Contributory mechanisms in the causation of neurodegenerative disorders

Lees, G.J.

doi:10.1016/0306-4522(93)90254-d

Cited by 215 publications

(107 citation statements)

References 419 publications

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“…The contribution of glutamate and its analogues to neuronal death occuring in animal models of neurological diseases is well established. [15][16][17][18] The neuronal cytotoxicity is mediated by excessive Ca + + -and Na + -influx through ionotropic glutamate receptors (NMDA-, AMPA-and Kainatreceptor), which trigger intracellular catabolic processes such as the activation of proteases, lipid peroxidases and phospholipases . This will lead to destruction of biological membranes and consecutive cellular necrosis.…”

Section: Resultsmentioning

confidence: 99%

High-dose S(+)- ketamine improves neurological outcome following incomplete cerebral ischemia in rats

Reeker

Werner

Möllenberg

et al. 2000

Can J Anesth/J Can Anesth

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572CAN J ANESTH 2000 / 47: 6 / pp [572][573][574][575][576][577][578] Purpose: To determine the effects of the non-competitive NMDA-receptor antagonist S(+)-ketamine on neurological outcome in a rat model of incomplete cerebral ischemia. Methods: Thirty rats were anesthetized, intubated and mechanically ventilated with isoflurane, O 2 30% and nitrous oxide 70%. Following surgery animals were randomly assigned to one of the following treatment groups: Rats in group 1 (n=10, control) received fentanyl (bolus: 10 µg·kg -1 iv; infusion 25 µg·kg -1 ·h -1 ) and N 2 O 70% / O 2 . Rats in group 2 (n=10) received O 2 30% in air and low-dose S(+)-ketamine (infusion: 0.25 mg·kg -1 ·min -1 ). Rats in group 3 (n=10) received O 2 30% in air and high-dose S(+)-ketamine (infusion: 1.0 mg·kg -1 ·min -1 ). Following 30 min equilibration period ischemia was induced by combined unilateral common carotid artery ligation and hemorrhagic hypotension to 35 mmHg for 30 min. Plasma catecholamines were assayed before and at the end of ischemia. Neurological deficit was evaluated for three postischemic days. Results: Neurological outcome was improved with high-dose S(+)-ketamine when compared to fentanyl / N 2 O -anesthetized controls (9 vs 1 stroke related deaths, P < 0.05). Increases in plasma catecholamine concentrations were higher in fentanyl / N 2 O -anesthetized (adrenaline baseline 105.5 ± 92.1 pg·ml -1 , during ischemia 948 ± 602.8 pg·ml -1 , P < 0.05; noradrenaline baseline 407± 120.2 pg·ml -1 , ischemia 1267 ± 422.2 pg·ml -1 , P < 0.05) than in high-dose S(+)-ketamine-treated animals (adrenaline baseline 71 ± 79.5 pg·ml -1 , ischemia 237 ± 131.9; noradrenaline baseline 317.9 ± 310.5 pg·ml -1 , ischemia 310.5 ± 85.7 pg·ml -1 ). Conclusion: Neurological outcome is improved following incomplete cerebral ischemia with S(+)-ketamine. Decreases in neuronal injury may be related to suppression of sympathetic discharge. Résultats : L'évolution neurologique a été meilleure avec de fortes doses de S(+)-kétamine qu'avec l'alfentanyl / N 2 O (9 vs 1 décès reliés à un accident ischémique cérébral, P < 0,05). L'augmentation des concentrations plasmatiques de catécholamines a été plus marquée avec l'alfentanyl / N 2 O (l'adrénaline de base à 105,5 ± 92,1 pg·ml -1 ; pendant l'ischémie, 948 ± 602,8 pg·ml -1 , P < 0,05; la noradrénaline de base à 407± 120,2 pg·ml -1 ; pendant l'ischémie, 1267 ± 422,2 pg·ml -1 , P < 0,05) qu'avec de fortes doses de S(+)-kétamine (l'adrénaline de base à 71 ± 79,5 pg·ml -1 ; pendant l'ischémie, 237 ± 131,9; la noradrénaline de base à 317,9 ± 310,5 pg·ml -1 ; pendant l'ischémie, 310,5 ± 85,7 pg·ml -1 ). Conclusion : L'utilisation de S(+)-kétamine permet une évolution neurologique supérieure après une ischémie cérébrale incomplète. Cette situation peut être reliée à la suppression de décharge sympathique.

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Section: Resultsmentioning

confidence: 99%

High-dose S(+)- ketamine improves neurological outcome following incomplete cerebral ischemia in rats

Reeker

Werner

Möllenberg

et al. 2000

Can J Anesth/J Can Anesth

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“…The explanations for AD should take into account the fact that age is the primary risk factor for the disease (Viel et al 2001). One important factor associated with aging is the accumulation of oxidative damage caused by free radicals (Ames et al 1993;Lees 1993). Free radicals are also involved in the neurodegeneration that occurs in AD.…”

Section: Discussionmentioning

confidence: 99%

Microglia enhance β‐amyloid peptide‐induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species

Qin

Liu

Cooper

et al. 2002

Journal of Neurochemistry

280

238

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The purpose of this study was to assess and compare the toxicity of b-amyloid (Ab) on primary cortical and mesencephalic neurons cultured with and without microglia in order to determine the mechanism underlying microglia-mediated Ab-induced neurotoxicity. Incubation of cortical or mesencephalic neuron-enriched and mixed neuron-glia cultures with Ab(1-42) over the concentration range 0.1-6.0 lM caused concentration-dependent neurotoxicity. High concentrations of Ab (6.0 lM for cortex and 1.5-2.0 lM for mesencephalon) directly injured neurons in neuron-enriched cultures. In contrast, lower concentrations of Ab (1.0-3.0 lM for cortex and 0.25-1.0 lM for mesencephalon) caused significant neurotoxicity in mixed neuron-glia cultures, but not in neuron-enriched cultures. Several lines of evidence indicated that microglia mediated the potentiated neurotoxicity of Ab, including the observations that low concentrations of Ab activated microglia morphologically in neuron-glia cultures and that addition of microglia to cortical neuron-glia cultures enhanced Ab-induced neurotoxicity. To search for the mechanism underlying the microglia-mediated effects, several proinflammatory factors were examined in neuron-glia cultures. Low doses of Ab significantly increased the production of superoxide anions, but not of tumor necrosis factor-a, interleukin-1b or nitric oxide. Catalase and superoxide dismutase significantly protected neurons from Ab toxicity in the presence of microglia. Inhibition of NADPH oxidase activity by diphenyleneiodonium also prevented Ab-induced neurotoxicity in neuron-glia mixed cultures. The role of NADPH oxidase-generated superoxide in mediating Ab-induced neurotoxicity was further substantiated by a study which showed that Ab caused less of a decrease in dopamine uptake in mesencephalic neuron-glia cultures from NADPH oxidase-deficient mutant mice than in that from wild-type controls. This study demonstrates that one of the mechanisms by which microglia can enhance the neurotoxicity of Ab is via the production of reactive oxygen species.

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“…First steps in these directions have very recently been made by synthesizing low molecular compounds which modify, in a more or less specific manner, the tyrosine kinase activity of the trk receptor family (44) (see also Hempstead (32a), this issue). Conversely, an understanding of the molecular mechanisms responsible for the pathological changes in human motoneuron diseases (2,8,47,88) would permit a more selective choice of animal models for preclinical investigations. For the time being, one is left with a simple empirical approach, comparing the effects in animal models with the results of clinical investigations from case to case for individual neurotrophic molecules.…”

Section: Future Perspectives For the Treatment Of Degenerative Disordmentioning

confidence: 99%

“…Therefore, the use of neurotrophic molecules in the treatment of degenerative diseases ofthe nervous system is a symptomatic one and strongly encourages further investigations aimed at a molecular understanding of the pathogenetic mechanisms of degenerative disorders of the nervous system. 47 In the following, we give a brief survey of the molecules with an established action on motoneurons (in vitro and/or in vivo) and the present and potential future approaches to the elucidation of the relative physiological and pathophysiological importance of these molecules. Finally, we discuss the essential criteria to be considered for a rational evaluation of neurotrophic molecules in the treatment of degenerative disease of the nervous system, in general, and of motoneuron disorders, in particular.…”

Section: Introductionmentioning

confidence: 99%

Trophic Support of Motoneurons: Physiological, Pathophysiological, and Therapeutic Implications

Thoenen¹,

Hughes²,

Sendtner³

1993

Experimental Neurology

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Contributory mechanisms in the causation of neurodegenerative disorders

Cited by 215 publications

References 419 publications

High-dose S(+)- ketamine improves neurological outcome following incomplete cerebral ischemia in rats

High-dose S(+)- ketamine improves neurological outcome following incomplete cerebral ischemia in rats

Microglia enhance β‐amyloid peptide‐induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species

Trophic Support of Motoneurons: Physiological, Pathophysiological, and Therapeutic Implications

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