Neurotoxins and neurotoxic species implicated in neurodegeneration

Segura‐Aguilar, Juan; Kostrzewa, Richard M.

doi:10.1007/bf03033456

Cited by 84 publications

(50 citation statements)

References 204 publications

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“…32,33 Treatment of dopaminergic cells with 6-OHDA elicits robust activation of ERK1/2, and pharmacological inhibition of ERK activation enhances neuronal survival. 34,35 Interestingly, 6-OHDA elicits a delayed phase of mitochondrial ROS production 35 that is associated with increased mitochondrial ERK activation.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress

Dagda¹,

Zhu²,

Kulich³

et al. 2008

Autophagy

243

227

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induce mitophagy to a degree comparable with that elicited by 6-OHDA, while constitutively active ERK2 (ERK2-CA) had a greater effect. We developed green fluorescent protein (GFP) fusion constructs of WT, CA, and kinase-deficient (KD) ERK2 to study the role of ERK2 localization in regulating mitophagy and cell death. Under basal conditions, cells transfected with GFP-ERK2-WT or GFP-ERK2-CA, but not GFP-ERK2-KD, displayed discrete cytoplasmic ERK2 granules of which a significant fraction colocalized with mitochondria and markers of autophagolysosomal maturation. The colocalizing GFP-ERK2/mitochondria granules are further increased by 6-OHDA and undergo autophagic degradation, as bafilomycin-A, an inhibitor of autolysosomal degradation, robustly increased their detection. Interestingly, increasing ERK2-WT or ERK2-CA expression was sufficient to promote comparable levels of macroautophagy as assessed by analysis of the autophagy marker microtubule-associated protein 1 light chain 3 (LC3). In contrast, the level of mitophagy was more tightly correlated with ERK activity levels, potentially explained by the greater localization of ERK2-CA to mitochondria compared to ERK2-WT. These data indicate that mitochondrial localization of ERK2 activity is sufficient to recapitulate the effects of 6-OHDA on mitophagy and autophagic cell death.

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Section: Introductionmentioning

confidence: 99%

Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress

Dagda¹,

Zhu²,

Kulich³

et al. 2008

Autophagy

243

227

View full text Add to dashboard Cite

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“…Glutamate, the major excitatory neurotransmitter in the brain, is also categorized as an excitotoxin (Segura-Aguilar and Kostrzewa, 2004). Monosodium glutamate (MSG) is used as a food additive, which causes only minor alterations in adults.…”

Section: Introductionmentioning

confidence: 99%

Development of neurological reflexes and motor coordination in rats neonatally treated with monosodium glutamate

et al. 2005

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Monosodium glutamate (MSG) treatment of neonatal rats causes neuronal degeneration in various brain areas and leads to several neurochemical, endocrinological and behavioral alterations. However, relatively little is known about the development of neurological reflexes and motor coordination of these animals. Therefore, the aim of the present study was to examine the neurobehavioral development of newborn rats treated with MSG. Rats received MSG at postnatal days 1, 3, 5, 7, and 9. Appearance of neural reflexes and reflex performance as well as motor coordination were examined for 5 weeks after birth. The efficacy of MSG treatment was confirmed by histological examination of the arcuate nucleus. We found that MSG treatment delayed the appearance of forelimb placing, forelimb grasp and righting reflexes, besides the retarded somatic development. The treated pups performed surface righting in significantly longer times. Also, worse performance was observed in the foot-fault and rota-rod tests. However, MSG-treated rats reached control levels by the end of the fifth postnatal week. These results show that MSG treatment does not cause permanent alterations in the neurobehavioral development, only delays the appearance of some reflexes and leads to temporary changes in reflex performance and motor coordination signs.

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“…Nowadays MPP + is believed to be a complex compound acting at different levels in DA neurons (see, for review, Segura Aguilar and Kostrzewa, 2004). In vitro studies with synaptosomes suggested that MPP + enters the cell using DAT (Bougria et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…Inside the cell, MPP + binds to complex-I of the mitochondrial respiratory chain, causing the inhibition of NAD-linked mitochondrial respiration (Javitch et al, 1985), an increase in the generation of reactive oxygen species (Akaneya et al, 1995;Jenner, 1998;Przedborski and Vila, 2003;SeguraAguilar and Kostrzewa, 2004) and caspase-3 activation (Du et al, 1997). Recently, it was reported that MPP + may act by other non-DAT dependent mechanisms; thus the precise mechanism of MPP + -induced degeneration is still under discussion (Mytilineou, 2001;Segura-Aguilar and Kostrzewa, 2004).…”

Section: Fp Graham Publishing Comentioning

confidence: 99%

Dopamine D2 agonists, bromocriptine and quinpirole, increase MPP+-induced toxicity in PC12 cells

et al. 2006

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Dopaminergic cell loss in the mesencephalic substantia nigra is the hallmark of Parkinson's disease and may be associated with abnormal oxidative metabolic activity. However, the delicate balance underlying dopamine decline and oxidative stress is still a matter of debate. The aim of this study was to analyze the possible modulation of D2 agonists and antagonists on MPP+ (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium ion) -induced cellular death in differentiated and undifferentiated PC12 cells. Using colorimetric assays, western blots and reverse transcriptase-PCR, we demonstrated that two D2 agonists, bromocriptine and quinpirole, consistently increased MPP+ -induced cytotoxicity in both differentiated and undifferentiated PC12 cells, whereas D2 antagonists do not modulate cell death. However, this increase in cellular death was reversed when bromocriptine or quinpirole were used in presence of D2 antagonists. On the other hand, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909), a potent inhibitor of the dopamine transporter, partially reversed MPP+ -induced cellular death and completely abolished the increase of cellular death induced by bromocriptine. Dopamine agonists and antagonists also modulate the expression of the dopamine transporter in PC12 cells; in particular, bromocriptine may alter MPP+ uptake by increasing DAT expression We also show that, in our cellular paradigm, D2 receptor mRNA levels are more abundant that D3 mRNA levels and MPP+ and /or bromocriptine could not modulate D2 gene expression while D3 gene expression clearly decrease after MPP+ and /or bromocriptine treatment.

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Neurotoxins and neurotoxic species implicated in neurodegeneration

Cited by 84 publications

References 204 publications

Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress

Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress

Development of neurological reflexes and motor coordination in rats neonatally treated with monosodium glutamate

Dopamine D2 agonists, bromocriptine and quinpirole, increase MPP+-induced toxicity in PC12 cells

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