Caloric Restriction Protects against Lactacystin-Induced Degeneration of Dopamine Neurons Independent of the Ghrelin Receptor

Coppens, Jessica; Bentea, Eduard; Bayliss, Jacqueline; Demuyser, Thomas; Walrave, Laura; Albertini, Giulia; Liefferinge, Joeri Van; Deneyer, Lauren; Aourz, Najat; Eeckhaut, Ann Van; Portelli, Jeanelle; Andrews, Zane B.; Massie, Ann; Bundel, Dimitri De; Smolders, Ilse Julia

doi:10.3390/ijms18030558

Cited by 6 publications

(4 citation statements)

References 63 publications

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“…In particular, IF was found to protect hippocampal or dopaminergic neuron degeneration when applied prior excitotoxic insults or mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in rodents (Bruce-Keller et al, 1999 ; Duan and Mattson, 1999 ). Pre-treatment with dietary restriction was also found to protect dopaminergic neurons in a murine PD model using lactacystin (Coppens et al, 2017 ). Attenuated motor deficits were observed in monkeys that were fed with 30% of calorie reduction for 6 months prior to treatment with MPTP (Maswood et al, 2004 ).…”

Section: Discussionmentioning

confidence: 99%

Intermittent Fasting Applied in Combination with Rotenone Treatment Exacerbates Dopamine Neurons Degeneration in Mice

Tatulli

Mitro

Cannata

et al. 2018

Front. Cell. Neurosci.

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Intermittent fasting (IF) was suggested to be a powerful nutritional strategy to prevent the onset of age-related neurodegenerative diseases associated with compromised brain bioenergetics. Whether the application of IF in combination with a mitochondrial insult could buffer the neurodegenerative process has never been explored yet. Herein, we defined the effects of IF in C57BL/6J mice treated once per 24 h with rotenone (Rot) for 28 days. Rot is a neurotoxin that inhibits the mitochondrial complex I and causes dopamine neurons degeneration, thus reproducing the neurodegenerative process observed in Parkinson’s disease (PD). IF (24 h alternate-day fasting) was applied alone or in concomitance with Rot treatment (Rot/IF). IF and Rot/IF groups showed the same degree of weight loss when compared to control and Rot groups. An accelerating rotarod test revealed that only Rot/IF mice have a decreased ability to sustain the test at the higher speeds. Rot/IF group showed a more marked decrease of dopaminergic neurons and increase in alpha-synuclein (α-syn) accumulation with respect to Rot group in the substantia nigra (SN). Through lipidomics and metabolomics analyses, we found that in the SN of Rot/IF mice a significant elevation of excitatory amino acids, inflammatory lysophospholipids and sphingolipids occurred. Collectively, our data suggest that, when applied in combination with neurotoxin exposure, IF does not exert neuroprotective effects but rather exacerbate neuronal death by increasing the levels of excitatory amino acids and inflammatory lipids in association with altered brain membrane composition.

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Section: Discussionmentioning

confidence: 99%

Intermittent Fasting Applied in Combination with Rotenone Treatment Exacerbates Dopamine Neurons Degeneration in Mice

Tatulli

Mitro

Cannata

et al. 2018

Front. Cell. Neurosci.

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“…As obestatin does not cross the BBB (Pan, Tu, & Kastin, 2006) the mechanism of obestatin-induced neuroprotection is likely distinct from AG. Notably, in the lactacystin model of PD, CR-mediated neuroprotection is seemingly independent of GHSR (Coppens et al, 2017) -obestatin may play a role in this paradigm.…”

Section: Gut-brain Signaling Of Energy Deficitmentioning

confidence: 99%

Ghrelin mediated neuroprotection - A possible therapy for Parkinson's disease?

et al. 2018

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Parkinson's disease is a common age-related neurodegenerative disorder affecting 10 million people worldwide, but the mechanisms underlying its pathogenesis are still unclear. The disease is characterised by dopamine nerve cell loss in the mid-brain and intra-cellular accumulation of α-synuclein that results in motor and non-motor dysfunction. In this review, we discuss the neuroprotective effects of the stomach hormone, ghrelin, in models of Parkinson's disease. Recent findings suggest that it may modulate mitochondrial function and autophagic clearance of impaired organelle in response to changes in cellular energy balance. We consider the putative cellular mechanisms underlying ghrelin-action and the possible role of ghrelin mimetics in slowing or preventing Parkinson's disease progression. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

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“…It is interesting to speculate on these dissimilar findings, and they may be related with age-related changes in mitochondrial metabolism and generation of reactive oxygen species, the distinct mechanism of action of MPTP in aged animals (Ali et al, 1994;Kuhn et al, 2003), and the nature of the induced cell loss (chronic and progressive for MPTP vs. acute for LAC and 6-OHDA). The different mechanism of action (proteasomal vs. mitochondrial inhibition) might also play a factor in the dissimilar findings in the two models, in line with the observation that targets, such as the ghrelin receptor, may differentially influence LAC-or MPTP-induced death of nigral dopaminergic neurons (Andrews et al, 2009;Coppens et al, 2017). Finally, the site of delivery (intracerebral vs. systemic) may also trigger different neuroinflammatory reactions in primed mice, that may subsequently contribute to the mechanisms of neurodegeneration.…”

Section: Discussionmentioning

confidence: 75%

Aged xCT-Deficient Mice Are Less Susceptible for Lactacystin-, but Not 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine-, Induced Degeneration of the Nigrostriatal Pathway

Bentea

Pauw

Verbruggen

et al. 2021

Front. Cell. Neurosci.

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The astrocytic cystine/glutamate antiporter system xc– (with xCT as the specific subunit) imports cystine in exchange for glutamate and has been shown to interact with multiple pathways in the brain that are dysregulated in age-related neurological disorders, including glutamate homeostasis, redox balance, and neuroinflammation. In the current study, we investigated the effect of genetic xCT deletion on lactacystin (LAC)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of the nigrostriatal pathway, as models for Parkinson’s disease (PD). Dopaminergic neurons of adult xCT knock-out mice (xCT–/–) demonstrated an equal susceptibility to intranigral injection of the proteasome inhibitor LAC, as their wild-type (xCT+/+) littermates. Contrary to adult mice, aged xCT–/– mice showed a significant decrease in LAC-induced degeneration of nigral dopaminergic neurons, depletion of striatal dopamine (DA) and neuroinflammatory reaction, compared to age-matched xCT+/+ littermates. Given this age-related protection, we further investigated the sensitivity of aged xCT–/– mice to chronic and progressive MPTP treatment. However, in accordance with our previous observations in adult mice (Bentea et al., 2015a), xCT deletion did not confer protection against MPTP-induced nigrostriatal degeneration in aged mice. We observed an increased loss of nigral dopaminergic neurons, but equal striatal DA denervation, in MPTP-treated aged xCT–/– mice when compared to age-matched xCT+/+ littermates. To conclude, we reveal age-related protection against proteasome inhibition-induced nigrostriatal degeneration in xCT–/– mice, while xCT deletion failed to protect nigral dopaminergic neurons of aged mice against MPTP-induced toxicity. Our findings thereby provide new insights into the role of system xc– in mechanisms of dopaminergic cell loss and its interaction with aging.

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Caloric Restriction Protects against Lactacystin-Induced Degeneration of Dopamine Neurons Independent of the Ghrelin Receptor

Cited by 6 publications

References 63 publications

Intermittent Fasting Applied in Combination with Rotenone Treatment Exacerbates Dopamine Neurons Degeneration in Mice

Intermittent Fasting Applied in Combination with Rotenone Treatment Exacerbates Dopamine Neurons Degeneration in Mice

Ghrelin mediated neuroprotection - A possible therapy for Parkinson's disease?

Aged xCT-Deficient Mice Are Less Susceptible for Lactacystin-, but Not 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine-, Induced Degeneration of the Nigrostriatal Pathway

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