Abstract
Rapamycin protects mice against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced loss of dopaminergic neurons, which is an established model for Parkinson’s disease. We demonstrated that rapamycin preserves astrocytic expression of glutamate transporters and glutamate reuptake. The protective effect was also observed in astrocyte cultures, indicating that rapamycin acts directly on astrocytes. In the MPTP model, rapamycin caused reduced expression of the E3 ubiquitin ligase Nedd4-2 (neuronal precursor cell expressed developmentally downregulated 4-2) and reduced colocalization of glutamate transporters with ubiquitin. Rapamycin increased interleukin-6 (IL-6) expression, which was associated with reduced expression of inflammatory cytokines, indicating anti-inflammatory properties of IL-6 in the MPTP model. NF-κB was shown to be a key mediator for rapamycin, whereas Janus kinase 2, signal transducer and activator of transcription 3, phosphoinositide 3-kinase, and Akt partially mediated rapamycin effects in astrocytes. These results demonstrate for the first time in a Parkinson’s disease animal model that the neuroprotective effects of rapamycin are associated with glial and anti-inflammatory effects.
Highlights
The motor symptoms of Parkinson’s disease (PD) are predominantly due to the degeneration of dopaminergic (DA) neurons in the pars compacta of substantia nigra (SNpc),[1] and multiple mechanisms are believed to contribute to neurodegeneration in PD, including α-synuclein toxicity,[2] mitochondrial impairment,[3] reactive oxygen species,[4] glutamate excitotoxicity,[5,6,7] and increased inflammation.[8,9] The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of PD model recapitulates the motor symptoms and preferential cell loss in the SNpc
Each bar represents the mean ± S.E.M. of at least three independent experiments. *Po0.05, **Po0.01, compared with the control group; #Po0.05, ##Po0.01, for MPP+ versus Rapa+MPP+ or MPP++Rapa groups (Figure 5e). These findings suggest that activation of IL-6/ Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway upon rapamycin/MPP+ combination treatment may be limited to astrocytes
This model causes striatal dopamine depletion nearly 50% in C57BL/6 mice, and the DA lesion stabilizes by 21 days after MPTP administration.[39,40]
Summary
The motor symptoms of Parkinson’s disease (PD) are predominantly due to the degeneration of dopaminergic (DA) neurons in the pars compacta of substantia nigra (SNpc),[1] and multiple mechanisms are believed to contribute to neurodegeneration in PD, including α-synuclein toxicity,[2] mitochondrial impairment,[3] reactive oxygen species,[4] glutamate excitotoxicity,[5,6,7] and increased inflammation.[8,9] The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of PD model recapitulates the motor symptoms and preferential cell loss in the SNpc. We demonstrate that rapamycin directly targets glial cells to limit two well-established contributing factors to PD pathology: astrocyte activation and the inflammatory response. The effects of rapamycin may be mediated via ubiquitin/proteasomal pathways and the modulation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
