Progesterone as a Postnatal Prophylactic Agent for Encephalopathy Caused by Prenatal Hypoxic Ischemic Insult

Abstract

Brain damage caused by hypoxic ischemic insult during the perinatal period causes hypoxic ischemic encephalopathies (HIEs). Therapeutic hypothermia is indicated for HIE, but because the therapeutic burden is large for its limited therapeutic effectiveness, another strategy is needed. Progesterone (P4) plays a neuroprotective role through the actions of its metabolite, allopregnanolone (Allo), on P4 receptor, γ-aminobutyric acid type A receptors or both. We examined the therapeutic potential of P4 using a newborn rat model of HIE. Fetal rats were exposed to transient ischemic hypoxia by 30-minute bilateral uterine artery clamping on gestational day 18. After spontaneous birth, newborn pups were subcutaneously injected with P4 (0.10 or 0.01 mg), medroxyprogesterone acetate (MPA; 0.12 mg), or Allo (0.10 mg) through postnatal days (PDs) 1 to 9. Brain damage in the rats was assessed using the rotarod test at PD50. The HIE insult reduced the rats’ ability in the rotarod task, which was completely reversed by P4 and Allo, but not by MPA. Histological examination revealed that the HIE insult decreased neuronal (the cortex and the hippocampal CA1 region) and oligodendroglial cell density (the corpus callosum) through PD0 to PD50. The axon fiber density and myelin sheath thickness in the corpus callosum were also reduced at PD50. The time-course study revealed that P4 restored oligodendroglial cells by PD5, which was followed by neuroprotective action of P4 that lasted long over the injection period. These results suggest that P4 protects the neonatal brain from HIE insult via restoration of oligodendroglial cells.

Progesterone as a Neuroprotective Agent in Neonatal Hypoxic-Ischaemic Encephalopathy: A Systematic Review

“…Four studies utilized carotid artery ligation as the model of ischaemia. One study utilized transient bilateral uterine artery clamping in the pregnant rats on gestational day 18 as the method of inducing ischaemia [ 49 ]. All but one administered PROG via the IP route.…”

“…Tskitishvili et al [ 48 ]administered either 1.6 or 16 mg/kg of PROG together with various doses of Estradiol (E2) and/or Estetrol (E4) in the relevant experiments in their study. Kawarai et al [ 49 ] administered 0.1 or 0.01 mg/day of loading dose PROG to pregnant Wistar rats. They reported in their paper that 0.1 mg/day of PROG corresponds to 20.0 and 5.0 mg/kg/day on postnatal day (PD) 1 and PD 9, respectively [ 49 ].…”

“…Kawarai et al [ 49 ] administered 0.1 or 0.01 mg/day of loading dose PROG to pregnant Wistar rats. They reported in their paper that 0.1 mg/day of PROG corresponds to 20.0 and 5.0 mg/kg/day on postnatal day (PD) 1 and PD 9, respectively [ 49 ].…”

Protective effect of sex steroid hormones on morphological and cellular outcomes after neonatal hypoxia-ischemia: A meta-analysis of preclinical studies

“…During full-text screening 20 were removed considering the following exclusion criteria: 3 papers do not have the full-text available, 2 papers were not written in English, 6 studies did not use comparable neonatal HI models, 3 studies did not expose animals to sex steroid hormone treatment, 3 studies did not report relevant data considering primary and secondary outcomes and 1 study did not report data. For 2 eligible articles some information was requested from the corresponding authors, however, no response was obtained [22,24]. Thereby, 22 articles were included in the meta-analysis and their main characteristics are described in Table 1.…”

“…Growing evidence suggests that sex steroid hormones affect cellular events following brain insults, causing a neuroprotective effect on both immature and adult brain [16][17][18]. Steroid hormones such as estradiol and progesterone, for example, are able to reduce cell death and DNA fragmentation [19], act as potent antioxidant and anti-in ammatory agents [20,21], prevent white matter injury [22], promote neurogenesis, increase neurotrophic support [23], and improve behavioral function [24][25][26]. Thereby, steroid hormones have shown to reduce infarct volume, mitochondrial and blood-brain barrier dysfunction, brain edema, neuroin ammation, and neurological and sensory-motor de cits [27,28].…”