Axonal Degeneration of Nigra-striatum Dopaminergic Neurons Induced by 1-Methyl-4-phenyl-1,2,3, 6-tetrahydropyridine in Mice

Li, LH; Hz, Qin; Jl, Wang; Wang, J; Xl, Wang; Gao, GD

doi:10.1177/147323000903700221

Cited by 22 publications

(16 citation statements)

References 15 publications

(36 reference statements)

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“…In the present study, an increase in the t-SOD activity observed in the SN and CS of the EF1 group was able to protect these regions from membrane LP measured as TBARS levels. The absence of FJC labeling in neuronal cell bodies of both brain regions reinforces these results, considering the efficacy of this reagent in detecting signals of neurodegeneration induced by conditions of OS, such as ischemia (Yang et al, 2011), glutamate excitotoxicity (Ehara and Ueda, 2009) or dopaminergic lesions induced by 6-OHDA (Ehara and Ueda, 2009) or MPTP (Bian et al, 2007; Li et al, 2009). …”

Section: Discussionmentioning

confidence: 64%

See 1 more Smart Citation

Differential vulnerability of substantia nigra and corpus striatum to oxidative insult induced by reduced dietary levels of essential fatty acids

Cardoso¹,

Passos²,

Lagranha³

et al. 2012

Front. Hum. Neurosci.

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Oxidative stress (OS) has been implicated in the etiology of certain neurodegenerative disorders. Some of these disorders have been associated with unbalanced levels of essential fatty acids (EFA). The response of certain brain regions to OS, however, is not uniform and a selective vulnerability or resilience can occur. In our previous study on rat brains, we observed that a two-generation EFA dietary restriction reduced the number and size of dopaminergic neurons in the substantia nigra (SN) rostro-dorso-medial. To understand whether OS contributes to this effect, we assessed the status of lipid peroxidation (LP) and anti-oxidant markers in both SN and corpus striatum (CS) of rats submitted to this dietary treatment for one (F1) or two (F2) generations. Wistar rats were raised from conception on control or experimental diets containing adequate or reduced levels of linoleic and α-linolenic fatty acids, respectively. LP was measured using the thiobarbituric acid reaction method (TBARS) and the total superoxide dismutase (t-SOD) and catalase (CAT) enzymatic activities were assessed. The experimental diet significantly reduced the docosahexaenoic acid (DHA) levels of SN phospholipids in the F1 (~28%) and F2 (~50%) groups. In F1 adult animals of the experimental group there was no LP in both SN and CS. Consistently, there was a significant increase in the t-SOD activity (p < 0.01) in both regions. In EF2 young animals, degeneration in dopaminergic and non-dopaminergic neurons and a significant increase in LP (p < 0.01) and decrease in the CAT activity (p < 0.001) were detected in the SN, while no inter-group difference was found for these parameters in the CS. Conversely, a significant increase in t-SOD activity (p < 0.05) was detected in the CS of the experimental group compared to the control. The results show that unbalanced EFA dietary levels reduce the redox balance in the SN and reveal mechanisms of resilience in the CS under this stressful condition.

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Section: Discussionmentioning

confidence: 64%

“…It has been shown that this protocol specifically labels damaged neurons and not glial cells in the SN and CS (Bian et al, 2007; Ehara and Ueda, 2009) when these regions are submitted to certain types of insult, especially under conditions that induce OS (Ehara and Ueda, 2009; Li et al, 2009; Yang et al, 2011). …”

Section: Methodsmentioning

confidence: 99%

Differential vulnerability of substantia nigra and corpus striatum to oxidative insult induced by reduced dietary levels of essential fatty acids

Cardoso¹,

Passos²,

Lagranha³

et al. 2012

Front. Hum. Neurosci.

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“…Early aggregation might result in early dysfunction at the presynaptic terminal, causing defects in neurotransmission long before cell death. In multiple models of PD, both toxin-induced (Herkenham et al, 1991; Orimo et al, 2008; Li et al, 2009a; Cartelli et al, 2010; Arnold et al, 2011; Kim-Han et al, 2011; Mijatovic et al, 2011) and genetic (Li et al, 2009b; Decressac et al, 2012) axon degeneration is observed prior to cell death, and in a higher percentage of cells. This has raised the question of whether PD represents a ‘dying back’ of dopaminergic neurons (Hornykiewicz, 1998), with synapse loss initiating a retrograde degenerative process that leads to cell death.…”

Section: Discussionmentioning

confidence: 99%

Axon degeneration and PGC1α-mediated protection in a vertebrate model of α-synuclein toxicity

O’Donnell

Lulla

Stahl

et al. 2014

Disease Models &Amp; Mechanisms

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α-synuclein (aSyn) expression is implicated in neurodegenerative processes, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). In animal models of these diseases, axon pathology often precedes cell death, raising the question of whether aSyn has compartment-specific toxic effects that could require early and/or independent therapeutic intervention. The relevance of axonal pathology to degeneration can only be addressed through longitudinal, in vivo monitoring of different neuronal compartments. With current imaging methods, dopaminergic neurons do not readily lend themselves to such a task in any vertebrate system. We therefore expressed human wild-type aSyn in zebrafish peripheral sensory neurons, which project elaborate superficial axons that can be continuously imaged in vivo. Axonal outgrowth was normal in these neurons but, by 2 days post-fertilization (dpf), many aSyn-expressing axons became dystrophic, with focal varicosities or diffuse beading. Approximately 20% of aSyn-expressing cells died by 3 dpf. Time-lapse imaging revealed that focal axonal swelling, but not overt fragmentation, usually preceded cell death. Co-expressing aSyn with a mitochondrial reporter revealed deficits in mitochondrial transport and morphology even when axons appeared overtly normal. The axon-protective protein Wallerian degeneration slow (WldS) delayed axon degeneration but not cell death caused by aSyn. By contrast, the transcriptional coactivator PGC-1α, which has roles in the regulation of mitochondrial biogenesis and reactive-oxygen-species detoxification, abrogated aSyn toxicity in both the axon and the cell body. The rapid onset of axonal pathology in this system, and the relatively moderate degree of cell death, provide a new model for the study of aSyn toxicity and protection. Moreover, the accessibility of peripheral sensory axons will allow effects of aSyn to be studied in different neuronal compartments and might have utility in screening for novel disease-modifying compounds.

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“…Interestingly, the MPTP model is an excellent tool for the study of axonal degeneration. Already within the first days after MPTP application, the number of tyrosine hydroxylase-immunoreactive fibres in the median forebrain bundle significantly decreases, whereas the dopaminergic neuron demise follows later (Li et al , 2009). In an elaborate study analysing synaptosomal preparations of MPTP-treated mice, chronically administered MPTP readily decreased the expression of the dopamine transporter at a time when cell bodies still remained intact (Muroyama et al , 2011).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson's disease

Tönges

Frank

Tatenhorst

et al. 2012

Brain

150

148

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Axonal degeneration is one of the earliest features of Parkinson’s disease pathology, which is followed by neuronal death in the substantia nigra and other parts of the brain. Inhibition of axonal degeneration combined with cellular neuroprotection therefore seem key to targeting an early stage in Parkinson’s disease progression. Based on our previous studies in traumatic and neurodegenerative disease models, we have identified rho kinase as a molecular target that can be manipulated to disinhibit axonal regeneration and improve survival of lesioned central nervous system neurons. In this study, we examined the neuroprotective potential of pharmacological rho kinase inhibition mediated by fasudil in the in vitro 1-methyl-4-phenylpyridinium cell culture model and in the subchronic in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Application of fasudil resulted in a significant attenuation of dopaminergic cell loss in both paradigms. Furthermore, dopaminergic terminals were preserved as demonstrated by analysis of neurite network in vitro, striatal fibre density and by neurochemical analysis of the levels of dopamine and its metabolites in the striatum. Behavioural tests demonstrated a clear improvement in motor performance after fasudil treatment. The Akt survival pathway was identified as an important molecular mediator for neuroprotective effects of rho kinase inhibition in our paradigm. We conclude that inhibition of rho kinase using the clinically approved small molecule inhibitor fasudil may be a promising new therapeutic strategy for Parkinson’s disease.

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Axonal Degeneration of Nigra-striatum Dopaminergic Neurons Induced by 1-Methyl-4-phenyl-1,2,3, 6-tetrahydropyridine in Mice

Cited by 22 publications

References 15 publications

Differential vulnerability of substantia nigra and corpus striatum to oxidative insult induced by reduced dietary levels of essential fatty acids

Differential vulnerability of substantia nigra and corpus striatum to oxidative insult induced by reduced dietary levels of essential fatty acids

Axon degeneration and PGC1α-mediated protection in a vertebrate model of α-synuclein toxicity

Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson's disease

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