Abstract
Hypoxic-ischemic (HI) brain injury remains an important cause of brain damage in neonates with potential life-long consequences. Caffeine, which is a competitive inhibitor of adenosine receptors, is commonly used as treatment for preterm apnoea in clinical settings. In the current study, we investigated the effects of caffeine given at 0 h, 6 h, 12 h or 24 h after HI in P10 mouse pups. Open field and rotarod behavioural tests were performed 2 weeks after injury, and brain morphology was then evaluated. Gene expression and immunohistological analyses were assessed in mice 1- and 5-day post-HI. A single dose of caffeine directly after HI resulted in a reduction of the lesion in the grey and white matter, judged by immunostaining of MAP2 and MBP, respectively, compared to PBS-treated controls. In addition, the number of amoeboid microglia and apoptotic cells, the area covered by astrogliosis, and the expression of pro-inflammatory cytokines were significantly decreased. Behavioural assessment after 2 weeks showed increased open-field activity after HI, and this was normalised if caffeine was administered immediately after the injury. Later administrations of caffeine did not change the outcomes when compared to the vehicle group. In conclusion, caffeine only yielded neuroprotection and immunomodulation in a neonatal model of brain hypoxia ischaemia if administered immediately after injury.
Highlights
IntroductionMild hypothermia is currently the only treatment that has proven to improve survival without disability in neonates with moderate (but not severe) hypoxia ischaemia (HI) [3]
Perinatal hypoxia ischaemia (HI) remains a main cause of morbidity and mortality in neonates, the latter accounting for Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.45% of the 5.9 million child deaths that occurred in 2015 globally, with the highest incidence in low-income countries [1]
As previously reported [21, 22], mice subjected to HI showed increased motor activity, indicative of anxiety behaviour and lack of retentiveness, which was instead normalised by early caffeine administration (0 h) to the level of noninjured animals
Summary
Mild hypothermia is currently the only treatment that has proven to improve survival without disability in neonates with moderate (but not severe) HI [3]. This neuroprotective strategy demands intensive care support, and potential side effects have to be considered, especially in low-income settings [4]. Caffeine is the most commonly used psychoactive drug worldwide It is a non-specific adenosine receptor (AR) antagonist and binds to some extent to three of the ARs (named A1, A2a, A2b) with a preference for A1R and A2aR under normal physiological conditions [5]. The A2aR is implicated in neuroinflammation, and its expression in microglial cells is increased after brain injury [7]
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