Blocking TGF- activity and Associated Inflammation May Halt Hydrocephalus

Lee, Philip; Monaco, Edward A. III; Friedlander, Robert M.

doi: 10.1227/01.neu.0000438332.72566.f5
Science Times

    Hydrocephalus is one of the most common neurosurgical problems, and for patients suffering from communicating hydrocephalus, cerebrospinal fluid (CSF) shunting is the usual treatment. Although shunting is an effective treatment and one of the most frequently performed neurosurgical procedures, it continues to be associated with risks such as infection and the all too frequent failure. Therefore, any approach that might limit the development of hydrocephalus would be of tremendous benefit to patients and potentially prevent the inevitably numerous shunt revisions performed annually by neurosurgeons. Recently, a promising study by Botfield, et al. found that inhibition of subarachnoid fibrosis was effective in preventing the development of communicating hydrocephalus (Botfield H, Gonzalez AM, Abdulla O, et al. Decorin prevents the development of juvenile communicating hydrocephalus. Brain. 2013; 136: 2842-2858).

    Intraventricular hemorrhage in premature infants is a well-known etiology for communicating hydrocephalus. One mechanism by which this may occur is via inflammation resulting from the activation of transforming growth factor-β (TGF-β). This TGF-β activation can lead to up-regulation of factors promoting fibroblast proliferation and, ultimately, subarachnoid fibrosis. In turn, these changes impair CSF egress, resulting in communicating hydrocephalus. Botfield et al. hypothesized that inhibition of TGF-β activity could disrupt this cascade of events leading to subarachnoid fibrosis and thereby prevent the development of hydrocephalus. Decorin is a naturally occurring proteoglycan that, amongst other functions, is known to inhibit TGF-β activity. To test their hypothesis, these investigators induced communicating hydrocephalus in juvenile rodents. Using a promising model, kaolin, an aluminum silicate substance, was injected into the basal cisterns. Decorin was then continuously infused for 14 days into the lateral ventricles of a subset of the rodents. Immunohistochemical testing demonstrated that decorin infusion inhibited the TGF-β pathway. Specifically, rodents treated with decorin showed decreased TGF-β staining in the ependyma of the ventricles. Downstream signaling induced by TGF-β was also suppressed, as evidenced by decreased intensity of ependymal phosphorylated Smad2/3 protein staining. This inhibition of the TGF-β was shown to be associated with decreased accumulation of neutrophils, macrophages, and eosinophils in the subarachnoid space, when compared to untreated rodents. These events seemed to be associated with decreased subarachnoid fibrosis, as the decorin group demonstrated meaningfully less laminin and fibronectin deposition in the extracellular matrix. In addition, there was less reactive gliosis in the corpus callosum and periventricular white matter, as demonstrated by decreased levels of GFAP immunostaining. Most importantly, Botfield et al. noted that decorin-mediated inhibition of TGF-β also prevented the development of ventriculomegaly. Conversely, in the absence of decorin treatment, significant ventriculomegaly was triggered by the kaolin injection.

    Taken together, this study by Botfield et al. has important implications for the continued study and treatment of hydrocephalus. First, these researchers confirmed the robustness of this useful model of communicating hydrocephalus by powerfully demonstrating that activation of a TGF-β-mediated cascade resulted in the development of both the characteristic cellular and radiographic changes associated with this condition. Moreover, they established that there are potential ways for inhibiting critical inflammatory pathways that can potentially prevent the development of hydrocephalus. Although further research needs to be done to determine the applicability of this animal model to humans, this study offers hope that there will be non-surgical treatments to prevent the development of this common and often devastating neurosurgical disease.

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