title: LSKL peptide alleviates subarachnoid fibrosis and hydrocephalus by inhibiting TSP1-mediated TGF-β1 signaling activity following subarachnoid hemorrhage in rats.
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.
authors.affiliation: Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Fan
authors.initials: F
authors.lastname: Liao
authors.affiliation: Department of Oncology, Zhuzhou Central Hospital, Zhuzhou, Hunan 412007, P.R. China.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Zhuzhou Central Hospital, Zhuzhou, Hunan 412007, P.R. China.
authors.forename: Wen
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Yuchun
authors.initials: Y
authors.lastname: Zuo
authors.affiliation: Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Kauthar
authors.initials: K
authors.lastname: Rashid
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92354, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
keywords: LSKL peptide; hydrocephalus; subarachnoid fibrosis; subarachnoid hemorrhage; transforming growth factor-β1