Peripheral Administration of Fetuin-A Attenuates Early Cerebral Ischemic Injury in Rats

Abstract

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 2–6 h, peaking around 24–48 h, and returning towards base-line at 72 h post MCAo. When given peripherally, exogenous fetuin-A gained entry across the blood-brain barrier into the ischemic brain tissue, and dose-dependently reduced brain infarct volume at 24 h post 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 is protective against early cerebral ischemic injury partly by attenuating the brain inflammatory response.

Sialylated Fetuin-A as a candidate predictive biomarker for successful grass pollen allergen immunotherapy

“…27,41 In murine models, FetA often mediates protective anti-inflammatory activity, such as against cerebral ischemic injury or lethal sepsis. 42,43 In human pathology the protein is considered either to be a negative or positive acute-phase protein because many inflammatory conditions are associated with either a decrease (eg, trauma, rheumatoid arthritis, infection, kidney disease, hematological malignancies, or myocardial infarction) 25,37,[44][45][46] or an increase (eg, obesity, type 2 diabetes, or ischemic stroke) 25,[47][48][49] in serum FetA levels. Although measurement of FetA levels in the blood is already used as a prognostic marker for some of those conditions, little is known about the significance of its posttranslational modifications.…”

Fetuin-A Regulation of Calcified Matrix Metabolism

“…49,50 Accordingly, the strong fetal expression of fetuin and spermine have been associated with the tolerance of the fetus, "nature's transplant," by mothers. 51 The strong antiinflammatory effects of fetuin were verified in vivo using several models of inflammation, including lipopolysaccharide-induced miscarriage in rats, 52 carrageenan injection, 53 cerebral ischemic injury in rodents, 54 and cecal ligation and puncture in mice. 55 In all cases fetuin-A was associated with reduced inflammatory response and increased survival, and administering additional fetuin generally improved outcome.…”

Peripheral Administration of Human Adrenomedullin and Its Binding Protein Attenuates Stroke-Induced Apoptosis and Brain Injury in Rats

“…Stroke was induced in male adult rats by permanent middle cerebral artery occlusion (MCAO), as described recently by us with minor modification (23). Briefly, rats were anesthetized by isoflurane inhalation, and the ventral neck and groin were shaved and washed with 10% povidone iodine.…”