Rapamycin upregulates glutamate transporter and IL-6 expression in astrocytes in a mouse model of Parkinson's disease.
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.
Department of Neurology, The First People's Hospital of Shunde Affiliated to Southern Medical University, Foshan, Guangdong 528300, China.|Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.|Department of Traditional Chinese Medicine, College of Medicine, Xiamen University, Xiamen Fujian 361102, China.
Yunlong
Y
Zhang
Department of Neurology, The First People's Hospital of Shunde Affiliated to Southern Medical University, Foshan, Guangdong 528300, China.|Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
Xiaoliang
X
He
Department of Neurology, The First People's Hospital of Shunde Affiliated to Southern Medical University, Foshan, Guangdong 528300, China.|Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
Xiaojuan
X
Wu
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Ming
M
Lei
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Zhiyun
Z
Wei
Teaching Center of Experimental Medicine, School of Basic Medical Sciences, Southern Medical University, Guangzhou Guangdong 510080, China.
Xiuping
X
Zhang
Department of Traditional Chinese Medicine, College of Medicine, Xiamen University, Xiamen Fujian 361102, China.
Lei
L
Wen
Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Guangdong 510080, China.
Pingyi
P
Xu
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Shaomin
S
Li
Department of Neurology, The First People's Hospital of Shunde Affiliated to Southern Medical University, Foshan, Guangdong 528300, China.|Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
Shaogang
S
Qu
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005971:Glutamates / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
D027322:Amino Acid Transport System X-AG; D016207:Cytokines; D005971:Glutamates; D015850:Interleukin-6; D016328:NF-kappa B; D018696:Neuroprotective Agents; D050796:STAT3 Transcription Factor; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019869:Phosphatidylinositol 3-Kinases; D053614:Janus Kinase 2; D020123:Sirolimus