Abstract
The hippocampal cell death that follows kainic acid (KA)-induced seizures is associated with blood–brain barrier (BBB) leakage and oxidative stress. Lipocalin-2 (LCN2) is an iron-trafficking protein which contributes to both oxidative stress and inflammation. However, LCN2′s role in KA-induced hippocampal cell death is not clear. Here, we examine the effect of blocking LCN2 genetically on neuroinflammation and oxidative stress in KA-induced neuronal death. LCN2 deficiency reduced neuronal cell death and BBB leakage in the KA-treated hippocampus. In addition to LCN2 upregulation in the KA-treated hippocampus, circulating LCN2 levels were significantly increased in KA-treated wild-type (WT) mice. In LCN2 knockout mice, we found that the expressions of neutrophil markers myeloperoxidase and neutrophil elastase were decreased compared to their expressions in WT mice following KA treatment. Furthermore, LCN2 deficiency also attenuated KA-induced iron overload and oxidative stress in the hippocampus. These findings indicate that LCN2 may play an important role in iron-related oxidative stress and neuroinflammation in KA-induced hippocampal cell death.
Highlights
Kainic acid (KA) is an analog of the excitatory amino acid transmitter glutamate, and experimental seizures induced by KA are accompanied by neuronal cell death associated with blood–brain barrier (BBB) leakage and oxidative stress [1,2]
Western blot analysis showed that the level of Rab5, an early endosome marker, in WT mice increased in the hippocampus 6 h after KA injection compared to its level in LCN2 (−/−) mice (Figure 1C)
The activation of heme oxygenase-1 (HO-1) in response to brain injury may be based on the induction of genes associated with the antioxidant response factor [22], and we found that KA-induced HO-1 expression was significantly increased at 24 h compared to its expression in LCN2 (−/−) mice (Figure 5F)
Summary
Kainic acid (KA) is an analog of the excitatory amino acid transmitter glutamate, and experimental seizures induced by KA are accompanied by neuronal cell death associated with blood–brain barrier (BBB) leakage and oxidative stress [1,2]. Lipocalin-2 (LCN2), known as neutrophil gelatinase-associated lipocalin, is an acute-phase brain-injury protein produced by the choroid plexus that induces several chemokines to participate in the inflammatory response [11,12] It has additional roles in a variety of processes, including iron-loaded bacterial siderophores, mammalian iron metabolism, anti- and pro-inflammatory responses, and both cell migration and Antioxidants 2021, 10, 100.
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