Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder, characterized by a loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Caloric restriction (CR) has been shown to exert ghrelin-dependent neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-based animal model for PD. We here investigated whether CR is neuroprotective in the lactacystin (LAC) mouse model for PD, in which proteasome disruption leads to the destruction of the DA neurons of the SNc, and whether this effect is mediated via the ghrelin receptor. Adult male ghrelin receptor wildtype (WT) and knockout (KO) mice were maintained on an ad libitum (AL) diet or on a 30% CR regimen. After 3 weeks, LAC was injected unilaterally into the SNc, and the degree of DA neuron degeneration was evaluated 1 week later. In AL mice, LAC injection significanty reduced the number of DA neurons and striatal DA concentrations. CR protected against DA neuron degeneration following LAC injection. However, no differences were observed between ghrelin receptor WT and KO mice. These results indicate that CR can protect the nigral DA neurons from toxicity related to proteasome disruption; however, the ghrelin receptor is not involved in this effect.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder affecting around 7 to 10 million people worldwide [1] and is characterized by the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) that send their axons mainly to the striatum
We here investigated whether Caloric restriction (CR) is neuroprotective in the lactacystin (LAC) mouse model for PD, in which proteasome disruption leads to the destruction of the DA neurons of the SNc, and whether this effect is mediated via the ghrelin receptor
These results indicate that CR can protect the nigral DA neurons from toxicity related to proteasome disruption; the ghrelin receptor is not involved in this effect
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder affecting around 7 to 10 million people worldwide [1] and is characterized by the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) that send their axons mainly to the striatum. In addition Morris et al showed that a high-fat diet induced more pronounced neurodegeneration in SNc and more DA depletion in the striatum of 6-hydroxydopamine (6-OHDA)-injected mice compared to a normal diet, possibly due to increased oxidative stress [6]. A study in Caenorhabditis elegans further showed a neuroprotective effect of CR in the 6-OHDA model, an effect mediated via silent information regulator (sir)-2.1, a nicotinamide adenine dinucleotide NAD+-dependent deacetylase known to extend lifespan [12]. These findings suggest that changes in energy homeostasis can influence neurodegeneration following toxic stimuli. The effect of CR on coexisting molecular pathways in PD remains presently unknown and is of particular interest given the heterogeneous nature of the pathogenesis in the human disorder [15]
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