Peripheral administration of fetuin-A attenuates early cerebral ischemic injury in rats.
Cerebral ischemia-elicited inflammatory responses are driven by inflammatory mediators produced both by central (e.g., neurons and microglia) and infiltrating peripheral immune cells (e.g., macrophage/monocyte), and contribute to the evolution of tissue injury. A ubiquitous molecule, spermine, is released from injured cells, and counter-regulates release of various proinflammatory cytokines. However, the spermine-mediated anti-inflammatory activities are dependent on the availability of fetuin-A, a liver-derived negative acute-phase protein. Using an animal model of focal cerebral ischemia (i.e., permanent middle cerebral artery occlusion, MCAo), we found that levels of fetuin-A in the ischemic brain tissue were elevated in a time-dependent manner, starting between 2 and 6 h, peaking around 24 to 48 h, and returning to baseline 72 h after MCAo. When administered peripherally, exogenous fetuin-A gained entry across the BBB into the ischemic brain tissue, and dose dependently reduced brain infarct volume at 24 h after MCAo. Meanwhile, fetuin-A effectively attenuated (i) ischemia-induced HMGB1 depletion from the ischemic core; (ii) activation of centrally (e.g., microglia) and peripherally derived immune cells (e.g., macrophage/monocytes); and (iii) TNF production in ischemic brain tissue. Taken together, these experimental data suggest that fetuin-A protects against early cerebral ischemic injury partly by attenuating the brain inflammatory response.
Wang
Haichao
H
The Feinstein Institute for Medical Research, Manhasset, New York, USA. hwang@nshs.edu
Li
Wei
W
Zhu
Shu
S
Li
Jianhua
J
D'Amore
Jason
J
Ward
Mary F
MF
Yang
Huan
H
Wu
Rongqian
R
Jahnen-Dechent
Willi
W
Tracey
Kevin J
KJ
Wang
Ping
P
Sama
Andrew E
AE
D000818:Animals; D001798:Blood Proteins / Q000008:administration & dosage / Q000032:analysis / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000502:physiology; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020768:Middle Cerebral Artery / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D012039:Regional Blood Flow / Q000187:drug effects; D060749:alpha-2-HS-Glycoprotein
C556357:Ahsg protein, mouse; D001798:Blood Proteins; D005456:Fluorescent Dyes; D060749:alpha-2-HS-Glycoprotein; D016650:Fluorescein-5-isothiocyanate