Presented at the Neonatal Society 2007 Autumn Meeting.
Aquilina K1, Hobbs C1, Tucker AM1, Whitelaw A2, Thoresen M1
1 Clinical Science at South Bristol, University of Bristol, Bristol, UK
2 Clinical Science at North Bristol, University of Bristol, Bristol, UK
Background and objective: Post-hemorrhagic ventricular dilatation (PHVD) remains a significant problem in preterm infants. No drug or intervention has reduced the need for cerebrospinal fluid (CSF) diversion (ventriculoperitoneal shunt insertion) which has high failure rates in this population. There is considerable evidence implicating transforming growth factor-β (TGF-β) in the pathogenesis of PHVD (1,2). Pirfenidone and losartan reduce expression of TGF-β and decrease post-inflammatory fibrosis in the lungs, kidneys, heart and liver. Both drugs penetrate the CSF well. We hypothesized that, by attenuating the TGF-β response, pirfenidone and losartan would prevent ventricular dilatation.
Method: All experiments were performed in accordance with Home Office regulations. Toxicity studies were performed to determine the maximal doses of pirfenidone and losartan tolerated by neonatal rat pups undergoing intraventricular haemorrhage. 92 rat pups underwent intraventricular injection of blood, under general anaesthesia, on postnatal days 7 and 8 and were randomly allocated to receive pirfenidone, losartan or water by gavage for 14 days using maximum tolerated doses. Neuromotor testing was carried out twice weekly. After sacrifice on day 21, ventricular area was measured on coronal sections using image-analysis software.
Results: 95 % of animals injected with blood developed ventricular dilatation. There was no significant difference in ventricular size or neuromotor performance between animals receiving either drug or water.
Conclusion: Further study is required to identify other potential cytokine targets and to determine how PHVD differs from post-inflammatory fibrosis in other organs.
References
1. Cherian S, Thoresen M, Silver IA, Whitelaw A, Love S. Neuropathol App Neurobiol 2004; 30:585-600
2. Cherian SS, Love S, Silver IA, Porter HJ, Whitelaw AGL, Thoresen M. J Neuropath Exp Neurol 2003; 62:292-303