Low dose rotenone treatment causes selective transcriptional activation of cell death related pathways in dopaminergic neurons in vivo

Meurers, Bernhard H.; Zhu, Chunni; Fernagut, Pierre‐Olivier; Richter, Franziska; Hsia, Yi-Chih; Fleming, Sheila M.; Oh, Myung Sook; Elashoff, David; DiCarlo, Cheryl Dawn; Seaman, Ronald L.; Chesselet, Marie‐Françoise

doi:10.1016/j.nbd.2008.10.001

Cited by 30 publications

(41 citation statements)

References 63 publications

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“…1c, d) or in other brain regions (not shown). The selective decrease of TH in the substantia nigra and striatum was in line with the known sensitivity of nigro-striatal dopaminergic neurons to rotenone toxicity (Sherer et al 2003b;Meurers et al 2008). To confirm that the observed decrease of TH levels was actually related to degeneration of nigro-striatal dopaminergic neurons and that VPA protected these neurons from rotenone toxicity we sought evidence from different experimental approaches.…”

Section: Resultssupporting

confidence: 58%

“…The model and the reasons for the peculiar sensitivity of nigro-striatal dopaminergic neurons to brain concentrations of rotenone that only partially inhibit mitochondrial complex 1 have been discussed elsewhere (Sherer et al 2003b). Furthermore, a recent study has confirmed, at the level of regulation of gene expression, the preferential response of these neurons also to sub-toxic doses of rotenone (Meurers et al 2008). In the present study, by using a standard dosage of rotenone administration (3 mg/Kg/day), continuously delivered through osmotic mini pumps, and by limiting the time of exposure to 7 days, we were able to obtain a sizable decrease of dopaminergic markers in the substantia nigra and striatum of the treated rats and to significantly revert the effect of the neurotoxic insult through chronic dietary administration of VPA that results in blood concentration of the drug close to the human therapeutic window (Hao et al 2004).…”

Section: Discussionmentioning

confidence: 95%

“…A recent study has shown that rotenone challenge regulates in nigral dopaminergic neurons the expression of a vast array of genes, some of which potentially dangerous while others neuroprotective (Meurers et al 2008). By increasing histone acetylation in the same neurons, VPA may shift the balance towards expression of neuroprotective genes.…”

Section: Discussionmentioning

confidence: 99%

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Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein

et al. 2009

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Valproic acid (VPA), an established antiepileptic and antimanic drug, has recently emerged as a promising neuroprotective agent. Among its many cellular targets, VPA has been recently demonstrated to be an effective inhibitor of histone deacetylases. Accordingly, we have adopted a schedule of dietary administration (2% VPA added to the chow) that results in a significant inhibition of histone deacetylase activity and in an increase of histone H3 acetylation in brain tissues of 4 weeks-treated rats. We have tested this schedule of VPA treatment in an animal model of Parkinson's disease (PD), in which degeneration of nigro-striatal dopaminergic neurons is obtained through sub-chronic administration of the mitochondrial toxin, rotenone, via osmotic mini pumps implanted to rats. The decrease of the dopaminergic marker tyrosine hydroxylase in substantia nigra and striatum caused by 7 days toxin administration was prevented in VPA-fed rats. VPA treatment also significantly counteracted the death of nigral neurons and the 50% drop of striatal dopamine levels caused by rotenone administration. The PD-marker protein alpha-synuclein decreased, in its native form, in substantia nigra and striatum of rotenone-treated rats, while monoubiquitinated alpha-synuclein increased in the same regions. VPA treatment counteracted both these alpha-synuclein alterations. Furthermore, monoubiquitinated alpha-synuclein increased its localization in nuclei isolated from substantia nigra of rotenone-treated rats, an effect also prevented by VPA treatment. Nuclear localization of alpha-synuclein has been recently described in some models of PD and its neurodegenerative effect has been ascribed to histone acetylation inhibition. Thus, the ability of VPA to increase histone acetylation is a novel candidate mechanism for its neuroprotective action.

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Section: Resultssupporting

confidence: 58%

Section: Discussionmentioning

confidence: 95%

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Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein

et al. 2009

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“…Snap frozen brains from the following groups were used for transcriptome analysis (n=5 each): wildtype + control, wildtype + TRO19622, Thy1-aSyn + control, Thy1-asyn + TRO19622; wildtype + control, wildtype + TRO40303, Thy1-aSyn + control, Thy1-asyn + TRO40303. For laser-capture microdissection (LCM) of TH-positive neurons, the substantia nigra was cut in 10 μm serial coronal sections and quickly immunostained for TH as described previously (Meurers et al, 2008; Richter et al, 2009) with adaptation for immunofluorescent staining as follows: following ethanol fixation for 1 minute, sections were incubated with a primary antibody recognizing TH (rabbit anti TH, 1:200, Millipore, Billerica, MA) for 2 minutes followed by incubation for 2 minutes in Cy3 conjugated goat anti-rabbit secondary antibody (1:200, Vector Laboratories, Burlingame, CA) on ice. Sections were rinsed in sterile ice-cold 1x PBS between each incubation step.…”

Section: Methodsmentioning

confidence: 99%

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Richter¹,

Gao²,

Medvedeva³

et al. 2014

Neurobiology of Disease

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Cholesterol-oximes TRO19622 and TRO40303 target outer mitochondrial membrane proteins and have beneficial effects in preclinical models of neurodegenerative diseases leading to their advancement to clinical trials. Dopaminergic neurons degenerate in Parkinson’s disease (PD) and are prone to oxidative stress and mitochondrial dysfunction. In order to provide insights into the neuroprotective potential of TRO19622 and TRO40303 for dopaminergic neurons in vivo, we assessed their effects on gene expression in laser captured nigrostriatal dopaminergic neurons of wildtype mice and of mice that over-express alpha-synuclein, a protein involved in both familial and sporadic forms of PD (Thy1-aSyn mice). Young mice were fed the drugs in food pellets or a control diet from 1 to 4 months of age, approximately 10 months before the appearance of striatal dopamine loss in this model. Unbiased weighted gene co-expression network analysis (WGCNA) of transcriptional changes revealed effects of cholesterol oximes on transcripts related to mitochondria, cytoprotection and anti-oxidant response in wild-type and transgenic mice, including increased transcription of stress defense (e.g. Prdx1, Prdx2, Glrx2, Hspa9, Pink1, Drp1, Trak1) and dopamine-related (Th, Ddc, Gch1, Dat, Vmat2, Drd2, Chnr6a) genes. Even at this young age transgenic mice showed alterations in transcripts implicated in mitochondrial function and oxidative stress (e.g. Bcl-2, Bax, Casp3, Nos2), and both drugs normalized about 20% of these alterations. Young Thy1-aSyn mice exhibit motor deficits that differ from parkinsonism and are established before the onset of treatment; these deficits were not improved by cholesterol oximes. However, high doses of TRO40303 improved olfaction and produced the same effects as dopamine agonists on a challenging beam test, specifically an increase in footslips, an observation congruent with its effects on transcripts involved in dopamine synthesis. High doses of TRO19622 increased alpha-synuclein aggregates in the substantia nigra; this effect, not seen with TRO40303 was inconsistent and may represent a protective mechanism as in other neurodegenerative diseases. Overall, the results suggest that cholesterol oximes, while not improving early effects of alpha-synuclein overexpression on motor behavior or pathology, may ameliorate the function and resilience of dopaminergic neurons in vivo and support further studies of neuroprotection in models with dopaminergic cell loss.

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“…Mitochondrial dysfunction is believed to play a prominent role in the etiology of PD, as patients with sporadic PD display systemic mitochondrial complex-1 dysfunction (Mizuno et al, 1989;Nicklas et al, 1985;Parker et al, 1989;Schapira et al, 1989). Furthermore, animal models of PD based exclusively on mitochondrial inhibition have revealed that nigrostriatal dopaminergic neurons are highly susceptible to the effects of mitochondrial dysfunction (Betarbet et al, 2000;German et al, 1992;Liang et al, 1996;Meurers et al, 2009;Sherer et al, 2002Sherer et al, ,2003.…”

Section: The Effect Of Tbi On Nigrostriatal Dopaminergic Neuronsmentioning

confidence: 99%

Traumatic Brain Injury in Adult Rats Causes Progressive Nigrostriatal Dopaminergic Cell Loss and Enhanced Vulnerability to the Pesticide Paraquat

Hutson

Lazo

Mortazavi

et al. 2011

Journal of Neurotrauma

118

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and the accumulation of alpha-synuclein. Both traumatic brain injury (TBI) and pesticides are risk factors for PD, but whether TBI causes nigrostriatal dopaminergic cell loss in experimental models and whether it acts synergistically with pesticides is unknown. We have examined the acute and long-term effects of TBI and exposure to low doses of the pesticide paraquat, separately and in combination, on nigrostriatal dopaminergic neurons in adult male rats. In an acute study, rats received moderate TBI by lateral fluid percussion (LFP) injury, were injected with saline or paraquat (10 mg/kg IP) 3 and 6 days after LFP, were sacrificed 5 days later, and their brains processed for immunohistochemistry. TBI alone increased microglial activation in the substantia nigra, and caused a 15% loss of dopaminergic neurons ipsilaterally. Paraquat increased the TBI effect, causing a 30% bilateral loss of dopaminergic neurons, reduced striatal tyrosine hydroxylase (TH) immunoreactivity more than TBI alone, and induced alpha-synuclein accumulation in the substantia nigra pars compacta. In a long-term study, rats received moderate LFP, were injected with saline or paraquat at 21 and 22 weeks post-injury, and were sacrificed 4 weeks later. At 26 weeks post injury, TBI alone induced a 30% bilateral loss of dopaminergic neurons that was not exacerbated by paraquat. These data suggest that TBI is sufficient to induce a progressive degeneration of nigrostriatal dopaminergic neurons. Furthermore, TBI and pesticide exposure, when occurring within a defined time frame, could combine to increase the PD risk.

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Low dose rotenone treatment causes selective transcriptional activation of cell death related pathways in dopaminergic neurons in vivo

Cited by 30 publications

References 63 publications

Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein

Valproic Acid is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: Involvement of α-Synuclein

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Traumatic Brain Injury in Adult Rats Causes Progressive Nigrostriatal Dopaminergic Cell Loss and Enhanced Vulnerability to the Pesticide Paraquat

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