Article Text

AMILORIDE IS NOT NEUROPROTECTIVE WHEN GIVEN AFTER PERINATAL HYPOXIC ISCHAEMIA
  1. T Kato1,
  2. A Bainbridge2,
  3. E DeVita2,
  4. A Kapetaniakis1,
  5. O Iwata1,
  6. S Iwata1,
  7. S Faulkner1,
  8. S Evans1,
  9. F Scaravilli3,
  10. E B Cady2,
  11. N J Robertson1
  1. 1Academic Neonatology, EGA UCL Institute for Women’s Health, University College London, London, UK
  2. 2Department of Medical Physics and Bioengineering, University College London Hospital NHS Foundation Trust, London, UK
  3. 3Division of Neuropathology, Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK

Abstract

Background Brain alkalosis following perinatal hypoxia–ischaemia (HI) is associated with neurodevelopmental outcome. Activation of the Na+/H+ exchanger (NHE) is considered to be responsible for this brain alkalosis. Amiloride, an NHE inhibitor, has been shown to be neuroprotective when admistered before HI in an in-vivo and ex-vivo rodent model.

Aim To determine whether amiloride administered immediately after transient HI ameliorates brain energy decline using magnetic resonance and is neuroprotective in a large animal model.

Methods Eighteen large white male piglets <24 h were randomly assigned to: HI with vehicle or HI with amiloride (3 mg/kg every 8 h). Brain phosphocreatine (PCr), nucleotide triphosphate (NTP), exchangeable phosphate pool (EPP), lactate, N-acetylaspartate, T2 and apparent diffusion coefficient (ADC) data were acquired at T4.7. At 48 h post HI the brain was removed for histological analysis. Data were analysed by fitting a linear mixed model by maximum likelihood.

Results and Conclusion Amiloride did not influence the overall brain pHi or the pHi evolution after HI. Adjusting for the HI severity, there was no effect of amiloride on basal ganglia lactate/N-acetylaspartate increase (p = 0.10), decrease in PCr/EPP (p = 0.28), ADC decline (p = 0.15) or T2 increase (p = 0.98). There was no evidence that amiloride treatment was neuroprotective (all brain regions) (p = 0.63). Half way through the experimental series there was an apparent change in response to a given insult, making a treatment effect difficult to detect.

Conclusions Amiloride administration following HI did not provide neuroprotection in this model of perinatal HI. Brain pHi was not influenced by amiloride; this may be due to suboptimal drug delivery to this region.

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