Inhibiting necroptosis to treat ischemic stroke

INDICATION: Stroke

Preventing neuronal necroptosis by disrupting the interaction between ASIC1A, an acid-sensing ion channel, RIPK1 and NSF could treat ischemic stroke. During acidosis, the interaction between ASIC1A’s C- and N-termini is disrupted, enabling the C terminus to activate RIPK1 and induce necroptosis. NSF can also bind ASIC1A’s N-terminus to free the C terminus. In cultured mouse cortical neurons, a 20-residue peptide corresponding to the N-terminal segment of ASIC1A; an shRNA against NSF; or NSF or RIPK1 inhibitor tool compounds were protective against acidotoxicity. In mice with middle cerebral artery occlusion-induced stroke, the 20-residue peptide or systemic ASIC1A knockout reduced ischemia-induced brain damage as assessed by infarct volume. ...