Decorin prevents the development of juvenile communicating hydrocephalus

Abstract

In post-haemorrhagic and other forms of communicating hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-β has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-β antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile communicating hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate-buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-β/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-β1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of hydrocephalus in juvenile rats by blocking transforming growth factor-β-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic communicating hydrocephalus.

Comprehensive Proteomic Characterization of the Human Colorectal Carcinoma Reveals Signature Proteins and Perturbed Pathways

“…TGF-β signaling molecules, including the ligands, receptors, and SMAD1-4, were enriched in CRCs. On the other hand, the TGF-β binding proteins CD109, decorin, dermatopontin, and TGF-β1-induced transcript-1 protein, which are known as negative regulators of cell proliferation1617, were significantly decreased in CRCs.…”

High fibrosis indices in cerebrospinal fluid of patients with shunt-dependent post-traumatic chronic hydrocephalus

“…A recent finding by Botfield demonstrates that decorin can regulate factor- b/ Smad2/3 and its anti-fibrosis effect can delay the development of hydrocephalus [3]. It may also provide evidence for the role of CSF flow pathway fibrosis in the pathogenesis of hydrocephalus.…”

An update on research priorities in hydrocephalus: overview of the third National Institutes of Health-sponsored symposium “Opportunities for Hydrocephalus Research: Pathways to Better Outcomes”

“…If axonal destruction has already occurred, improvements are less likely with shunt placement. Targets of pharmacological interventions aim at reducing CSF production, enhancing CSF flow and absorption, decreasing neuroinflammation, 13,81 providing neuroprotection, and improving recovery/regeneration of damaged tissues. 28,60,78 Recurrent hypoxia-ischemia is common in critically ill preterm infants, but maturation of oligodendrocytes affords increased resistance to this condition.…”

“…In animal models, the reactive astrocytes can be involved in the production of tumor necrosis factor-a (TNFa) that could have a role in hippocampal and neocortical impairment. Thus, TNFa 114 and transforming growth factor-b1 13,51,73,137 may be suitable biomarkers for diagnosis and prognosis in different forms of hydrocephalus.…”