Neuroprotection, excitotoxicicity and nmda antagonists

Gagliardi, Rubens José

doi:10.1590/s0004-282x2000000300030

Cited by 67 publications

(51 citation statements)

References 17 publications

(25 reference statements)

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“…A ctivation of the N-methyl-D-aspartate (NMDA) 3 receptors to a large extent mediates the glutamate excitotoxicity and neuronal death in several neurodegenerative diseases and ischemic stroke (1)(2)(3). Subsequent to activation of NMDA receptors occurs toxic calcium influx, which activates numerous enzymes, including neuronal NO synthase (NOS).…”

mentioning

confidence: 99%

Minocycline Provides Neuroprotection AgainstN-Methyl-d-aspartate Neurotoxicity by Inhibiting Microglia

Tikka

Koistinaho

2001

The Journal of Immunology

498

330

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Glutamate excitotoxicity to a large extent is mediated through activation of the N-methyl-d-aspartate (NMDA)-gated ion channels in several neurodegenerative diseases and ischemic stroke. Minocycline, a tetracycline derivative with antiinflammatory effects, inhibits IL-1β-converting enzyme and inducible nitric oxide synthase up-regulation in animal models of ischemic stroke and Huntington’s disease and is therapeutic in these disease animal models. Here we report that nanomolar concentrations of minocycline protect neurons in mixed spinal cord cultures against NMDA excitotoxicity. NMDA treatment alone induced microglial proliferation, which preceded neuronal death, and administration of extra microglial cells on top of these cultures enhanced the NMDA neurotoxicity. Minocycline inhibited all these responses to NMDA. Minocycline also prevented the NMDA-induced proliferation of microglial cells and the increased release of IL-1β and nitric oxide in pure microglia cultures. Finally, minocycline inhibited the NMDA-induced activation of p38 mitogen-activated protein kinase (MAPK) in microglial cells, and a specific p38 MAPK inhibitor, but not a p44/42 MAPK inhibitor, reduced the NMDA toxicity. Together, these results suggest that microglial activation contributes to NMDA excitotoxicity and that minocycline, a tetracycline derivative, represents a potential therapeutic agent for brain diseases.

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mentioning

confidence: 99%

Minocycline Provides Neuroprotection AgainstN-Methyl-d-aspartate Neurotoxicity by Inhibiting Microglia

Tikka

Koistinaho

2001

The Journal of Immunology

498

330

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“…The N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) was used for this study because this drug has been studied widely and has demonstrated efficiency. 12,13 The neuroprotective effects of MK-801 were evaluated versus placebo in the permanent suture MCAO model (group I), which induces hypothalamic damage and hyperthermia, and in the macrosphere MCAO model (group II), which avoids these side effects. In a third experiment, MK-801 was tested with the use of a modified macrosphere MCAO technique that causes hypothalamic damage (group III).…”

mentioning

confidence: 99%

Neuroprotective Effects of MK-801 in Different Rat Stroke Models for Permanent Middle Cerebral Artery Occlusion

Gerriets

Stolz

Walberer

et al. 2003

Stroke

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Background and Purpose-Permanent middle cerebral artery occlusion (MCAO) with the use of the suture technique causes hypothalamic damage with subsequent hyperthermia, which can confound neuroprotective drug studies. In the present study the neuroprotective effects of dizocilpine (MK-801) were compared in different permanent MCAO models with and without hypothalamic damage and hyperthermia. Methods-Sixty Sprague-Dawley rats were treated with MK-801 or placebo, beginning 15 minutes before MCAO, and assigned to the following groups: suture MCAO (group I), macrosphere MCAO without hypothalamic damage (group II), or macrosphere MCAO with intentionally induced hypothalamic infarction (group III). Body temperature was measured at 3, 6, and 24 hours. Lesion size was determined after 24 hours (2,3,5-triphenyltetrazolium chloride staining). Results-Hypothalamic damage was present in animals in group I and was intentionally induced in group III with the use of a modified macrosphere MCAO technique. Body temperature was significantly increased 3, 6, and 24 hours after MCAO in these 2 groups of animals. Hypothalamic damage and subsequent hyperthermia could be avoided effectively by limiting the number of macrospheres (group II). MK-801 provided a highly significant neuroprotective effect in group II but not in groups I and III. Conclusions-Hypothalamic damage with subsequent hyperthermia masked the neuroprotective effect of MK-801. This side effect can be avoided by using the macrosphere MCAO technique with a limited number of spheres. This model therefore may be more appropriate to study the effects of neuroprotective drugs in permanent focal cerebral ischemia than the suture method.

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“…NP drugs are those that reduce excitotoxicity, opposing the excessive release of excitatory amino acids and their intracellular effects 30 . Among those most intensely studied are the antagonists of the NMDA receptors of glutamate, among them ketoprofen.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the neuroprotective effect of ketoprofen on rats submitted to permanent focal brain ischemia

Silva

Colli

Coimbra

et al. 2007

Arq. Neuro-Psiquiatr.

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-Objective: To study the neurobehavioral, biochemical and histopathological consequences of permanent focal brain ischemia, and the putative neuroprotective action of ketoprofen. Method: Onehundred-and-three Wistar rats divided into groups A and B were respectively submitted to 48 hours and 15 days of ischemia. Each group was divided into 4 subgroups: ischemic not treated, ischemic treated, sham not treated, and sham treated. Ischemic animals had the left middle cerebral artery coagulated. Ketoprofen was administered to treated subgroups 15 minutes before arterial coagulation (manipulation in the sham group). Results: Exploratory activity and defecation were reduced in all ischemic animals in the first postoperative days and constant histopathological changes were observed in each group. The total brain glutamate levels were higher in treated animals 48 hours after surgery. Conclusion: No clear parallelism among behavioral, biochemical and histopathological findings was observed. Ketoprofen demonstrated no neuroprotective effect on the behavioral or histopathological aspects of focal permanent brain ischemia.KEY WORDS: focal brain ischemia, rat, open field, glutamate, histopathology, neuroprotection, ketoprofen. Avaliação do efeito neuroprotetor do cetoprofeno em ratos submetidos à isquemia cerebral focal permanenteRESUMO -Objetivo: Estudar as conseqüências comportamentais, bioquímicas e histopatológicas da isquemia cerebral focal permanente e o possível efeito neuroprotetor do cetoprofeno. Método: Foram utilizados 103 ratos Wistar, divididos em grupos A e B, submetidos, respectivamente, a 48 horas e a 15 dias de isquemia. Cada grupo foi dividido em 4 subgrupos: isquêmico não tratado; isquêmico tratado; sham não tratado; sham tratado. Nos animais isquêmicos foi coagulada a artéria cerebral média esquerda. Os subgrupos tratados receberam cetoprofeno 15 minutos antes da oclusão ou manipulação arterial. Resultados: Os animais isquêmicos reduziram a atividade exploratória e as evacuações nos primeiros dias pós-operatórios e mostraram alterações histopatológicas constantes em cada grupo. As concentrações do glutamato total 48 horas após a cirurgia foram maiores nos animais tratados. Conclusão: Não houve um paralelismo entre os achados comportamentais, bioquímicos e histopatológicos. O cetoprofeno não apresentou efeito protetor contra isquemia cerebral focal permanente, nos aspectos comportamentais e histopatológicos.

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Neuroprotection, excitotoxicicity and nmda antagonists

Cited by 67 publications

References 17 publications

Minocycline Provides Neuroprotection AgainstN-Methyl-d-aspartate Neurotoxicity by Inhibiting Microglia

Minocycline Provides Neuroprotection AgainstN-Methyl-d-aspartate Neurotoxicity by Inhibiting Microglia

Neuroprotective Effects of MK-801 in Different Rat Stroke Models for Permanent Middle Cerebral Artery Occlusion

Evaluation of the neuroprotective effect of ketoprofen on rats submitted to permanent focal brain ischemia

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