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Do drugs that block transforming growth factor beta reduce posthaemorrhagic ventricular dilatation in a neonatal rat
Kristian Aquilina1, Catherine Hobbs, Alexander Tucker
1Department of Clinical Science at South Bristol, University of Bristol, Bristol, United Kingdom.
Insights
Transforming growth factor-beta (TGF-beta) inhibitors pirfenidone and losartan did not reduce posthaemorrhagic ventricular dilatation (PHVD) in preterm infant rats. Further research is needed to find effective treatments for PHVD.
Area of Science:
- Neonatal neurology
- Pediatric neurosurgery
- Developmental neuroscience
Background:
- Posthaemorrhagic ventricular dilatation (PHVD) is a serious complication in preterm infants following intraventricular hemorrhage (IVH).
- Current treatments for PHVD, such as cerebrospinal fluid (CSF) diversion, do not fully address the underlying pathology.
- Transforming growth factor-beta (TGF-beta) is implicated in PHVD pathogenesis, and its inhibition may offer a therapeutic strategy.
Purpose of the Study:
- To investigate the efficacy of pirfenidone and losartan, TGF-beta inhibitors, in reducing ventricular dilatation in a rat model of PHVD.
- To assess the impact of these drugs on neuromotor function in affected pups.
Main Methods:
- A rat model of intraventricular hemorrhage (IVH) was established by injecting blood into the ventricles of rat pups.
- Pups were randomized to receive pirfenidone, losartan, or water (control) via gavage for 14 days.
- Neuromotor function was assessed, and ventricular area was measured post-mortem.
Main Results:
- 95% of IVH animals developed PHVD.
- Neither pirfenidone nor losartan significantly reduced ventricular size compared to controls.
- Neuromotor testing revealed significantly worse performance in IVH animals, with no improvement observed in drug-treated groups.
Conclusions:
- TGF-beta inhibiting drugs pirfenidone and losartan are ineffective in reducing ventricular dilatation in this PHVD model.
- Further investigation into alternative cytokine targets is necessary for effective PHVD treatment.
- Understanding the differences between PHVD and postinflammatory fibrosis in other organs is crucial for developing targeted therapies.
Aim:
Posthaemorrhagic ventricular dilatation (PHVD) after intraventricular haemorrhage (IVH) remains a significant problem in preterm infants. No treatment has reduced the need for cerebrospinal fluid (CSF) diversion. Considerable evidence implicates transforming growth factor-beta (TGF-beta) in the pathogenesis of PHVD. Pirfenidone and losartan reduce TGF-beta expression and decrease postinflammatory fibrosis in the lungs, kidneys, heart and liver. They have excellent CSF and brain penetration. We hypothesized that administration of pirfenidone or losartan would reduce ventricular dilatation.
Methods:
Ninety-two rat pups underwent intraventricular blood injection on postnatal days (PN) 7 and 8, and were randomised to pirfenidone, losartan or water by gavage for 14 days. Neuromotor testing was carried out twice weekly. After sacrifice at PN21, ventricular area was measured on coronal sections using image-analysis software.
Results:
Ninety-five percent of animals undergoing IVH developed PHVD. Ventricular size was not significantly different between animals receiving either drug or water. Neuromotor testing at PN14 was significantly worse in IVH animals than in controls; neither drug improved performance in IVH animals.
Conclusion:
Drugs that block TGF-beta do not reduce ventricular dilatation in this model. Further study is required to identify other cytokine targets and to determine how PHVD differs from postinflammatory fibrosis in other organs.
