Current
therapy for
ischemic stroke primarily relies on
tissue plasminogen activator (tPA), but it is limited by narrow treatment time window,
bleeding complications and neurotoxicity. The preliminary study of tPA plus
Danhong injection (DHI) shows that it can significantly reduce the side effects of tPA and improve its thrombolytic effect, but the mechanism of this action has not been further studied. In this study, the rats were randomly divided into
sham group, vehicle group, DHI group (4 mL/kg), tPA group (5 mg/kg) and DHI+tPA group (4 mL/kg+ 2.5 mg/kg), administered intravenously 4.5 h since focal
embolic stroke modeling. After 3 days and 7 days of
cerebral ischemia, the neurological function of each treatment group was significantly improved compared with the vehicle group. The combination of DHI and tPA significantly reduced
Evans blue (EB) penetration as well as the expressions of the
proteins MMP-9,
PAI-1 and
P-selectin, while upregulating the expressions of
claudin-5,
occludin, and ZO-1
mRNA. Furthermore, the effect of continuous 7-day treatment was more conspicuous than 3-day treatment. Then, it significantly reduced the expressions of the
proteins DLL-4 and
VEGFR-2, increased the expressions of Notch-1, HIF-1α and HES-1
mRNA, and promoted the expressions of
VEGF/HIF-1α-positive cells at 14 days following
stroke.
Hematoxylin-
eosin (HE) staining and transmission electron microscopy (TEM) also showed that it improved pathological changes of ischemic brain tissue and the cerebral cortex micro-structure. These indicate that DHI combined with tPA may significantly ameliorate blood-brain barrier (BBB) disruption by activating Notch-
VEGF signaling pathway to promote angiogenesis for long-term outcomes.