Based on these pathophysiological changes and the identified molecular targets, many directed anti-stroke therapies are now under investigation to prevent destruction of the BBB. Of the potential molecular targets, the MMPs and the AQPs form the predominant focus of our study. Acupuncture and electroacupuncture are both potential therapeutic strategies to repair brain injury and improve functional outcomes following acute ischemic stroke. Here, we showed that acupuncture or electroacupuncture at Baihui and left Zusanli significantly reduced the infiltration of inflammatory cells and the expression of the proinflammatory enzyme, MMP2, in CIRI model rats. Acupuncture and electroacupuncture also significantly attenuated the expression of the water channel proteins, AQP4 and AQP9, in the ischemic brain, suggesting that the protective mechanisms of these alternative treatments are partially dependent on the mitigation of inflammation-related brain edema. Consistent with the smaller observed infarct size, acupuncture and electroacupuncture both promoted significant improvements in the mNSS in CIRI model rats, indicative of enhanced neurological function. MMPs and other proteases are products of a molecular inflammatory cascade that damages the BBB following CIRI. BBB tight junction proteins and basal lamina proteins,which form the endothelial barrier, are vulnerable to attack by MMPs. MMP2 is especially important in astrocytes and endothelial cells, and its activation generally leads to a biphasic opening of the BBB. For this reason, agents that protect the brain from edema by interfering with BBB are under pursuit by many researchers. Notably, our study showed that MMP2 colocalized with both GFAP in astrocytes and CD34 in endothelial cells within the ischemic penumbra, strengthening the idea that synthetic MMPs inhibitors could be used in CIRI management. We also showed that acupuncture and electroacupuncture significantly reversed MMP2 upregulation in CIRI model rats, although edaravone was more effective than either acupuncture or electroacupuncture. AQPs, like MMP2, play essential roles in the pathogenesis of brain edema. The MCAO model, which utilizes focal brain ischemia to impart tissue damage, was previously reported to increase AQP4 expression in the infarct zone shortly after the insult. On the other hand, another study suggested that AQP4 inhibition may provide a new therapeutic option for reducing brain edema. Yet another study reported two peaks of brain swelling following CIRI, coinciding with two peaks of AQP4 expression in both the infarct and the peri-infarct area. AQP9, along with AQP4, is associated with brain damage after CIRI. AQP9 is upregulated in the ischemic core and the lesion border, with lower expression reported in the core. Our data showed elevated expression of APQ9 and AQP4 in both the ischemic penumbra and the core, but the highest expression was found in the core zone.