Allopregnanolone in the brain: protecting pregnancy and birth outcomes

• Published in: Progress in neurobiology Vol. 113; pp. 106 - 136
• Main Authors: Brunton, Paula J, Russell, John A, Hirst, Jonathan J
• Format: Journal Article
• Language: English
• Published: England 01.02.2014
• Subjects: Animals; Brain - metabolism; Female; Fetus - metabolism; Humans; Pregnancy; Pregnancy Outcome; Pregnanolone - metabolism; vasopressin receptor type 1b; PR; glucocorticoid receptor; eCB; 3αHSD; neuropeptide Y; ACTH; PVN; pENK-A; OTR; adrenocorticotropic hormone; PRP; MPOA; central nucleus of the amygdala; PNS; AgRP; hypothalamo-pituitary-adrenal; MC-2; opioid receptor-like receptor; nitric oxide; 5α-Reductase; Hypothalamo-pituitary-adrenal axis; MR; nucleus tractus solitarii; pro-opiomelanocortin; V1b; gamma-aminobutyric acid; medial preoptic area; mineralocorticoid receptor; myelin basic protein; IL-1β; pPVN; ER; ORL1; cannabinoid receptor type 1; CB1; 3α-hydroxysteroid dehydrogenase; dihydroprogesterone; IUGR; nNOS; CRH; GABA; HPA; Endogenous opioids; MAP-2; AVP; melanocortin-2; paraventricular nucleus; NO; cyclic guanosine monophosphate; microtubular associated protein-2; parvocellular subdivision of the paraventricular nucleus; cholecystokinin; oxytocin receptor; cGMP; CRH-R1; corticotropin releasing hormone receptor type 1; Gestation; corticotropin releasing hormone receptor type 2; NTS; magnocellular neurones; CRH-R2; DHP; progesterone receptor; corticotropin releasing hormone; interleukin-1β; GABA(A) receptor; NPY; intrauterine growth restriction; intracerebroventricular; MBP; MCNs; estrogen receptor; neuronal nitric oxide synthase; prenatally stressed; CCK; GR; POMC; depolarising after-potential; DAP; arginine vasopressin; agouti-related peptide; i.c.v; proenkephalin-A; endocannabinoids; DA; dopamine; prolactin releasing peptide; CeA
• ISSN: 0301-0082; 1873-5118
• DOI: 10.1016/j.pneurobio.2013.08.005

A successful pregnancy requires multiple adaptations in the mother's brain that serve to optimise foetal growth and development, protect the foetus from adverse prenatal programming and prevent premature delivery of the young. Pregnancy hormones induce, organise and maintain many of these adaptations. Steroid hormones play a critical role and of particular importance is the progesterone metabolite and neurosteroid, allopregnanolone. Allopregnanolone is produced in increasing amounts during pregnancy both in the periphery and in the maternal and foetal brain. This review critically examines a role for allopregnanolone in both the maternal and foetal brain during pregnancy and development in protecting pregnancy and birth outcomes, with particular emphasis on its role in relation to stress exposure at this time. Late pregnancy is associated with suppressed stress responses. Thus, we begin by considering what is known about the central mechanisms in the maternal brain, induced by allopregnanolone, that protect the foetus(es) from exposure to harmful levels of maternal glucocorticoids as a result of stress during pregnancy. Next we discuss the central mechanisms that prevent premature secretion of oxytocin and consider a role for allopregnanolone in minimising the risk of preterm birth. Allopregnanolone also plays a key role in the foetal brain, where it promotes development and is neuroprotective. Hence we review the evidence about disruption to neurosteroid production in pregnancy, through prenatal stress or other insults, and the immediate and long-term adverse consequences for the offspring. Finally we address whether progesterone or allopregnanolone treatment can rescue some of these deficits in the offspring.