Granulocyte-colony stimulating factor attenuates striatal degeneration with activating survival pathways in 3-nitropropionic acid model of Huntington's disease.
Huntington's disease (HD) has a mitochondrial dysfunction causing the vulnerability to the excitotoxicity and activations of multiple cell death pathways. Recent evidences suggest that the hematopoietic cytokine, granulocyte-colony stimulating factor (G-CSF), exerts pleiotropic neuroprotection in acute neural injury with activating various survival pathways. Thus, we investigated whether G-CSF can modulate neurodegeneration in an HD animal model induced by 3-nitropropionic acid (3NP), which inhibits mitochondrial succinate dehydrogenase complex II. Either G-CSF (50 microg/kg/day) or saline (as vehicle) was administered intraperitoneally for 5 days with 3NP (63 mg/kg/day) continuous osmotic pump infusion into male Lewis rats. We measured motor scales (0-8) daily and sacrificed rats at 5 days. We observed that G-CSF receptors were expressed in 3NP-induced degenerating striatum. Rats treated with G-CSF showed less degree of neurologic deficits. In the G-CSF-treated rats, the striatal lesion volume measured by Nissl staining, TUNEL+ apoptotic cells, Fluorojade C+ degenerating neurons, and c-Jun+ cells were all decreased. In western blotting, G-CSF activated survival pathways including p-ERK, p-eNOS, p-STAT3, and p-Akt. In summary, G-CSF was found to have neuroprotective effects and save striatal cells through activations of survival pathways in the 3NP-induced striatal degeneration model for HD.
Lee
Soon-Tae
ST
Department of Neurology, Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea.
Park
Jung-Eun
JE
Kim
Dong-Hyun
DH
Kim
Seungchan
S
Im
Woo-Seok
WS
Kang
Lami
L
Jung
Se Hee
SH
Kim
Min-Wook
MW
Chu
Kon
K
Kim
Manho
M
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D004347:Drug Interactions; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006816:Huntington Disease / Q000139:chemically induced* / Q000150:complications*; D020287:In Situ Nick-End Labeling; D008297:Male; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D009574:Nitro Compounds; D009930:Organic Chemicals; D011422:Propionates; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D018709:Statistics, Nonparametric
D005452:Fluoresceins; D009574:Nitro Compounds; D009930:Organic Chemicals; D011422:Propionates; C435731:fluoro jade; D016179:Granulocyte Colony-Stimulating Factor; C015392:3-nitropropionic acid