Effects of progesterone on the neonatal brain following hypoxia-ischemia

Abstract

Progesterone displays a strong potential for the treatment of neonatal hypoxic-ischemic encephalopathy since it has been shown to be beneficial in the treatment of the central nervous system injuries in adult animals. Here, we evaluated the effects of the administration of progesterone (10 mg/kg) in seven-days-old male Wistar rats submitted to neonatal hypoxia-ischemia (HI). Progesterone was administered immediately before ischemia and/or 6 and 24 h after the onset of hypoxia. The body weight of the animals, the volume of brain lesion and the expression of p-Akt and procaspase-3 in the hippocampus were evaluated. All animals submitted to HI showed a reduction in the body weight. However, this reduction was more remarkable in those animals which received progesterone before surgery. Administration of progesterone was unable to reduce the volume of brain damage caused by HI. Moreover, no significant differences were observed in the expression of p-Akt and procaspase-3 in animals submitted to HI and treated with either progesterone or vehicle. In summary, progesterone did not show a neuroprotective effect on the volume of brain lesion in neonatal rats submitted to hypoxia-ischemia. Furthermore, progesterone was unable to modulate p-Akt and procaspase-3 signaling pathways, which may explain the absence of neuroprotection. On the other hand, it seems that administration of progesterone before ischemia exerts some systemic effect, leading to a remarkable reduction in the body weight.

Long-Lasting Actions of Progesterone Protect the Neonatal Brain Following Hypoxia-Ischemia

“…PROG (Sigma) was dissolved in 22.5% cyclodextrin (2-hydroxypropyl-β-cyclodextrin) and administered at a dose of 10 mg/kg of body weight (at a concentration of 5 mg/ml). Animals were assigned to five experimental groups depending on the schedule of PROG and/or vehicle (cyclodextrin) administration, according to our previous paper (Fabres et al 2018) (see Fig. 1 for details): SHAM, HI, HI + PROG-BEFORE (BEF), HI + PROG-AFTER (AFT), HI + PROG-BEFORE/AFTER (BA).…”

“…Second and third injections were administered 6 h e 24 h after the beginning of hypoxia, respectively. Animals were assigned to five experimental groups (lower panel) depending on the schedule of PROG and/or vehicle administration, according to our previous paper (Fabres et al 2018): SHAM, HI, HI + PROG-BEFORE (BEF), HI + PROG-AFTER (AFT), HI + PROG-BEFORE/ AFTER (BA). SHAM group was used as a control group and injected only with vehicle.…”

“…One-week post-injury period was chosen because it encompasses brain damage due to all mechanisms of injury (Teo et al 2015). Notwithstanding we did not observe any neuroprotective effect of PROG 24 h following HI (Fabres et al 2018), PROG neuroprotective effects had already been demonstrated when neonatal animals submitted to HI reach adulthood (Peterson et al 2015).…”

“…A neuroprotective role of PROG has already been shown in several studies of lesions in the adult central nervous system (for review see Deutsch et al 2013), including stroke (for review see Guennoun et al 2019). On the other hand, just a few studies using PROG have been performed in animal models of neonatal HI; still, results are controversial (Tsuji et al 2012;Wang et al 2013;Li et al 2014bLi et al , 2015Peterson et al 2015;Fabres et al 2018).…”

Die Sexualsteroide Östradiol und Progesteron – eine neue Therapieoption für Frühgeborene?

“…Bei der hypoxisch-ischämischen Enzephalopathie des Neugeborenen könnte die Aufrechterhaltung der hohen E 2 -Plasmakonzentrationen neuroprotektiv sein [46]. Für P finden sich diesbezüglich uneinheitliche Effekte [47,48]. Möglicherweise würde eine kombinierte E 2 -und P-Substitution additive neuroprotektive Effekte zeigen.…”