HH-A, a modified honokiol, protects against cerebral ischemia/reperfusion induced brain injury in rodent via Nrf2/HO-1 signaling pathways

摘要

Honokiol, a bioactive component found in Magnolia officinalis, has shown in protecting against ischemic stroke in animal models. However, its poor water solubility has limited its clinical applications. In this study, we introduced a hydrophilic building block on the aromatic ring of honokiol, resulting in the synthesis of four new compounds (HH-A, -B, -C and -D) with significantly improved water solubility. We then investigated the neuroprotective effects of these compounds in mouse and rat models of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) brain injury. Among the compounds tested, HH-A, also known as (S)-6-((3 ',5-diallyl-2,4 '-dihydroxy-1,1 '-biphenyl-3-yl)amino)-6-oxohexane-1,5-diaminium chloride, showed the most promising results. HH-A was found to significantly reduced the infarct volume and brain edema in mice. It also outperformed the other three compounds and honokiol, even surpassing the effects of edaravone dexborneol. Additionally, HH-A demonstrated dose-dependent improvements in body weight, neurological deficits, and infarct volume. Further analysis in tMCAO/R rat model revealed that HH-A treatment led to significant upregulations of Nrf2 and HO-1 in the brain. HH-A also significantly reduced the expression of HNE, and exhibited anti-apoptotic effects by decreasing the expression of Bax and increasing the expression of Bcl-2. This was further supported by a decrease in the number of TUNEL positive cells. Taken together, the neuroprotective effects of HH-A may be attributed to its ability to target the Nrf2/HO-1 signaling pathway, leading to reduced oxidative stress and apoptosis in the brain. These findings suggest that HH-A has potential as a therapeutic agent for the treatment of ischemic stroke.