Decorin alleviated chronic hydrocephalus via inhibiting TGF b1/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 b1(TGF b1) is a potent fibrogenic factor implicated in wide range of fibrotic diseases. To investigate whether decorin, a natural antagonist for TGF b1, protects against subarachnoid fibrosis and chronic hydrocephalus after SAH, two hemorrhage injection SAH 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 SAH. TGF b1, p Smad2/3, connective tissue growth factor (CTGF) collagen I and pro collagen I c terminal propeptide were assessed via western blotting, enzyme linked immunosorbent assay, radioimmunoassay and immunofluorescence. And neurobehavioral tests and Morris water maze were employed to evaluate long term neurological functions after SAH. We found that SAH induced heightened activation of TGF b1/Smad/CTGF axis, presenting as a two peak response of TGF b1 in cerebrospinal fluid, elevation of TGF b1, 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 b1, p Smad2/3, CTGF, collagen I and pro collagen I c terminal propeptide after SAH. Moreover, rhDecorin treatment significantly reduced lateral ventricular index and incidence of chronic hydrocephalus after SAH. Importantly, rhDecorin improved neurocognitive deficits after SAH. In conclusion, rhDecorin suppresses extracellular matrix accumulation and following subarachnoid fibrosis via inhibiting TGF b1/Smad/CTGF pathway, preventing development of hydrocephalus and attenuating long term neurocognitive defects after SAH.
Brain Research