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Synergistic neuroprotective effect by combination treatment with DAPK1 and Pin1 inhibitor on ischemic stroke

DAPK1 (death‐associated protein kinase 1) and Pin1 (peptidyl‐prolyl isomerase 1) are positive mediators of the neuronal death signaling pathway in cerebral ischemia. Pin1 induces the cis‐trans conversion on a phosphorylated serine/threonine (pS/T) amino acid residue of target protein that is regulated by the calcium/calmodulim (CaM)‐dependent kinase termed DAPK1. Whereas DAPK1 and Pin1 activation is required for neuronal death induced by ischemia/reperfusion (I/R) injury, this mechanism has not been elucidated. Thus, the purpose of this study was to determine the effects of DAPK1/Pin1 on pathogenesis of cerebral ischemia. Ischemic stroke model was induced by middle cerebral artery occlusion (MCAo). Experimental animals were randomly divided into three groups; vehicle (control), single inhibitor (DAPK1 inhibitor or Pin1 inhibitor), inhibitor combination (DAPK1 inhibitor and Pin1 inhibitor). Inhibitor groups including single injection and combined injection groups showed the decrease of neurological deficit and the altered body weight compared to control. Also, the low mortality rates were shown in inhibitor groups. In addition, the expansion of ischemic core from the striatum to the cerebral cortex was inhibited in inhibitor groups. Particularly, combination group showed significantly decreased ischemic lesions compared to control group. These results indicated that suppression of DAPK1 and Pin1 catalytic activity could enhance the neuroprotective effect against ischemic insult.