , Ratos , Ratos Wistar , Convulsões/etiologiaRESUMO
BACKGROUND: Glutamate homeostasis plays a critical role in mediating the addiction-related behaviors. Therefore, preventing the disruption or reestablishing of it is a novel strategy for the treatment of addiction. Glutamate transporters are responsible for clearing extracellular glutamate and maintaining glutamate homeostasis. Our previous work demonstrated that aquaporin-4 (AQP4) deficiency attenuated morphine dependence, but the mechanisms are unclear. According to the recent evidence that AQP4 might form a functional complex with glutamate transporter-1 (GLT-1), this study focused on whether AQP4 participates in the modulation of GLT-1 and glutamate homeostasis in morphine-dependent mice. RESULTS: We found that AQP4 knockout prevented the down-regulations of GLT-1 expression and glutamate clearance when mice were repeatedly treated with morphine. Further study revealed that inhibition of GLT-1 by dihydrokainic acid (DHK) initiated morphine dependence in AQP4 knockout mice. In addition, AQP4 knockout abolished both decreases and increases in the extracellular glutamate levels in the prefrontal cortex during repeated morphine treatment and naloxone-precipitated withdrawal. CONCLUSION: AQP4 deficiency suppresses the down-regulation of GLT-1, and the disruption of glutamate homeostasis caused by repeated exposure to morphine, pointing to a strategy for maintaining glutamate homeostasis and thereby treating addiction through the modulation of AQP4 function and expression.
Assuntos
Aquaporina 4/deficiência , Regulação para Baixo/genética , Transportador 2 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Homeostase/genética , Dependência de Morfina/genética , Dependência de Morfina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Transportador 2 de Aminoácido Excitatório/genética , Homeostase/efeitos dos fármacos , Ácido Caínico/análogos & derivados , Ácido Caínico/uso terapêutico , Camundongos , Camundongos Knockout , Microdiálise , Morfina/administração & dosagem , Dependência de Morfina/tratamento farmacológico , Dependência de Morfina/patologia , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Trítio/metabolismoRESUMO
Reactive gliosis is a hallmark of many retinal neurodegenerative conditions, including glaucoma. Although a majority of studies to date have concentrated on reactive gliosis in the optic nerve head, very few studies have been initiated to investigate the role of reactive gliosis in the retina. We have previously shown that reactive glial cells synthesize elevated levels of proteases, and these proteases, in turn, promote the death of retinal ganglion cells (RGCs). In this investigation, we have used two glial toxins to inhibit reactive gliosis and have evaluated their effect on protease-mediated death of RGCs. Kainic acid was injected into the vitreous humor of C57BL/6 mice to induce reactive gliosis and death of RGCs. C57BL/6 mice were also treated with glial toxins, alpha-aminoadipic acid (AAA) or Neurostatin, along with KA. Reactive gliosis was assessed by immunostaining of retinal cross sections and retinal flat-mounts with glial fibrillary acidic protein (GFAP) and vimentin antibodies. Apoptotic cell death was assessed by TUNEL assays. Loss of RGCs was determined by immunostaining of flat-mounted retinas with Brn3a antibodies. Proteolytic activities of matrix metalloproteinase-9 (MMP-9), tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA) were assessed by zymography assays. GFAP-immunoreactivity indicated that KA induced reactive gliosis in both retinal astrocytes and in Muller cells. AAA alone or in combination with KA decreased GFAP and vimentin-immunoreactivity in MÏller cells, but not in astrocytes. In addition AAA failed to decrease KA-mediated protease levels and apoptotic death of RGCs. In contrast, Neurostatin either alone or in combination with KA, decreased reactive gliosis in both astrocytes and MÏller cells. Furthermore, Neurostatin decreased protease levels and prevented apoptotic death of RGCs. Our findings, for the first time, indicate that inhibition of reactive gliosis decreases protease levels in the retina, prevents apoptotic death of retinal neurons, and provides substantial neuroprotection.
Assuntos
Apoptose/efeitos dos fármacos , Gliose/tratamento farmacológico , Glicoesfingolipídeos/uso terapêutico , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/efeitos dos fármacos , Ácido 2-Aminoadípico/uso terapêutico , Animais , Gliose/induzido quimicamente , Gliose/metabolismo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Técnicas In Vitro , Ácido Caínico/uso terapêutico , Ácido Caínico/toxicidade , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Células Ganglionares da Retina/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/metabolismoAssuntos
Antipsicóticos/uso terapêutico , Doença de Huntington , Neurotransmissores/uso terapêutico , Simpatolíticos/uso terapêutico , Anfetamina/uso terapêutico , Encéfalo/metabolismo , Encéfalo/patologia , Butirofenonas , Humanos , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Ácido Caínico/uso terapêutico , Levodopa/uso terapêutico , Lítio/uso terapêutico , Fenotiazinas , Tetrabenazina/uso terapêutico , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
Pharmacological inhibition of excitatory neurotransmission attenuates cell death in models of global ischemia/reperfusion and hypoglycemia. The current investigations extend these observations to a model of focal ischemia. Kynurenic acid, a broad-spectrum antagonist at excitatory amino acid receptors, was used as treatment (300 mg/kg; 3 doses at 4-hour intervals) before and after focal cerebral ischemia in rats (n = 54). Preischemia but not 1 hour postischemia treatment with kynurenate attenuated infarction size (p less than 0.001) and improved neurological outcome (p less than 0.001) studied at 24 hours after injury. These data support the role of excitatory neurotransmission in acute neuronal injury and support pharmacological inhibition of cell excitation as a potential therapy for stroke.