Objectives
Sarcoma family
kinase activity is associated with multiple diseases including
ischemia and
cancer; however, its role in the mechanism of
migraine aura has been less well characterised. This study aims to investigate whether
sarcoma family
kinase is required for cortical spreading depression. Methods Cortical spreading depression was induced by topical application of K+ to the cerebral cortex and was monitored using electrophysiology in rats, and intrinsic optical signal in mouse brain slices. Drugs were perfused into the contralateral cerebral ventricle for pharmacological manipulations in rats. Western blot analysis was used for detecting the level of phosphorylated, and total,
sarcoma family
kinase in the ipsilateral cortex of rats. Key results The data demonstrate that a single cortical spreading depression in rats induced ipsilateral cortical
sarcoma family
kinase phosphorylation at the Y416 site. Deactivation of
sarcoma family
kinase by its inhibitor (3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1 H-pyrazolo[3,4- dpyrimidin-4-
amine) suppressed the elevated
enzyme activity and cortical susceptibility to cortical spreading depression. Interestingly, the inhibitory effect of the
N-methyl-D-aspartate receptor antagonist
NVP-AAM077 on cortical spreading depression was reversed by the
sarcoma family
kinase activator pYEEI (EPQY(PO3H2)EEEIPIYL), suggesting a link between this
enzyme and
N-methyl-D-aspartate receptors. Similarly, after deactivation of
sarcoma family
kinase, a reduction of
sarcoma family
kinase phosphorylation and cortical susceptibility to cortical spreading depression was observed with
NVP-AAM077. Conclusions We conclude that activation of
sarcoma family
kinase is required for cortical spreading depression, and this process is regulated by recruiting
N-methyl-D-aspartate receptors. This study provides novel insight for
sarcoma family
kinase function in the mechanism of
migraine aura.