title: Effects of metformin treatment on glioma-induced brain edema.
abstract: Considerable evidence has demonstrated that metformin can activate 5'-AMP-activated protein kinase (AMPK) signaling pathway, which plays a critical role in protection of endothelial cell permeability. Hence, the present study evaluated the effects of metformin on blood brain barrier permeability and AQP4 expression in vitro, and assessed the effects of metformin treatment on tumor-induced brain edema in vivo. Hypoxia or VEGF exposure enhanced bEnd3 endothelial cell monolayer permeability and attenuated the expression of tight junction proteins including Occludin, Claudin-5, ZO-1, and ZO-2. However, 0.5 mM metformin treatment protected bEnd3 endothelial cell monolayer from hypoxia or VEGF-induced permeability, which was correlated with increased expression of tight junction proteins. Furthermore, metformin treatment attenuated AQP4 protein expression in cultured astrocytes. Such an effect involved the activation of AMPK and inhibition of NF-κB. Finally, metformin treatment dose-dependently reduced glioma induced vascular permeability and cerebral edema in vivo in rats. Thus, our results suggested that metformin may protect endothelial cell tight junction, prevent damage to the blood brain barrier induced by brain tumor growth, and alleviate the formation of cerebral edema. Furthermore, since the formation of cytotoxic edema and AQP4 expression was positively correlated, our results indicated that metformin may reduce the formation of cytotoxic edema. However, given that AQP4 plays a key role in the elimination of cerebral edema, attenuation of AQP4 expression by metformin may reduce the elimination of cerebral edema. Hence, future studies will be necessary to dissect the specific mechanisms of metformin underlying the dynamics of tumor-induced brain edema in vivo.
authors.affiliation: The Second Department of Neurosurgery, The Second Hospital of Jilin University Changchun, P. R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: The Second Department of Neurosurgery, The Second Hospital of Jilin University Changchun, P. R. China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The Second Hospital of Hebei Medical University Shijiazhuang, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zheng
authors.affiliation: The Second Department of Neurosurgery, The Second Hospital of Jilin University Changchun, P. R. China.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Wang
authors.affiliation: The Second Department of Neurosurgery, The Second Hospital of Jilin University Changchun, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
keywords: Metformin; aquaporin 4; blood brain barrier; brain edema; glioma; vascular endothelial growth factor