Golexanolone, a GABAA receptor modulating steroid antagonist, restores motor coordination and cognitive function in hyperammonemic rats by dual effects on peripheral inflammation and neuroinflammation

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Golexanolone, a GABAA receptor modulating steroid antagonist, restores motor coordination and cognitive function in hyperammonemic rats by dual effects on peripheral inflammation and neuroinflammation

Mincheva, Gergana (författare): Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain

Gimenez-Garzo, Carla (författare): Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain

Izquierdo-Altarejos, Paula (författare): Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain

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Martinez-Garcia, Mar (författare): Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain

Doverskog, Magnus (författare): Umecrine Cognition AB, Solna, Sweden

Blackburn, Thomas P. (författare): Umecrine Cognition AB, Solna, Sweden

Hällgren, Anneli (författare): Umecrine Cognition AB, Solna, Sweden

Bäckström, Torbjörn (författare): Umeå universitet,Obstetrik och gynekologi,Umecrine Cognition AB, Solna, Sweden

Llansola, Marta (författare): Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain

Felipo, Vicente (författare): Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain

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2022-07-26
2022
Engelska.
Ingår i: CNS Neuroscience & Therapeutics. - : John Wiley & Sons. - 1755-5930 .- 1755-5949. ; 28:11, s. 1861-1874

Relaterad länk:: https://doi.org/10.1...; visa fler...; https://umu.diva-por... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.1...; visa färre...

Tidskriftsartikel (refereegranskat)

Abstract Ämnesord

Stäng

Aims: Hyperammonemic rats show peripheral inflammation, increased GABAergic neurotransmission and neuroinflammation in cerebellum and hippocampus which induce motor incoordination and cognitive impairment. Neuroinflammation enhances GABAergic neurotransmission in cerebellum by enhancing the TNFR1-glutaminase-GAT3 and TNFR1-CCL2-TrkB-KCC2 pathways. Golexanolone reduces GABAA receptors potentiation by allopregnanolone. This work aimed to assess if treatment of hyperammonemic rats with golexanolone reduces peripheral inflammation and neuroinflammation and restores cognitive and motor function and to analyze underlying mechanisms.Methods: Rats were treated with golexanolone and effects on peripheral inflammation, neuroinflammation, TNFR1-glutaminase-GAT3 and TNFR1-CCL2-TrkB-KCC2 pathways, and cognitive and motor function were analyzed.Results: Hyperammonemic rats show increased TNFα and reduced IL-10 in plasma, microglia and astrocytes activation in cerebellum and hippocampus, and impaired motor coordination and spatial and short-term memories. Treating hyperammonemic rats with golexanolone reversed changes in peripheral inflammation, microglia and astrocytes activation and restored motor coordination and spatial and short-term memory. This was associated with reversal of the hyperammonemia-enhanced activation in cerebellum of the TNFR1-glutaminase-GAT3 and TNFR1-CCL2-TrkB-KCC2 pathways.Conclusion: Reducing GABAA receptors activation with golexanolone reduces peripheral inflammation and neuroinflammation and improves cognitive and motor function in hyperammonemic rats. The effects identified would also occur in patients with hepatic encephalopathy and, likely, in other pathologies associated with neuroinflammation.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)

Nyckelord

GR3027
inflammation
minimal hepatic encephalopathy
motor incoordination
spatial memory

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Av författaren/redakt...: Mincheva, Gergan ...; Gimenez-Garzo, C ...; Izquierdo-Altare ...; Martinez-Garcia, ...; Doverskog, Magnu ...; Blackburn, Thoma ...; visa fler...; Hällgren, Anneli; Bäckström, Torbj ...; Llansola, Marta; Felipo, Vicente; visa färre...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Neurologi

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Av lärosätet: Umeå universitet

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