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

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.

Strict blood pressure control following thrombectomy is associated with neuronal injury and poor functional outcome

“…To conclude, neuronal survival in stroke patients seems to be dependent on a fine‐tuned balance of factors influencing neuronal activity 8,9,19 . Our findings suggest that strict adherence to BP targets ≤160/90 mmHg within the first 24 h following successful recanalization of LVO by MT is associated with worse functional outcome.…”

“…To conclude, neuronal survival in stroke patients seems to be dependent on a fine-tuned balance of factors influencing neuronal activity. 8,9,19 Our findings suggest that strict adherence to BP targets ≤160/90 mmHg within the first 24 h following successful recanalization of LVO by MT is associated with worse functional outcome. We suggest that this might be attributable to hypotensioninduced neuronal loss, as is suggested by increased sNfL levels in these patients and the observed independent association of sNfL with minimum MAP values.…”

Plasma Proteomics of Genetic Brain Arteriosclerosis and Dementia Syndrome Identifies Signatures of Fibrosis, Angiogenesis, and Metabolic Alterations

“…ENPP2 is an abundantly expressed member of the ectonucleotide pyrophosphatase/phosphodiesterase family with lysophospholipase activity, catalyzing lysophosphatidic acid (LPA) formation ( 71 ). Despite mounting evidence for an excitotoxic potential in acute stroke ( 72 ), other studies have noted potentially beneficial effects in oligodendrocyte maturation ( 73 ), protection of endothelial cells from hypoxia ( 74 ) and suppression of CD8+ T cell infiltration in tumors ( 75 ). These results suggest that ENP22 might confer protection in chronic, but not acute injury, and thus its depletion could reflect long-term changes in CADASIL rather than the effects of strokes.…”

Crosstalk of Astrocytes and Other Cells during Ischemic Stroke

“…The enzyme autotaxin in astrocytic presynaptic processes synthesizes lysophosphatidic acid 2 (LPA2) and influences glutamatergic transmission via presynaptic LPA2 receptors. Astrocyte-specific deletion of autotaxin reduces cortical excitability and subsequent negative stroke outcome [43].…”