Early Electroacupuncture Extends the rtPA Time Window to 6 h in a Male Rat Model of Embolic Stroke via the ERK1/2-MMP9 Pathway

Abstract

Background. Recombinant tissue plasminogen activator (rtPA) is the only recommended pharmacological treatment for acute ischemic stroke, but it has a restricted therapeutic time window. When administered at time points greater than 4.5 h after stroke onset, rtPA disrupts the blood-brain barrier (BBB), which leads to serious brain edema and hemorrhagic transformation. Electroacupuncture (EA) exerts a neuroprotective effect on cerebral ischemia; however, researchers have not clearly determined whether EA increases the safety of thrombolysis and extends the therapeutic time window of rtPA administration following ischemic stroke. Objective. The present study was conducted to test the hypothesis that EA extends the therapeutic time window of rtPA for ischemic stroke in a male rat model of embolic stroke. Methods. SD rats were randomly divided into the sham operation group, model group, rtPA group, EA+rtPA group, and rtPA+MEK1/2 inhibitor group. An injection of rtPA was administered 6 h after ischemia. Rats were treated with EA at the Shuigou (GV26) and Neiguan (PC6) acupoints at 2 h after ischemia. Neurological function, infarct volume, BBB permeability, brain edema, and hemorrhagic transformation were assessed at 24 h after ischemia. Western blotting and immunofluorescence staining were performed to detect the levels of proteins involved in the ERK1/2 signaling pathway (MEK1/2 and ERK1/2), tight junction proteins (Claudin5 and ZO-1), and MMP9 in the ischemic penumbra at 24 h after stroke. Results. Delayed rtPA treatment aggravated hemorrhagic transformation and brain edema. However, treatment with EA plus rtPA significantly improved neurological function and reduced the infarct volume, hemorrhagic transformation, brain edema, and EB leakage in rats compared with rtPA alone. EA increased the levels of tight junction proteins, inhibited the activation of the ERK1/2 signaling pathway, and reduced MMP9 overexpression induced by delayed rtPA thrombolysis. Conclusions. EA potentially represents an effective adjunct method to increase the safety of thrombolytic therapy and extend the therapeutic time window of rtPA administration following ischemic stroke. This neuroprotective effect may be mediated by the inhibition of the ERK1/2-MMP9 pathway and alleviation of the destruction of the BBB.