LSKL peptide alleviates subarachnoid fibrosis and hydrocephalus by inhibiting TSP1-mediated TGF-β1 signaling activity following subarachnoid hemorrhage in rats

Liao,Fan; Li,Gaofeng; Yuan,Wen; Chen,Yujie; Zuo,Yuchun; Rashid,Kauthar; Zhang,John   H.; Feng,Hua; Liu,Fei

doi:10.3892/etm.2016.3640

LSKL peptide alleviates subarachnoid fibrosis and hydrocephalus by inhibiting TSP1-mediated TGF-β1 signaling activity following subarachnoid hemorrhage in rats

Authors:
- Fan Liao
- Gaofeng Li
- Wen Yuan
- Yujie Chen
- Yuchun Zuo
- Kauthar Rashid
- John H. Zhang
- Hua Feng
- Fei Liu
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Affiliations: Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China, Department of Oncology, Zhuzhou Central Hospital, Zhuzhou, Hunan 412007, P.R. China, Department of Neurosurgery, Zhuzhou Central Hospital, Zhuzhou, Hunan 412007, P.R. China, Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China, Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92354, USA
Published online on: August 31, 2016 https://doi.org/10.3892/etm.2016.3640
Pages: 2537-2543
Copyright: © Liao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hydrocephalus has been demonstrated to be an independent risk factor for poor outcomes in patients with subarachnoid hemorrhage (SAH). Blockage of cerebrospinal fluid (CSF) flow and drainage is widely considered to play a vital role in communicating hydrocephalus, possibly due to subarachnoid fibrosis. A previous study indicated that transforming growth factor‑β1 (TGF‑β1), a key fibrogenic factor, is significantly increased in the CSF following SAH, implying a pivotal role in the development of chronic hydrocephalus. To investigate whether LSKL peptide, a small molecular peptide and competitive antagonist for TGF‑β1, protects against subarachnoid fibrosis and hydrocephalus after SAH, a two‑hemorrhage injection model of SAH was created in Sprague‑Dawley rats. LSKL (1 mg/kg) was administered intraperitoneally immediately following the first intravenous injection of blood in the SAH model, with repeated injections of LSKL every 12 h until sacrifice. Thrombospondin‑1 (TSP1), TGF‑β1, p‑Smad2/3, collagen I and pro‑collagen I c‑terminal propeptide levels were assessed via western blotting and ELISA. Lateral ventricular index, Masson staining and Morris water maze tests were employed to evaluate subarachnoid fibrosis, hydrocephalus and long‑term neurological function following SAH. It was found that the LKSL peptide readily crossed the blood brain barrier, was protective against subarachnoid fibrosis, attenuated ventriculomegaly and effectively suppressed hydrocephalus. In addition, the results indicated that the protective effects of the LSKL peptide were achieved via the inhibition of TGF‑β1 activity and subsequent Smad2/3 signaling. Importantly, the LSKL peptide may improve long‑term neurocognitive deficits after SAH. In conclusion, the LSKL peptide suppresses subarachnoid fibrosis via inhibition of TSP1‑mediated TGF‑β1 activity, prevents the development of chronic hydrocephalus and improves long‑term neurocognitive defects following SAH.

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