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

Abstract

Abstract Honokiol, a bioactive component of Magnolia officinalis, has been shown to protect against ischemic stroke in animal models. However, the poor water solubility of honokiol has hindered its clinical applications. In this study, we introduced a hydrophilic building block on the aromatic ring of honokiol and obtained four new compounds (HH-A, -B, -C and -D) with significantly improved water solubility. We investigated their neuroprotective effects against brain injury in transient middle cerebral artery occlusion/reperfusion (tMCAO/R) mouse and rat models. We found that (S)-6-((3',5-diallyl-2,4'-dihydroxy-[1,1'-biphenyl]-3-yl)amino)-6-oxohexane-1,5-diaminium chloride (i.e., HH-A) significantly reduced the infarct volume and edema of the experimental animal brains showing a distinct efficiency comparing to the other three compounds. HH-A also significantly improved neurological deficits in a dose-dependent manner. In the brain of tMCAO/R rat model, treatment with HH-A resulted in significant upregulations of nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). HH-A also significantly reduced the up-regulation of 4-hydroxynonenal (HNE), a major end-product of oxidation. Further, HH-A treatment reduced the increased expression of Bcl-2-associated X protein (Bax) and reverted the reduced expression of Bcl-2, suggesting its anti-apoptotic effect, which is supported by the reduced number of TUNEL positive cells. Collectively, the neuroprotection of HH-A against the brain injury observed in this study may be via targeting the Nrf2/HO-1 signaling pathway.