Abstract
Cerebral ischemia, while causing neuronal injury, can activate innate neuroprotective mechanisms, minimizing neuronal death. In this report, we demonstrate that experimental cerebral ischemia/reperfusion injury in the mouse causes upregulation of the secretory protein trefoil factor 3 (TFF3) in the hepatocyte in association with an increase in serum TFF3. Partial hepatectomy (~60% liver resection) immediately following cerebral injury significantly lowered the serum level of TFF3, suggesting a contribution of the liver to the elevation of serum TFF3. Compared to wild-type mice, TFF3-/- mice exhibited a significantly higher activity of caspase 3 and level of cell death in the ischemic cerebral lesion, a larger fraction of cerebral infarcts, and a smaller fraction of the injured cerebral hemisphere, accompanied by severer forelimb motor deficits. Intravenous administration of recombinant TFF3 reversed changes in cerebral injury and forelimb motor function due to TFF3 deficiency. These observations suggest an endocrine neuroprotective mechanism involving TFF3 from the liver in experimental cerebral ischemia/reperfusion injury.
Highlights
Cerebral ischemia, while causing neuronal injury and neurological deficits, can activate innate neuroprotective mechanisms, minimizing neuronal death and improving cerebral function
We demonstrate a novel endocrine neuroprotective mechanism involving the secretory protein trefoil factor 3 (TFF3), which is upregulated in the liver in response to cerebral ischemia/reperfusion injury and released into the circulation, exerting a protective action against irreversible cerebral injury
Cerebral ischemia/reperfusion injury was induced in TFF3-/and background-marched 129S1/SvImJ wild-type mice by ligating the right middle cerebral artery and both common carotid arteries for 1 hr, a modified method based on previous reports [52,53]
Summary
While causing neuronal injury and neurological deficits, can activate innate neuroprotective mechanisms, minimizing neuronal death and improving cerebral function. Recognized neuroprotective factors include, but are not limited to, adenosine [1,2], Gamma-aminobutyric acid (GABA) [1,3,4,5], opioids [6,7], interleukin 1α (IL1α)/IL1β [8], IL6 [9,10,11,12,13], leukemia inhibitory factor (LIF) [12], erythropoietin [14,15], brain-derived neurotrophic factor (BDNF) [16,17], nerve growth factor (NGF) [17], transforming growth factor β (TGFβ) [18,19,20,21,22,23,24], and vascular endothelial growth factor (VEGF) [25] These factors can interact with cognate receptors, activate cell survival signaling networks, and suppress injurious cell signaling events, thereby rescuing neurons from irreversible injury in the ischemic penumbra [1,25,26,27]. We demonstrate a novel endocrine neuroprotective mechanism involving the secretory protein trefoil factor 3 (TFF3), which is upregulated in the liver in response to cerebral ischemia/reperfusion injury and released into the circulation, exerting a protective action against irreversible cerebral injury
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