Rhein and rhubarb similarly protect the blood-brain barrier after experimental traumatic brain injury via gp91phox subunit of NADPH oxidase/ROS/ERK/MMP-9 signaling pathway

Abstract

Oxidative stress chiefly contributes to the disruption of the BBB following traumatic brain injury (TBI). The Chinese herbal medicine rhubarb is a promising antioxidant in treating TBI. Here we performed in vivo and in vitro experiments to determine whether rhubarb and its absorbed bioactive compound protected the BBB after TBI by increasing ZO-1 expression through inhibition of gp91phox subunit of NADPH oxidase/ROS/ERK/MMP-9 pathway. Rats were subjected to the controlled cortical impact (CCI) model, and primary rat cortical astrocytes were exposed to scratch-wound model. The liquid chromatography with tandem mass spectrometry method showed that rhein was the compound absorbed in the brains of CCI rats after rhubarb administration. The wet-dry weights and Evans blue measurements revealed that rhubarb and rhein ameliorated BBB damage and brain edema in CCI rats. Western blots showed that rhubarb and rhein downregulated GFAP in vitro. RT-PCR, immunohistochemistry, Western blot and dichlorodihydrofluorescein diacetate analysis indicated that rhubarb prevented activation of gp91phox subunit of NADPH oxidase induced ROS production, subsequently inhibited ERK/MMP-9 pathway in vivo and in vitro. Interestingly, rhein and rhubarb similarly protected the BBB by inhibiting this signaling cascade. The results provide a novel herbal medicine to protect BBB following TBI via an antioxidative molecular mechanism.

Adjuvant rhubarb alleviates organs dysfunction and inhibits inflammation in heat stroke

“…The active components of rhubarb may have an important role in heat stroke by modulating molecular signaling pathways including junction proteins (25) and JAK1/STAT3 (10). Although experimental studies claim that rhubarb and rhein have a protective effect on rats with brain damage (26,27), such a phenomenon occurring in the brains of the patients of the present study was not observable to judge the improvement of the state of mind of patients linked to the application of rhubarb.…”

Medicinal plants in traumatic brain injury: Neuroprotective mechanisms revisited

“…Rhubarb also prevented the gp91 phox subunit of NADPH oxidase activation‐induced ROS production. Additionally, this inhibited ERK/MMP‐9 pathway both in vivo and in vitro as well as downregulated GFAP in vitro . Oral administration of polysaccharide extracted from R. tanguticum (RTP) for 5 days exhibited marked protective effects on oxidative stress and brain edema on the WDIAI model of TBI in rats by reduction of water content and MDA levels.…”

“…The underlying mechanisms of GTS on TBI induced and modified Feeney's method could be potentially mediated through various mechanisms including reducing MDA level, expression of TNFα and IL‐1β, generation of reactive oxygen species (ROS), and elevating the activity of SOD and inflammatory reactions . R. tanguticum has been shown to have neuroprotective effects on TBI by inhibiting oxidative stress …”

“…Additionally, this inhibited ERK/MMP-9 pathway both in vivo and in vitro as well as downregulated GFAP in vitro. 25,26 Oral administration of polysaccharide extracted from R. tanguticum (RTP) for 5 days exhibited marked protective effects on oxidative stress and brain edema on the WDIAI model of TBI in rats by reduction of water content and MDA levels. This also resulted in the enhancement of SOD and Na+K+ATPase activity after injury.…”

“…135 R. tanguticum has been shown to have neuroprotective effects on TBI by inhibiting oxidative stress. [25][26][27] The potential mechanism for protective effects of luteolin could be due to the inhibition of the release of inflammatory cytokines. 28 The possible mechanisms of TQ on TBI are by improving the redox balance, abating the inflammatory cytokines, and restoring the balance between apoptotic and antiapoptotic factors.…”