Show simple item record

dc.contributor.authorBalan, Irina
dc.contributor.authorBeattie, Matthew C.
dc.contributor.authorO’Buckley, Todd K.
dc.date.accessioned2019-03-29T14:42:00Z
dc.date.available2019-03-29T14:42:00Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85061052580&doi=10.1038%2fs41598-018-37409-6&partnerID=40&md5=157e282574c8db2f2476d02ea05e43e0
dc.identifier.urihttp://hdl.handle.net/10713/8571
dc.description.abstractThe endogenous neurosteroid (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone) has protective activity in animal models of alcoholism, depression, traumatic brain injury, schizophrenia, multiple sclerosis, and Alzheimer's disease that is poorly understood. Because these conditions involve proinflammatory signaling through toll-like receptors (TLRs), we examined the effects of 3α,5α-THP, and pregnenolone on TLR4 activation in both the periphery and the central nervous system (CNS). We used monocytes/macrophages (RAW264.7) as a model of peripheral immune signaling and studied innately activated TLR4 in the ventral tegmental area (VTA) of selectively bred alcohol-preferring (P) rats. LPS activated the TLR4 pathway in RAW264.7 cells as evidenced by increased levels of p-TAK1, TRAF6, NF-κB p50, phospho-NF-κB- p65, pCREB, HMGB1, and inflammatory mediators, including MCP-1 and TNFα. Both 3α,5α-THP and pregnenolone (0.5-1.0μM) substantially (~80%) inhibited these effects, indicating pronounced inhibition of TLR4 signaling. The mechanism of inhibition appears to involve blockade of TLR4/MD-2 protein interactions in RAW246.7 cells. In VTA, 3α,5α-THP (15 mg/kg, IP) administration reduced TRAF6 (~20%), CRF (~30%), and MCP-1 (~20%) levels, as well as TLR4 binding to GABA A receptor α2 subunits (~60%) and MyD88 (~40%). The data suggest that inhibition of proinflammatory neuroimmune signaling underlies protective effects of 3α,5α-THP in immune cells and brain, apparently involving blocking of protein-protein interactions that initiate TLR4-dependent signaling. Inhibition of pro-inflammatory TLR4 activation represents a new mechanism of 3α,5α-THP action in the periphery and the brain. © 2019, The Author(s).en_US
dc.description.urihttps://dx.doi.org/10.1038/s41598-018-37409-6en_US
dc.language.isoen_USen_US
dc.publisherNature Publishing Groupen_US
dc.relation.ispartofScientific Reports
dc.subject.meshBraine
dc.subject.meshMacrophagesen_US
dc.subject.meshNeuroimmunomodulationen_US
dc.subject.meshNeurotransmitter Agents--physiologyen_US
dc.subject.meshToll-Like Receptor 4--antagonists & inhibitorsen_US
dc.titleEndogenous Neurosteroid (3α,5α)3-Hydroxypregnan-20-one Inhibits Toll-like-4 Receptor Activation and Pro-inflammatory Signaling in Macrophages and Brainen_US
dc.title.alternativeEndogenous Neurosteroid (3 alpha,5 alpha)3-Hydroxypregnan-20-one Inhibits Toll-like-4 Receptor Activation and Pro-inflammatory Signaling in Macrophages and Brainen_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41598-018-37409-6
dc.identifier.pmid30718548


This item appears in the following Collection(s)

Show simple item record