Role of Lipocalin-2 in Thrombin-Induced Brain Injury

Abstract

Background and Purpose Thrombin and lipocalin-2 (LCN2) contribute to intracerebral hemorrhage-induced brain injury. Thrombin-induced brain damage is partially through a thrombin receptor, protease-activated receptor-1 (PAR-1). LCN2 is involved in cellular iron transport and neuroinflammation. The present study investigated the role of LCN2 in thrombin-induced brain injury. Methods There was three parts in this study. First, male adult C57BL/6 wild type (WT) or LCN2 knockout (LCN2 KO) mice had an intracaudate injection of thrombin (0.4U) or saline. Second, LCN2 KO mice had an injection of thrombin (0.4U) with recombinant mouse LCN2 protein (1µg) into the right caudate. Third, PAR-1 KO or WT mice had an intracaudate injection of thrombin or saline. All mice had T2-weighted magnetic resonance imaging and behavioral tests. Brains were used for histology, immunohistochemistry and Western blotting. Results Intracerebral thrombin injection caused LCN2 upregulation and brain injury in mice. Thrombin-induced brain swelling, blood-brain barrier disruption, neuronal death and neurologic deficits were markedly less in LCN2 KO mice (p<0.05) and were exacerbated by exogenous LCN2 co-injection. In addition, thrombin injection resulted in less LCN2 expression and brain injury in PAR-1 KO mice. Conclusions Thrombin upregulates LCN2 through PAR-1 activation and causes brain damage.

White matter T2 hyperintensities and blood‐brain barrier disruption in the hyperacute stage of subarachnoid hemorrhage in male mice: The role of lipocalin‐2

“…Our current results also demonstrated that LCN2 deletion attenuates the occurrence of T2 hyperintensities, BBB disruption, oligodendrocyte loss, and myelin degradation in the hyperacute (4 hours) phase after SAH. LCN2 deficiency has also been found to reduce BBB disruption and neuroinflammation and oxidative stress at 24 hours after ICH, thrombin induced hydrocephalus and SAH . The exact mechanisms by which LCN2 is involved in BBB disruption, oligodendrocyte injury, and myelin damage are still unclear.…”

“…LCN2 deficiency has also been found to reduce BBB disruption and neuroinflammation and oxidative stress at 24 hours after ICH, thrombin induced hydrocephalus and SAH. 8,21,22 The exact mechanisms by which LCN2 is involved in BBB disruption, oligodendrocyte injury, and myelin damage are still unclear. Some studies on ischemic stroke have proposed a hypoxia-HIF-1α-LCN2vascular endothelial growth factor (VEGF)A axis signaling mechanism.…”

The Neuroprotective Effects of Necrostatin-1 on Subarachnoid Hemorrhage in Rats Are Possibly Mediated by Preventing Blood–Brain Barrier Disruption and RIP3-Mediated Necroptosis

“…All the MRI data were analyzed by an independent researcher using NIH ImageJ software. Brain swelling was measured in images of nine sections as described in a previous publication 31 , and the values were calculated as follows: ((volume of the left hemisphere – volume of the right hemisphere)/volume of the right hemisphere) × 100% 32 . Ventricular volume was determined using the method reported in a previous study 33 and was measured from the frontal horn of the lateral ventricle to the lateral aperture of the fourth ventricle using the formula Σ(A n + A n + 1 ) × d / 2, where A represents the ventricular area and d the distance between sections.…”

Mesenchymal Stem Cells Transplantation in Intracerebral Hemorrhage: Application and Challenges

“…Thrombin, derived from blood after ICH, is an essential component of the coagulation cascade, which has been observed to induce the brain injury through activating the protease-activated receptors (PAR) ( Gao et al, 2014 ; Mao et al, 2016 ). Although thrombin is a proven tissue damage mechanism in ICH, thrombin-activated platelet-rich plasma was reported to provide a higher proliferation rate and MSC marker expression in long-term cultured MSCs ( Kocaoemer et al, 2007 ).…”