AIM Up to now, the only currently approved treatment for acute ischemic stroke (AIS) is alteplase, a thrombolytic agent given intravenously within 4.5 h of symptom onset, in an attempt to re-open occluded intracerebral arteries.However, no more than 5% of all AIS patients receive alteplase because of too long symptom-onset-to-hospital intervals.Moreover, this strategy is effective for less than half of the patients treated within the therapeutic window.So far there have been no challenges and novel strategies for treatment of ischemic stroke.METHODS Based on the multiparametric interaction within the network in pharmacological system biology, our laboratory has developed novel agents with multiple targets for the treatment of ischemic stroke.Pinocembrin is one of the novel NVU network regulated natural products of great significance.RESULTS In 2008, pinoeembrin has been approved by the State Food and Drug Administration of China for clinical use in stroke patients.It has been clearly confirmed to have protective effects on the neurovascular unit (NVU) in ischemic animal models.This compound has a good bioavailability and high BBB penetration.The therapeutic dose-range was demonstrated to be much wider.If pinocembrin was intravenouslyinjected at 0, 8 and 16 h after MCAO, neurological deficit scores and cerebral infarct volumes were preserved from 3 mg·kg-1 to 30 mg-kg-1 at 24 and 48 h.Our results also suggested that pinocembrin conferred robust neurovascular coupling protection in MCAO rats.Major components of NVU were maintained by the increased fluorescent intensities under confocal microscopy, which was related to the preservation of microvascular integrity and the attenuation of serious neuronal loss.The rCBF value was gradually recovered from 10.37% to 43.16% of the basic level.The BBB was well protected, and the percentage of cortical microvessels presenting lanthanum ion leakage showed a significant decrease from 28.2% to 35.6%.Further, pinocembrin specially affected RAGE and CREB, and then, markedly depressed the activation of RAGE-controlled NVU network, and improved the modification of ERK/CREB/BDNF response in the cholinergic neuronal transmission.CONCLUSION In practice, we suggest that the most promising emerging strategy is a combination of multiple targets in the network of NVU.The natural product pinocembrin is iaken as a successful example.Pinocembrin-induced reversal of the ischemic impairment might be parfly related to multiple targets and the NVU network regulation.These effects are closely related to the conservation of neurovascular RAGE signaling pathways and cholinergic neuronal regulation of cortical cerebral blood flow.