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Neurotoxic Insult (neurotoxic + insult)
Selected AbstractsDipyridamole protects cultured rat embryonic cortical neurons from neurotoxic insultJOURNAL OF NEUROCHEMISTRY, Issue 2002A. D. Blake The effects of a clinically useful cardiovascular agent, dipyridamole, were examined in a rodent tissue culture model of neural protection. Dipyridamole effectively protected rat embryonic day 18 (E18) cortical neurons from either trophic deprivation or endogenous glutathione depletion by l -buthionine (R,S) sulfoximine (BSO). Trophic deprivation was associated with an increase in intracellular oxidative stress, as determined by the increased fluorescence of dichloro, dihydrofluorescein (H2DCFDA). Dipyridamole's neural protection was time and concentration-dependent (EC50 = 342 nm), and its continuous presence in the culture medium was required. Dipyridamole or exogenously added glutathione markedly decreased trophic deprivation induced H2DCFDA fluorescence, indicating a reduction in neuronal oxidative stress. These results demonstrate that dipyridamole protects primary neuronal cultures against either trophic or chemically mediated insults, and suggest that dipyridamole has a potent antioxidant ability that compensates for glutathione depletion in primary neuronal cells. [source] Protection from MPTP-induced neurotoxicity in differentiating mouse N2a neuroblastoma cellsJOURNAL OF NEUROCHEMISTRY, Issue 3 2001Luigi A. De Girolamo We have shown previously that subcytotoxic concentrations of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) inhibit axon outgrowth and are associated with increased neurofilament heavy chain (NF-H) phosphorylation in differentiating mouse N2a neuroblastoma cells while higher doses (>,100 µm) cause cell death. In this work we assessed the ability of potential neuroprotective agents to alleviate both MPTP-induced cell death (cytotoxicity) and MPTP-induced NF-H phosphorylation/reduction in axon outgrowth (neurotoxicity) in N2a cells induced to differentiate by dbcAMP. The neurotoxic effects of MPTP occurred in the absence of significant alterations in energy status or mitochondrial membrane potential. The hormone oestradiol (100 µm) reduced the cytotoxic effect of MPTP, but blocked di-butyryl cyclic AMP (dbcAMP)-induced differentiation, i.e. axon outgrowth. Both the cytotoxic and neurotoxic effects of MPTP were reduced by the monoamine osidase (MAO) inhibitors deprenyl and, to a lesser extent, clorgyline. Alleviation of both neurotoxicity and cytotoxicity was also achieved by conditioned medium derived from rat C6 glioma cells. In contrast, whilst the p38 MAP kinase inhibitor, SB202190, protected cells against MPTP-induced neurotoxicity, it could not maintain cell viability at high MPTP exposures. In each case neuroprotection involved maintenance of the differentiating phenotype linked with attenuation of NF-H hyper-phosphorylation; the latter may represent a mechanism by which neuronal cells can moderate MPTP-induced neurotoxicity. The use of a simplified neuronal cell model, which expresses subtle biochemical changes following neurotoxic insult, could therefore provide a valuable tool for the identification of potential neuroprotective agents. [source] Dopaminergic neurotoxicity by 6-OHDA and MPP+: Differential requirement for neuronal cyclooxygenase activityJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2005Emilce Carrasco Abstract Cyclooxygenase (COX), a key enzymatic mediator of inflammation, is present in microglia and surviving dopaminergic neurons in Parkinson's disease (PD), but its role and place in the chain of neurodegenerative events is unclear. Epidemiologic evidence showed that regular use of nonsteroidal antiinflammatory drugs (NSAIDs), specifically non-aspirin COX inhibitors like ibuprofen, lowers the risk for PD; however, the putative cause-and-effect relationship between COX activity in activated microglia and neuronal loss was challenged recently. We examined whether neuronal COX activity is involved directly in dopaminergic cell death after neurotoxic insult. Using low concentrations of 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridium ion (MPP+), neurotoxicants used to model selective dopaminergic cell loss in PD, and cultures of embryonic rat mesencephalic neurons essentially devoid of glia, we tested whether the nonselective COX inhibitor ibuprofen attenuated 6-OHDA and MPP+ neurotoxicity. At levels close to its IC50 for both COX isoforms, ibuprofen protected dopaminergic neurons against 6-OHDA but not MPP+ toxicity. Experiments with selective inhibitors of COX-1 (SC-560) and COX-2 (NS-398 and Cayman 10404), indicated that COX-2, but not COX-1, was involved in 6-OHDA toxicity. Accordingly, 6-OHDA, but not MPP+, increased prostaglandin (PG) levels twofold and this increase was blocked by ibuprofen. At concentrations well above its IC50 for COX, ibuprofen also prevented MPP+ toxicity, but had only limited efficacy against loss of structural complexity. Taken together, our data suggest that selective 6-OHDA toxicity to dopaminergic neurons is associated with neuronal COX-2, whereas MPP+ toxicity is COX independent. This difference may be important for understanding and manipulating mechanisms of dopaminergic cell death. © 2005 Wiley-Liss, Inc. [source] GRAPE SEED PROANTHOCYANIDIN EXTRACT CHELATES IRON AND ATTENUATES THE TOXIC EFFECTS OF 6-HYDROXYDOPAMINE: IMPLICATIONS FOR PARKINSON'S DISEASEJOURNAL OF FOOD BIOCHEMISTRY, Issue 2 2010TZU-HUA WU ABSTRACT Proanthocyanidins are potent antioxidants associated with protection against diseases. We tested the reducing capacity, iron chelating activity, and anti-auto-oxidation ability of grape seed proanthocyanidin extract (GSPE). The mechanisms underlying GSPE attenuation of oxidative processes induced by 6-hydroxydopamine (6-OHDA), a neurotoxin used to induce Parkinson's disease, were investigated in cell-based systems. At high concentrations, GSPE (50 µg/µL) was a mild pro-oxidant in a Fenton-type reaction. GSPE (300 µg/mL) was as potent as 30 µM deferoxamine in its iron-chelating capacity, and as efficient as 5 mM ascorbic acid in delaying 6-OHDA auto-oxidation. In PC-12 cell cultures, 100 and 300 µg/mL GSPE significantly protected (P < 0.05) cells from 6-OHDA-induced (400 µM) toxicity. GSPE-induced cytoprotection is enhanced by a nitric oxide synthase inhibitor (NOSI), implying that the cytoprotective effect of GSPE does not require NOS activation. In conclusion, the iron-chelating activity of GSPE minimizes its pro-oxidant activity and delays 6-OHDA auto-oxidation to provide cytoprotection. PRACTICAL APPLICATIONS Parkinson's disease is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons. The recognized pharmacological strategies to prevent or treat Parkinson's disease include the minimization of oxidative stress, iron release and excitotoxicity resulting from excess nitric oxide formation. One of the best ways to delay or prevent the onset of the disease is to improve the biological antioxidant status by providing additional radical scavengers that are not pro-oxidants. The pro-oxidant activity, such as that of the antioxidant ascorbic acid, enhances radical cycling under certain conditions, and therefore may be detrimental. Grape seed proanthocyanidin extracts (GSPEs) are used as a dietary supplement in food products in several countries. Our current report provides evidence that GSPE has limited pro-oxidant activity, presumably because of its iron-chelating abilities, and protects cells from neurotoxic insults. GSPE may be effective as a dietary supplement for prophylactic use against the progressive neurodegeneration seen in Parkinson's disease. [source] NSAIDs protect dopaminergic neurons against 6-OHDA and MPP+ toxicityJOURNAL OF NEUROCHEMISTRY, Issue 2002P. Werner Endogenous and environmental neurotoxins are among the suspected causes of the loss of dopaminergic (DA) neurons in Parkinson's disease (PD). Non-steroidal anti-inflammatory drugs (NSAIDs) reduce inflammation by inhibiting cyclooxygenase (COX)-dependent synthesis of prostaglandins (PG) from arachidonic acid. NSAIDs decrease the incidence of Alzheimer's disease, but little is known about their potential benefit for PD. Therefore, we examined whether NSAIDs could protect DA neurons from neurotoxic insults. NSAIDs can protect DA neurons against excitotoxicity (Casper et al. 2000), and against 6-hydroxydopamine (6-OHDA) toxicity (Carrasco et al. 2001). Here, we compared in primary mesencephalic/DA neuron cultures the effect of NSAIDs on the toxicity of 1-methyl-phenylpyridinium (MPP+) or 6-OHDA. 6-OHDA significantly (*p < 0.0001) increased PG production, whereas MPP+ did not (p < 0.05). We then compared the competitive/unspecific COX inhibitors ibuprofen and naproxen and the noncompetitive/unspecific inhibitor acetylsalicylic acid (ASA, aspirin) for their ability to protect DA neurons against either 6-OHDA or MPP+ toxicity. Interestingly, all three nonselective COX inhibitors protected DA neurons in cultures against both 6-OHDA and MPP+ (p < 0.05), despite the difference in PG induction by 6-OHDA vs. MPP+. The selective COX-2 inhibitor NS398 did protect DA neurons against 5 ,m MPP+ (*p < 0.05), but failed to protect DA neurons against 5 ,m 6-OHDA (p < 0.05). Our results suggest that COX-inhibitors may have neuroprotective benefits unrelated to inhibition of PG synthesis, and that 6-OHDA and MPP+ have partially overlapping mechanisms of neurodegeneration possibly involving COX activity. Acknowledgement:, Supported, in part, by the International Federation for Parkinson's disease, NY, NY. [source] | ||||||||||