Decorin alleviated chronic hydrocephalus via inhibiting TGF-beta 1/Smad/CTGF pathway after subarachnoid hemorrhage in rats

Chronic hydrocephalus is one of the severe complications after subarachnoid hemorrhage (SAH). However, there is no efficient treatment for the prevention of chronic hydrocephalus, partially due to poor understanding of underlying pathogenesis, subarachnoid fibrosis. Transforming growth factor-beta 1(TGF-beta 1) is a potent fibrogenic factor implicated in wide range of fibrotic diseases. To investigate whether decorin, a natural antagonist for TGF-beta 1, protects against subarachnoid fibrosis and chronic hydrocephalus after SAN, two-hemorrhage-injection SAN model was conducted in 6-week-old rats. Recombinant human decorin(rhDecorin) (30ug/2ul) was administered before blood injection and on the 10th day after SAN. TGF-beta 1, p-Smad2/3, connective tissue growth factor (CTGF), collagen I and pro-collagen I c-terminal propeptide were assessed via western blotting, enzyme-linked immunosotbent assay, radioimmunoassay and immunofluorescence. And neurobehavioral tests and Morris water maze were employed to evaluate long-term neurological functions after SAN. We found that SAN induced heightened activation of TGF-beta 1/Smad/CTGF axis, presenting as a two peak response of TGF-beta 1 in cerebrospinal fluid, elevation of TGF-beta 1, p-Smad2/3, CTGF, collagen I in brain parenchyma and pro-collagen I c-terminal propeptide in cerebrospinal fluid, and increased lateral ventricle index. rhDecorin treatment effectively inhibited up-regulation of TGF-beta 1, p-Smad2/3, CTGF, collagen I and pro-collagen I c-terminal propeptide after SAN. Moreover, rhDecorin treatment significantly reduced lateral ventricular index and incidence of chronic hydrocephalus after SAN. Importantly, rhDecorin improved neurocognitive deficits after SAN. In conclusion, rhDecorin suppresses extracellular matrix accumulation and following subarachnoid fibrosis via inhibiting TGF-beta 1/Smad/CTGF pathway, preventing development of hydrocephalus and attenuating long-term neurocognitive defects after SAN. (C) 2015 Elsevier B.V. All rights reserved.