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Neurotoxic Agent (neurotoxic + agent)

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Life Sciences	50%

Selected Abstracts

Adaptative response of antioxidant enzymes in different areas of rat brain after repeated d -amphetamine administration

ADDICTION BIOLOGY, Issue 3 2001
Félix Carvalho
d-Amphetamine has been shown to be a potential brain neurotoxic agent, particularly to dopaminergic neurones. Reactive oxygen species indirectly generated by this drug have been indicated as an important factor in the appearance of neuronal damage but little is known about the adaptations of brain antioxidant systems to its chronic administration. In this study, the activities of several antioxidant enzymes in different areas of rat brain were measured after repeated administration of d-amphetamine sulphate (sc, 20 mg/kg/day, for 14 days), namely glutathione-S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GRed), catalase, and superoxide dismutase (SOD). When compared to a pair-fed control group, d-amphetamine treatment enhanced the activity of GST in hypothalamus to 167%, GPx in striatum to 127%, in nucleus accumbens to 192%, and in medial prefrontal cortex to 139%, GRed in hypothalamus to 139%, as well as catalase in medial prefrontal cortex to 153%. However, the same comparison revealed a decrease in the activity of GRed in medial pre-frontal cortex by 35%. Food restriction itself reduced GRed activity by 49% and enhanced catalase activity to 271% in nucleus accumbens. The modifications observed for the measured antioxidant enzymes reveal that oxidative stress probably plays a role in the deleterious effects of this drug in CNS and that, in general, the brain areas studied underwent adaptations which provided protection against the continuous administration of the drug. [source]

Effects of aluminum on activity of Krebs cycle enzymes and glutamate dehydrogenase in rat brain homogenate

FEBS JOURNAL, Issue 10 2000
P. Zatta
Aluminum is a neurotoxic agent for animals and humans that has been implicated as an etiological factor in several neurodegenerative diseases and as a destabilizer of cell membranes. Due to its high reactivity, Al3+ is able to interfere with several biological functions, including enzymatic activities in key metabolic pathways. In this paper we report that, among the enzymes that constitute the Krebs cycle, only two are activated by aluminum: ,-ketoglutarate dehydrogenase and succinate dehydrogenase. In contrast, aconitase, shows decreased activity in the presence of the metal ion. Al3+ also inhibits glutamate dehydrogenase, an allosteric enzyme that is closely linked to the Krebs cycle. A possible correlation between aluminum, the Krebs cycle and aging processes is discussed. [source]

Distinct effects of atypical 1,4-dihydropyridines on 1-methyl-4-phenylpyridinium-induced toxicity

CELL BIOCHEMISTRY AND FUNCTION, Issue 1 2007
Linda Klimaviciusa
Abstract Our previous data obtained from in vivo experiments demonstrated high neuroprotective effects of three novel atypical neuronal non-calcium antagonistic 1,4-dihydropyridine (DHP) derivatives cerebrocrast, glutapyrone and tauropyrone. The present studies were carried out in vitro to clarify, at least in part, their mechanism of action in primary culture of cerebellar granule cells by use of 1-methyl-4-phenylpyridinium (MPP+) as a neurotoxic agent which causes dramatic oxidative stress. Cerebrocrast (highly lipophilic, with a classical two-ring structure) dose-dependently (0.01,10.0,µM, EC50,=,13,nM) reduced MPP+ -induced cell death. At the same time, the calcium antagonist nimodipine (reference drug) protected cell death at much higher concentrations (EC50,=,12.4,µM). Cerebrocrast decreased also the generation of reactive oxygen species and loss of mitochondrial membrane potential. In contrast, low lipophilic amino acid-containing DHPs glutapyrone and tauropyrone (glutamate- and taurine-containing, correspondingly) were without significant effects indicating their distinct mode of action in comparison to cerebrocrast. We have demonstrated for the first time an ability of atypical non-calcium antagonistic DHP cerebrocrast (which has classical DHP structure elements and high lipophilicity) to protect MPP+ -induced deterioration of mitochondrial bioenergetics. One may suggest mitochondria as an essential intracellular target for the neuroprotective action of cerebrocrast and indicate its usefulness in the treatment of Parkinson's disease. Copyright © 2006 John Wiley & Sons, Ltd. [source]

Vincristine sulfate liposomes injection (Marqibo) in heavily pretreated patients with refractory aggressive non-Hodgkin lymphoma,

CANCER, Issue 15 2009
Report of the Pivotal Phase 2 Study
Abstract BACKGROUND: Marqibo, a sphingosomal/cholesterol encapsulation of vincristine sulfate has targeted, increased, and sustained delivery of vincristine to tumor tissues. A phase 2, open-label, single-arm, and multinational study evaluated the efficacy and tolerability of Marqibo as a single agent in patients with multiply relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). METHODS: Eligible patients had relapsed or refractory de novo or transformed aggressive NHL and prior treatment with at least 2 multiagent chemotherapy regimens. Marqibo was administered at 2 mg/m2, every 2 weeks, for a maximum of 12 cycles or until toxicity or disease progression. RESULTS: One hundred and nineteen patients were enrolled and treated on trial. Ninety-six had histological confirmed de novo (N = 89) or transformed (N = 7) aggressive NHL. Median number of cycles was 4 (median dose/cycle 4 mg). Overall response (CR and complete response unconfirmed and PR) was 25% (95% confidence interval [CI], 17, 35), CR and complete response unconfirmed confirmed by external reviewers was 5%. Median overall survival was 6.6 months (Kaplan-Meier estimate, 95% CI, 4.7, 9.8). Grade 3 of 4 neurotoxicity occurred in 32% of patients. All patients had prior neurotoxic agents, and 85% had baseline residual neuropathy symptoms (grades 1-2) from prior treatment. CONCLUSIONS: Marqibo is an active agent in patients with heavily pretreated aggressive NHL, and tolerated at approximately twice the dose intensity of standard vincristine. Its activity supports further investigation as a substitution for vincristine in combination treatment of lymphoid disorders. Cancer 2009. © 2009 American Cancer Society. [source]