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

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. Description Inhibition of synaptic LPA-synthesizing enzyme ATX ameliorates stroke outcomes in rodents by reducing LPA-mediated hyperexcitability. Reducing excitation surrounding stroke After stroke, excessive glutamate release from damaged cells contributes to secondary injury in the stroke penumbra. Preserving the penumbra is critical for improving stroke outcome; however, current pharmacological approaches have not been successful. Here, Bitar et al. studied the mechanisms mediating excitotoxicity in the penumbra and showed that autotaxin (ATX) was increased in astrocytes after stroke in mice, and ATX increase was also found in the cerebrospinal fluid of patients after stroke. ATX increase mediated lysophosphatidic acid (LPA)–induced hyperexcitability in rodents, and its inhibition ameliorated stroke outcome, suggesting that the ATX-LPA signaling might be a potential target for treating stroke.