Cerdulatinib Improves Sensorimotor Function and Memory Ability in Mice Suffering from Ischemic Stroke through Targeting Caspase-3-Dependent Apoptosis.

Abstract

Caspase-3-dependent apoptosis is believed to contribute to the brain injury of ischemic stroke, and a caspase-3 inhibitor has been repeatedly reported to reduce the brain injury of ischemic stroke. However, currently recognized caspase-3 inhibitors are still only used as a research tool, and none of them is available in the clinic to treat brain injury of ischemic stroke. Based on the concept of drug repositioning and bioinformatics techniques, we have identified Cerdulatinib, a multitargeted tyrosine kinase inhibitor to treat tumors and immune-related diseases in the clinic, as a potential caspase-3 inhibitor. This study aims to explore the effect of Cerdulatinib on brain injury from ischemic stroke and the underlying mechanisms. In mice with ischemic stroke, Cerdulatinib significantly decreased infarct volume and improved sensorimotor function, memory ability, and cognitive function. In nerve cells exposed to hypoxia, Cerdulatinib increased cell viability and decreased LDH release. Mechanistically, Cerdulatinib inhibited the protein level of cleaved caspase-3 and the activity of caspase-3, resulting in a decrease in brain cell apoptosis. Based on these results, we conclude that Cerdulatinib can protect the brain against ischemic injury by reducing apoptosis, which is related to the suppression of caspase-3 cleavage and caspase-3 activity. This study may extend the clinical indications of Cerdulatinib in the treatment of patients with an ischemic stroke.