Allopregnanolone and its antagonist modulate neuroinflammation and neurological impairment

Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation...

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Vydané v:Neuroscience and biobehavioral reviews Ročník 161; s. 105668
Hlavní autori: Bäckström, Torbjörn, Doverskog, Magnus, Blackburn, Thomas P., Scharschmidt, Bruce F., Felipo, Vicente
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Elsevier Ltd 01.06.2024
Predmet:
Animals
Astrocytes
Astrocytes - drug effects
Astrocytes - metabolism
Cognitive disorders
GABA-A receptor
GABA-A Receptor Antagonists - pharmacology
Humans
Microglia
Microglia - drug effects
Microglia - metabolism
Neuroinflammation
Neuroinflammatory Diseases - drug therapy
Neuroinflammatory Diseases - metabolism
Pregnanolone - metabolism
Pregnanolone - pharmacology
Steroid-PAMs
NO
PCS
Steroid-PAM
AMPA
KCC2
GAMSA
Cl
Steroid-PAMs
Cognitive disorders
BDL
PFC
TNF
LPS
PBC
GR 3027
GABA-A
NMDA
TSPO
NKCC1
SN
GABA-AR
IL
BDNF
THDOC
Astrocytes
LID
MS
EAE
Neuroinflammation
GABA-A receptor
Microglia
ALLO
PTBR
TGR5
PD
ROS
3α5α20α-HHP
MAO
HE
NK
ISSN:0149-7634, 1873-7528, 1873-7528
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Popis
Shrnutí:Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation and their levels in the brain may vary because of increased or decreased local production or import from the systemic circulation. The increased synthesis of steroid-PAMs is possibly due to increased expression of the mitochondrial cholesterol transporting protein (TSPO) in neuroinflammatory tissue, and reduced production may be due to changes in the enzymatic activity. Microglia and astrocytes play an important role in neuroinflammation, and their production of inflammatory mediators can be both activated and inhibited by steroid-PAMs and GABA. What is surprising is the finding that both allopregnanolone, a steroid-PAM, and golexanolone, a novel GABA-A receptor modulating steroid antagonist (GAMSA), can inhibit microglia and astrocyte activation and normalize their function. This review focuses on the role of steroid-PAMs in neuroinflammation and their importance in new therapeutic approaches to CNS and liver disease. •Positive steroid Allosteric GABAA Modulators and antagonists influences neuroinflammation.•Local steroid-PAM concentrations are enhanced by increased expression of Transporter protein TSPO.•Steroid-PAM and a GABA-A receptor modulating steroid antagonist golexanolone dampens neuroinflammation.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
ObjectType-Review-3
content type line 23
ISSN:0149-7634
1873-7528
1873-7528
DOI:10.1016/j.neubiorev.2024.105668