Attenuation of astrogliosis and modulation of endothelial growth factor receptor in lipid rafts by simvastatin after traumatic brain injury.
OBJECTIVE
The authors' previous studies have demonstrated that simvastatin treatment promotes neuronal survival and reduces inflammatory cytokine release from astrocytes after traumatic brain injury (TBI) in rats. Since reactive astrocytes produce inflammation mediators, in the current study the authors investigated the effect of simvastatin on astrocyte activation after TBI and its underlying signaling mechanisms.


METHODS
Saline or simvastatin (1 mg/kg) was orally administered to rats starting at Day 1 after TBI and then daily for 14 days. Rats were killed at 1, 3, 7, and 14 days after treatment. Brain sections and tissues were prepared for immunohistochemical staining and Western blot analysis, respectively. Cultured astrocytes were subjected to oxygen-glucose deprivation (OGD) and followed by immunocytochemical staining with glial fibrillary acidic protein/caveolin-1 and Western blot analysis. Lipid rafts were isolated from the cell lysate and Western blotting was carried out to detect the changes in epidermal growth factor receptor (EGFR) expression and phosphorylation in the lipid rafts.


RESULTS
Simvastatin significantly promoted neuronal survival after TBI and attenuated activation of astrocytes. Simvastatin modified the caveolin-1 expression in lipid rafts in astrocyte cell membrane, suppressed the phosphorylation of EGFR in lipid rafts of astrocytes after OGD, and inhibited the OGD-induced interleukin-1 production.


CONCLUSIONS
These data suggest that simvastatin reduces reactive astrogliosis and rescues neuronal cells after TBI. These beneficial effects of simvastatin may be mediated by inhibiting astrocyte activation after TBI through modifying the caveolin-1 expression in lipid rafts and the subsequent modulation of EGFR phosphorylation in lipid rafts.
Wu
Hongtao
H
Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Mahmood
Asim
A
Lu
Dunyue
D
Jiang
Hao
H
Xiong
Ye
Y
Zhou
Dong
D
Chopp
Michael
M
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005911:Gliosis / Q000150:complications / Q000188:drug therapy*; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*
C495537:Cav1 protein, rat; D051242:Caveolin 1; D007375:Interleukin-1; D018696:Neuroprotective Agents; D019821:Simvastatin; D040262:Receptors, Vascular Endothelial Growth Factor; D005947:Glucose