Bitar, Lynn ORCID: 0000-0002-7347-6099, Uphaus, Timo, Thalman, Carine ORCID: 0000-0001-7147-1887, Muthuraman, Muthuraman, Gyr, Luzia, Ji, Haichao, Domingues, Micaela, Endle, Heiko ORCID: 0000-0002-1012-4563, Groppa, Sergiu, Steffen, Falk ORCID: 0000-0003-3708-8600, Koirala, Nabin, Fan, Wei, Ibanez, Laura, Heitsch, Laura, Cruchaga, Carlos ORCID: 0000-0002-0276-2899, Lee, Jin-Moo, Kloss, Florian, Bittner, Stefan ORCID: 0000-0003-2179-3655, Nitsch, Robert, Zipp, Frauke and Vogt, Johannes (2022). Inhibition of the enzyme autotaxin reduces cortical excitability and ameliorates the outcome in stroke. Sci. Transl. Med., 14 (641). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1946-6242

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Abstract

Stroke penumbra injury caused by excess glutamate is an important factor in determining stroke outcome; however, several therapeutic approaches aiming to rescue the penumbra have failed, likely due to unspecific targeting and persistent excitotoxicity, which continued far beyond the primary stroke event. Synaptic lipid signaling can modulate glutamatergic transmission via presynaptic lysophosphatidic acid (LPA) 2 receptors modulated by the LPA- synthesizing molecule autotaxin (ATX) present in astrocytic perisynaptic processes. Here, we detected long-lasting increases in brain ATX concentrations after experimental stroke. In humans, cerebrospinal fluid ATX concentration was increased up to 14 days after stroke. Using astrocyte-specific deletion and pharmacological inhibition of ATX at different time points after experimental stroke, we showed that inhibition of LPA-related cortical excitability improved stroke outcome. In transgenic mice and in individuals expressing a single-nucleotide polymorphism that increased LPA-related glutamatergic transmission, we found dysregulated synaptic LPA signaling and subsequent negative stroke outcome. Moreover, ATX inhibition in the animal model ameliorated stroke outcome, suggesting that this approach might have translational potential for improving the outcome after stroke.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bitar, LynnUNSPECIFIEDorcid.org/0000-0002-7347-6099UNSPECIFIED
Uphaus, TimoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thalman, CarineUNSPECIFIEDorcid.org/0000-0001-7147-1887UNSPECIFIED
Muthuraman, MuthuramanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gyr, LuziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ji, HaichaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Domingues, MicaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Endle, HeikoUNSPECIFIEDorcid.org/0000-0002-1012-4563UNSPECIFIED
Groppa, SergiuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steffen, FalkUNSPECIFIEDorcid.org/0000-0003-3708-8600UNSPECIFIED
Koirala, NabinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fan, WeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ibanez, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heitsch, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cruchaga, CarlosUNSPECIFIEDorcid.org/0000-0002-0276-2899UNSPECIFIED
Lee, Jin-MooUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloss, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bittner, StefanUNSPECIFIEDorcid.org/0000-0003-2179-3655UNSPECIFIED
Nitsch, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zipp, FraukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogt, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-684499
DOI: 10.1126/scitranslmed.abk0135
Journal or Publication Title: Sci. Transl. Med.
Volume: 14
Number: 641
Date: 2022
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 1946-6242
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
LYSOPHOSPHATIDIC ACID; ISCHEMIC-STROKE; CELL-DEATH; MECHANISMS; PRG-1; ASTROCYTES; PLASTICITY; BINDING; BRAIN; SERUMMultiple languages
Cell Biology; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68449

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