Fetal asphyctic preconditioning - an alternative explanation Floris Groenendaal, University Medical Center Utrecht 4 February 2013 Utrecht, February 4, 2013 Dear Sir, With great interest we have read the paper of Vlassaks et al. on neuroprotection by fetal asphyctic preconditioning. The authors conclude that fetal asphyctic preconditioning is neuroprotective through a protective inflammatory phenotype in the brain. However, both IL-6 and IL-10 were elevated in fetuses with asphyctic preconditioning just before perinatal asphyxia, so this presumed protective phenotype is not obvious at first sight. The authors state that IL-10 is an anti-inflammatory cytokine. Perinatal asphyxia (without fetal preconditioning) results in IL-10 elevations at 2h and 6h. After fetal preconditioning and perinatal asphyxia, however, IL-10 is decreased compared to perinatal asphyxia without preconditioning. This is in contrast with the suggestion, that IL-10 is associated with neuroprotection after preconditioning. In similar way, it is not clear whether the authors think that IL-6 expression after perinatal asphyxia and reduction of IL-6 after fetal preconditioning and perinatal asphyxia is contributing to neuroprotection. Furthermore, the authors suggest that the post-ischemic inflammatory neuronal damage is amplified by activation of the STAT signaling pathway and that inhibition of P-STAT is associated with neuroprotection. P-STAT levels are decreased after perinatal asphyxia, but are elevated after fetal preconditioning and perinatal asphyxia at 12h which is in contrast with the previous statement. We think that there is a better explanation for their observations. In the discussion of their paper the authors mention briefly, that fetuses subjected to fetal asphyctic preconditioning have a higher survival chance after perinatal asphyxia. Unfortunately, they do not provide data on the mortality during or after perinatal asphyxia in their model with or without preconditioning. It is very likely that this improved survival is a result of cardiac alterations after fetal preconditioning, since death during or immediately after perinatal asphyxia is due to cardiac failure. Cardiac functioning has not been measured in the experiments of Vlassaks et al., but preserved cardiac output during perinatal asphyxia will definitely have been a key player in the neuroprotection which was observed. By focusing on the brain as the target organ of fetal preconditioning, the authors may have missed the importance of cerebral perfusion in neuronal damage and neuroprotection. Since this may have serious implications for future experimental and clinical neuroprotective strategies, we regret that this aspect has not been discussed in the present manuscript. Floris Groenendaal Cora Nijboer Frank van Bel Reference Vlassaks E, Strackx E, Vles JS, Nikiforou M, Martinez-Martinez P, Kramer BW, Gavilanes AW. Fetal asphyctic preconditioning modulates the acute cytokine response thereby protecting against perinatal asphyxia in neonatal rats. J Neuroinflammation. 2013 Jan 26;10(1):14. [Epub ahead of print] Competing interests No conflicts of interest to be reported.