Despite
of its high morbidity and mortality, there is still a lack of effective
treatment for ischemic stroke in part due to our incomplete
understanding of molecular mechanisms of its pathogenesis. In this
study, we demonstrate that SHH-PTCH1-GLI1-mediated axonal guidance
signaling and its related neurogenesis, a central pathway for neuronal
development, also plays a critical role in early stage of an acute
stroke model. Specifically, in vivo, we evaluated the effect of
GXNI on ischemic stroke mice via using the middle cerebral artery
embolization model, and found that GXNI significantly alleviated
cerebral ischemic reperfusion (I/R) injury by reducing the volume of
cerebral infarction, neurological deficit score and cerebral edema,
reversing the BBB permeability and histopathological changes. A combined
approach of RNA-seq and network pharmacology analysis was used to
reveal the underlying mechanisms of GXNI followed by RT-PCR,
immunohistochemistry and western blotting validation. It was pointed out
that axon guidance signaling pathway played the most prominent role in
GXNI action with Shh, Ptch1, and Gli1 genes
as the critical contributors in brain protection. In addition, GXNI
markedly prevented primary cortical neuron cells from oxygen-glucose
deprivation/reoxygenation damage in vitro, and promoted axon growth and synaptogenesis of damaged neurons, which further confirmed the results of in vivo
experiments. Moreover, due to the inhibition of the SHH-PTCH1-GLI1
signaling pathway by cyclopropylamine, the effect of GXNI was
significantly weakened. Hence, our study provides a novel option for the
clinical treatment of acute ischemic stroke by GXNI via
SHH-PTCH1-GLI1-mediated axonal guidance signaling, a neuronal
development pathway previously considered for after-stroke recovery.
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