Inhibition of the enzyme autotaxin reduces cortical excitability and ameliorates the outcome in stroke

• Published in: Science translational medicine Vol. 14; no. 641; p. eabk0135
• Main Authors: Bitar, Lynn, Uphaus, Timo, Thalman, Carine, Muthuraman, Muthuraman, Gyr, Luzia, Ji, Haichao, Domingues, Micaela, Endle, Heiko, Groppa, Sergiu, Steffen, Falk, Koirala, Nabin, Fan, Wei, Ibanez, Laura, Heitsch, Laura, Cruchaga, Carlos, Lee, Jin-Moo, Kloss, Florian, Bittner, Stefan, Nitsch, Robert, Zipp, Frauke, Vogt, Johannes
• Format: Journal Article
• Language: English
• Published: United States 20-04-2022
• Subjects: Animals; Cortical Excitability; Lysophospholipids - pharmacology; Mice; Mice, Transgenic; Phosphoric Diester Hydrolases; Receptors, Lysophosphatidic Acid; Stroke - drug therapy
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.abk0135

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.