Abstract
Ischemic reperfusion (IR) during the perinatal period is a known causative factor of fetal brain damage. So far, both morphologic and histologic evidence has shown that fetal brain damage can be observed only several hours to days after an IR insult has occurred. Therefore, to prevent fetal brain damage under these circumstances, a more detailed understanding of the underlying molecular mechanisms involved during an acute response to IR is necessary. In the present work, pregnant mice were exposed to IR on day 18 of gestation by clipping one side of the maternal uterine horn. Simultaneous fetal electrocardiography was performed during the procedure to verify that conditions resulting in fetal brain damage were met. Fetal brain sampling within 30 minutes after IR insult revealed molecular evidence that a fetal response was indeed triggered in the form of inhibition of the Akt-mTOR-S6 synthesis pathway. Interestingly, significant changes in mRNA levels for both HIF-1α and p53 were apparent and gene regulation patterns were observed to switch from a HIF-1α-dependent to a p53-dependent process. Moreover, pre-treatment with pifithrin-α, a p53 inhibitor, inhibited protein synthesis almost completely, revealing the possibility of preventing fetal brain damage by prophylactic pifithrin-α treatment.
Highlights
During the late stages of development, HIF-1a is known to play a central role in brain development, along with down-regulation of both P53 protein and mRNA [1,2,3] around the same time
Molecular confirmation revealed the acute response to Ischemic reperfusion (IR) in fetal brains
Successful IR was confirmed by fetal electrocardiography (FECG) in the clipped side (Figure 1B, 1C and Supporting Information S2)
Summary
During the late stages of development, HIF-1a is known to play a central role in brain development, along with down-regulation of both P53 protein and mRNA [1,2,3] around the same time. HIF-1a and P53 have established antagonistic responses to Ischemic reperfusion (IR) and their overall balance gives us a glimpse of the underlying ongoing homeostatic process [4,5,6,7]. Berger and Ganier have attributed fetal ischemic reperfusion to intrauterine asphyxia during the perinatal period [8,9]. In the course of IR, mediators such as hypoxanthine, oxygen free radicals and cytokines are observed to accumulate [10,11,12,13], resulting in fetal brain injuries such as hypoxia ischemic encephalopathy and cerebral palsy [14]. An example of which is the appearance of IL-1b mRNA within 15 minutes of cerebral ischemia [8,9]
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