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Introduction
Subarachnoid hemorrhage (SAH) is a fatal subtype of hemorrhagic stroke associated with significant morbidity and a high mortality rate of up to 50% (1). Hydrocephalus is an independent risk factor for poor outcomes in patients with SAH (2). Blockage of cerebrospinal fluid (CSF) flow and drainage is widely considered to play a vital role in communicating hydrocephalus (3), possibly by inducing subarachnoid fibrosis (4,5). Therefore, to improve long-term neurological outcomes of patients with SAH, it is important to develop new therapies for subarachnoid fibrosis and chronic hydrocephalus.
Antifibrinolytic therapy, commonly used for reducing the rate of further hemorrhage in patients with SAH, has also been reported to be associated with hydrocephalus and delayed brain injury after SAH (6). A previous study by the authors of the present study indicated that transforming growth factor-β1 (TGF-β1), a key fibrogenic factor, is significantly elevated in the CSF after SAH (7), which implies a pivotal role in the development of chronic hydrocephalus (8,9). TGF-β is usually stored in the extracellular matrix by binding to latency-associated peptide (LAP). Thrombospondin-1 (TSP1) converts the latent TGF-β/LAP complex to its active form by binding to LAP, releasing TGF-β, and making it available to bind to and activate the TGF-β receptor (10).
Several previous studies have reported that a small peptide (molecular weight, 458.6 Da), the leucine-serine-lysine-leucine (LSKL) peptide, can inhibit the binding of TSP1 to LAP (11–13) and alleviate renal interstitial fibrosis (12) as well as hepatic fibrosis (13). It remains unclear, however, whether LSKL is protective against subarachnoid fibrosis and chronic hydrocephalus following SAH. Thus, the present study sought to investigate the potential protective role of LSKL in SAH-induced subarachnoid fibrosis, specifically whether it acts via inhibition of TGF-β1 signaling, prevention of chronic hydrocephalus, and improvement in long-term cognitive deficits in a rat model of SAH.
Materials and methods
Animals
All experimental protocols were approved by the Ethics Committee of Central South University (Changsha, China), and all animal procedures were conducted in accordance with the eighth edition of the National Institutes of Health Guide for the Care and Use of Laboratory Animals (2011).
In total, 103 male Sprague-Dawley rats (age, 6 weeks; weight, 160–180 g; Experimental Center of Central South University) were used. These rats were divided into four groups: Sham...