Blockade of 67-kDa Laminin Receptor Facilitates AQP4 Down-Regulation and BBB Disruption via ERK1/2-and p38 MAPK-Mediated PI3K/AKT Activations

Abstract

Recently, we have reported that dysfunctions of 67-kDa laminin receptor (67LR) induced by status epilepticus (SE, a prolonged seizure activity) and 67LR neutralization are involved in vasogenic edema formation, accompanied by the reduced aquaporin 4 (AQP4, an astroglial specific water channel) expression in the rat piriform cortex (PC). In the present study, we found that the blockade of 67LR activated p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways, which enhanced phosphatidylinositol 3 kinase (PI3K)/AKT phosphorylations in endothelial cells and astrocytes, respectively. 67LR-p38 MAPK-PI3K-AKT activation in endothelial cells increased vascular permeability. In contrast, 67LR-ERK1/2-PI3K-AKT signaling pathways in astrocytes regulated astroglial viability and AQP4 expression. These findings indicate that PI3K/AKT may integrate p38 MAPK and ERK1/2 signaling pathways to regulate AQP4 expression when 67LR functionality is reduced. Thus, we suggest that 67LR-p38 MAPK/ERK1/2-PI3K-AKT-AQP4 signaling cascades may mediate serum extravasation and AQP4 expression in astroglio-vascular systems, which is one of the considerable therapeutic targets for vasogenic edema in various neurological diseases.

Epigallocatechin-3-Gallate and PEDF 335 Peptide, 67LR Activators, Attenuate Vasogenic Edema, and Astroglial Degeneration Following Status Epilepticus

“…The blockade of 67LR functionality increases p38 MAPK and ERK1/2 activities [ 20 , 21 , 22 , 23 ]. Thus, we explored the effects of EGCG and NU335 on their phosphorylations (activities).…”

“…p38 MAPK-mediated PI3K/AKT activations are involved in SE-induced serum extravasation [ 39 , 40 ]. In addition, PI3K and ERK1/2 reciprocally regulate each other [ 23 , 41 , 42 , 43 ]. Indeed, ERK1/2-mediated AKT phosphorylation downregulates AQP4 expression in astrocytes [ 44 ].…”

“…The time of seizure onset was defined as the time point showing paroxysmal discharges (4–10 Hz with 2 times higher amplitude than the basal level) that lasted more than 3 seconds. Spectrograms were also automatically calibrated using a Hanning sliding window with 50% overlap [ 21 , 22 , 23 ].…”

“…The areas showing vasogenic edema and glial fibrillary acidic protein (GFAP, an astroglial marker) deletion (10 sections per each animal) were measured using AxioVision Rel. 4.8 software (Carl Zeiss Korea, Seoul, Korea) [ 23 , 36 , 37 , 38 ]. To quantify fluorescent intensity, sections (10 sections per each animal) were captured using an AxioImage M2 microscope.…”

“…Recently, we have reported that SE decreases 67LR expression concomitant with BBB breakdown in the rat piriform cortex (PC). Similar to SE, 67LR neutralization evokes vasogenic edema by reducing aquaporin 4 (AQP4) expression and increasing p38 MAPK/vascular endothelial growth factor (VEGF) activities in the PC [ 21 , 22 , 23 ]. Therefore, it is likely that 67LR may play an important role in the maintenance of BBB integrity.…”