Abstract
Status epilepticus (a prolonged seizure activity, SE) differently affects vasogenic edema formation and dystrophin-aquaporin 4 (AQP4) expressions between the rat hippocampus and the piriform cortex (PC). In the present study, we explored whether the 67-kDa laminin receptor (LR) expression was relevant to the regional specific susceptibility of vasogenic edema at 3 days after SE. In spite of no difference in expression levels of 67-kDa LR, dystrophin, and AQP4 under physiological conditions, SE-induced serum extravasation was more severe in the PC than the hippocampus. Western blots demonstrated that SE reduced expression levels of 67-kDa LR, dystrophin, and AQP4 in the PC, but not in the hippocampus proper. Immunofluorescent studies revealed that SE increased 67-kDa LR expression in reactive CA1 astrocyte, but reduced it in the PC and the molecular layer of the dentate gyrus due to massive astroglial loss. Furthermore, SE decreased expressions of endothelial 67-kDa LR and SMI-71 (endothelial brain barrier antigen) in these regions. The 67-kDa LR neutralization evoked serum extravasation in these regions of normal animals without astroglial loss. Similar to SE, 67-kDa LR neutralization also reduced dystrophin-AQP4 expressions in the PC more than the total hippocampus. Furthermore, 67-kDa LR IgG infusion increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), but not c-Jun N-terminal kinase, independent of phosphoprotein enriched in astrocytes of 15 kDa (PEA15) activity. Co-treatment of U0126 (an ERK1/2 inhibitor) alleviated vasogenic edema formation and the reduced dystrophin-AQP4 expressions induced by 67-kDa LR neutralization. The 67-kDa LR IgG infusion also increased the susceptibility to SE induction. Therefore, our findings suggested that the cellular specific alterations in 67-kDa LR expression might be involved in the severity of SE-induced vasogenic edema formation in regional specific manners, which might affect the susceptibility to SE induction.
Highlights
Status epilepticus is a neurologic emergency and one of the risk factors of developing acquired epilepsy [1,2]
67-kDa laminin receptor (LR) is expressed in neurons [24], we found that 67-kDa LR in astrocytes modulated aquaporin 4 (AQP4) expression [15]
There was no difference in the expression levels of 67-kDa LR, dystrophin, and AQP4 between the total hippocampus and the piriform cortex (PC) (Figure 1C–F and Supplementary Figure S1)
Summary
Status epilepticus (a prolonged seizure activity, SE) is a neurologic emergency and one of the risk factors of developing acquired epilepsy [1,2]. In addition to neuronal death, SE evokes severe vasogenic edema in the hippocampus and the extrahippocampal limbic systems, including the piriform cortex (PC), due to the blood-brain barrier (BBB) disruption [3,4]. Vasogenic edema is considered as one of the modulating factors for pharmacoresistant temporal lobe epilepsy [6]. The 67-kDa LR plays a role in cell adherence to laminin and stabilizes or modulates the binding of laminin to other receptors [13,14]. Blockade of 67-kDa LR evokes vasogenic edema by activating p38 mitogen-activated protein kinase (p38 MAPK)/vascular endothelial growth factor (VEGF), concomitant with decreasing the expressions of dystrophin-aquaporin 4 (AQP4) complex in the rat piriform cortex (PC) [15]. Since SE differently affects vasogenic edema formation between the hippocampus and the PC [3,4], it is likely that the distinct responses of 67-kDa LR expression would be relevant to the regional specific vasogenic formation in both regions following SE
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