Endotoxin Increases Sleep and Brain Allopregnanolone Concentrations in Newborn Lambs

Abstract

Infection has been identified as a risk factor for sudden infant death syndrome (SIDS). Synthesis of allopregnanolone, a neuroactive steroid with potent sedative properties, is increased in response to stress. In this study, we investigated the effect of endotoxin (lipopolysaccharide, LPS) on brain and plasma allopregnanolone concentrations and behavior in newborn lambs. LPS was given intravenously (0.7 g/kg) at 12 and 15 d of age (n ϭ 7), and resulted in a biphasic febrile response (p Ͻ 0.001), hypoglycemia, lactic acidemia (p Ͻ 0.05), a reduction in the incidence of wakefulness, and increased nonrapid eye movement sleep and drowsiness (p Ͻ 0.05) compared with saline-treated lambs (n ϭ 5). Plasma allopregnanolone and cortisol were significantly (p Ͻ 0.05) increased after LPS treatment. These responses to LPS lasted 6 -8 h, and were similar at 12 and 15 d of age. Each lamb was then given LPS at 20 d of age and killed 3 h posttreatment to obtain samples of the brain. Allopregnanolone concentrations were increased (p Ͻ 0.05) in all brain areas except the cerebellum and diencephalon. We suggest that LPS-induced increase of allopregnanolone in the brain may contribute to somnolence in the newborn, and may be responsible for the reduced arousal thought to contribute to the risk of SIDS in human infants. Infection is a stress often faced by neonates and has been proposed as a risk factor in SIDS. The potential mechanism(s) by which infection could increase susceptibility to SIDS remain unclear. It is likely, however, that a SIDS death results from the coincidence of a number of events that together create a period of increased risk (1). We propose that one of the mechanisms involved is the increased production of sedative neuroactive steroids in response to infection, and that these steroids contribute to the lethargy and increased sleep associated with infection in neonates.The pathology of infection and its effects on sleep-wake states has been extensively studied (2-4). Together with fever and other "acute phase" changes (such as increased cytokine production and cortisol levels), increased somnolence is one of the cardinal responses to infection in adults. Several components of the body's response to infection, including increased production of cytokines and prostaglandins, have been shown to induce sleep. Muramyl peptides and LPS associated with the cell wall of bacteria have also been shown to be somnifacient (5, 6). Although sleepiness may have an adaptive role that promotes rest and conserves energy, the combination of infection and somnolence in the newborn, with its high metabolic rate and low pulmonary oxygen stores, may increase the susceptibility of the infant to episodes of periodic breathing, sleep-associated apnea, and SIDS by ablating essential cardiorespiratory responses to hypoxia and asphyxia.Neuroactive steroids are a group of steroids that influence CNS function and, in the adult, can be produced in the brain from cholesterol, or in peripheral organs such as the adrenal cortex and gonads. Progest...

Increased allopregnanolone levels in the fetal sheep brain following umbilical cord occlusion

“…The rise in AP concentrations following the asphyxia challenge is consistent with our previous finding of responses to hypoxic stress in newborn lambs (Billiards et al 2002) and of others of responses to stress in adult animals (Barbaccia et al 1996). We previously found that lambs of 10–26 days postnatal age subjected to 2 h of hypoxia displayed a dramatic elevation in brain AP content within 1 h (Billiards et al 2002), while 1 min of CO 2 inhalation in adult rats has been shown to cause an increase in AP within 30 min in the brain (Barbaccia et al 1994). Furthermore, brain and spinal cord injury has also been shown to result in the accumulation of neurosteroids, including AP around the focal point of injury (Di Michele et al 2000).…”

“…The finding that plasma AP and one of its important precursors, pregnenolone, did not change following UCO, in contrast to the changes seen in the brain extracellular fluid, supports the contention that mechanisms within the brain are primarily responsible for the rise in AP concentrations following UCO. Our previous findings with neonates (Billiards et al 2002) and in the fetus (Nguyen et al 2004) suggest that adrenal synthesis contributes to plasma AP concentrations. The present observations suggest that these mechanisms do not contribute to the changes seen immediately after an asphyxial challenge.…”

5α-reduced progestogens ameliorate mood-related behavioral pathology, neurotoxicity, and microgliosis associated with exposure to HIV-1 Tat

“…Progesterone can attenuate microglial activation, microgliosis, astrogliosis, and can suppress cytokine release (Labombarda et al, 2011; Munroe, 1971; Robinson & Klein, 2012). Unlike progesterone, AlloP is a potent, positive allosteric modulator of GABA A receptors (Majewska et al, 1986; Paul & Purdy, 1992), a potential negative allosteric modulator of NMDA receptors (Johansson & Le Grevès, 2005; Maurice et al, 2006), is produced in response to immune challenge (Billiards et al, 2002; Ghezzi et al, 2000), and can reduce excitotoxicity partly through rapid increases of tonic inhibition in models of CNS insult (Baulieu & Schumacher, 2000; Brunton et al, 2014; Mellon et al, 2008; Sayeed & Stein, 2009). Allopregnanolone is produced rapidly in response to stress challenges to restore sympathetic and parasympathetic tone (Barbaccia et al, 1996; Patchev et al, 1994, 1996), functions which are observed to be dysregulated among some HIV + individuals (Chittiprol et al, 2007, 2008; Hurwitz et al, 2005).…”

Increased anxiety‐like phenotype in female guinea pigs following reduced neurosteroid exposure in utero

“…Plasma was treated with 1% acetic acid and 50% methanol and homogenised before being added to Sep‐Pak 18 cartridges. The extracts were treated 5% in potassium permanganate in water to reduce cross‐reactivity of progesterone in samples, before re‐extraction with 50%v/v diethyl‐ether/n‐hexane (Billiards et al, 2002). Concentrations of allopregnanolone were quantified using polyclonal antibody to allopregnanolone (Agrisera, Sapphire Bioscience, Vannas, Sweden), and tritium‐labelled allopregnanolone tracer (5α‐[9,11, 12, 3 H(N)]; PerkinElmer Life and Analytical Sciences, Boston, MA, USA) as previously described (Bennett et al, 2015).…”