Role of Lipocalin-2 in Brain Injury after Intracerebral Hemorrhage

Abstract

Lipocalin-2 (LCN2) is a siderophore-binding protein involved in cellular iron transport and neuroinflammation. Both iron and inflammation are involved in brain injury after intracerebral hemorrhage (ICH) and this study examined the role of LCN2 in such injury. Male adult C57BL/6 wild-type (WT) or LCN2-deficient (LCN2 − / − ) mice had an intracerebral injection of autologous blood or FeCl 2 . Control animals had a sham operation or saline injection. T2-weighted magnetic resonance imaging and behavioral tests were performed at days 1, 3, 7, 14, and 28 after injection. In WT mice, brain LCN2 levels were increased in the ipsilateral basal ganglia after ICH or iron injection. Lipocalin-2-positive cells were astrocytes, microglia, neurons, and endothelial cells. Intracerebral hemorrhage resulted in a significant increase in ferritin expression in the ipsilateral basal ganglia. Compared with WT mice, ICH caused less ferritin upregulation, microglia activation, brain swelling, brain atrophy, and neurologic deficits in LCN2− / − mice (P o0.05). The size of the lesion induced by FeCl 2 injection as well as the degree of brain swelling and blood-brain barrier disruption were also less in LCN2− / − mice (P o 0.05). These results suggest a role of LCN2 in enhancing brain injury and iron toxicity after ICH.

Role of Lipocalin-2 in Thrombin-Induced Brain Injury

“…Most of the LCN2-positive cells were astrocytes. This finding is consistent with previous reports 9, 11, 19, 20 , although neurons, microglia, and endothelial cells can also express LCN2 12, 21 . Our data also found that thrombin results in a significant neutrophil infiltration which may also contribute to increased brain LCN2 levels (LCN2 is also known as neutrophil gelatinase-associated lipocalin).…”

“…Thrombin and iron are two major factors causing brain damage after ICH 1 . Our data have shown that LCN2 has a role in iron-mediated brain damage 12 . It is still unclear whether LCN2 has a role in thrombin-induced brain damage.…”

“…Imaging was carried out in a 7.0-T Varian MR scanner (183-mm horizontal bore; Varian, Palo Alto, CA) at the University of Michigan 12 . Mice were anesthetized with 2% isoflurane/air mixture throughout MRI examination.…”

“…Brain swelling calculation was based upon seven every other sections whose center was the anterior commissure layer. The value was: volume of (ipsilateral hemisphere- contralateral hemisphere)/volume of contralateral hemisphere×100 % 12, 14 .…”

“…It is an acute phase protein that is up-regulated in a variety of central nervous system injuries 7–11 . Our recent studies have demonstrated that brain LCN2 is upregulated after ICH and that ICH-induced brain injury is much less in LCN2 knockout (KO) mice 12, 13 . Thrombin and iron are two major factors causing brain damage after ICH 1 .…”