Cerebroprotection of flavanol (-)-epicatechin after traumatic brain injury via Nrf2-dependent and -independent pathways

Abstract

Traumatic brain injury (TBI), which leads to disability, dysfunction, and even death, is a prominent health problem worldwide with no effective treatment. A brain-permeable flavonoid named (−)-epicatechin (EC) modulates redox/oxidative stress and has been shown to be beneficial for vascular and cognitive function in humans and for ischemic and hemorrhagic stroke in rodents. Here we examined whether EC is able to protect the brain against TBI-induced brain injury in mice and if so, whether it exerts neuroprotection by modulating the NF-E2-related factor (Nrf2) pathway. We used the controlled cortical impact model to mimic TBI. EC was administered orally at 3 h after TBI and then every 24 h for either 3 or 7 days. We evaluated lesion volume, brain edema, white matter injury, neurologic deficits, cognitive performance and emotion-like behaviors, neutrophil infiltration, reactive oxygen species (ROS), and a variety of injury-related protein markers. Nrf2 knockout mice were used to determine the role of the Nrf2 signaling pathway after EC treatment. In wild-type mice, EC significantly reduced lesion volume, edema, and cell death and improved neurologic function on days 3 and 28; cognitive performance and depression-like behaviors were also improved with EC administration. In addition, EC reduced white matter injury, heme oxygenase-1 expression, and ferric iron deposition after TBI. These changes were accompanied by attenuation of neutrophil infiltration and oxidative insults, reduced activity of matrix metalloproteinase 9, decreased Keap 1 expression, increased Nrf2 nuclear accumulation, and increased expression of superoxide dismutase 1 and quinone 1. However, EC did not significantly reduce lesion volume or improve neurologic deficits in Nrf2 knockout mice after TBI. Our results show that EC protects the TBI brain by activating the Nrf2 pathway, inhibiting heme oxygenase-1 protein expression, and reducing iron deposition. The latter two effects could represent an Nrf2-independent mechanism in this model of TBI.

Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways

“…Primary cortical neurons were prepared from the pups of pregnant C57BL/6 mice at 15–18 days’ gestation. The website Randomization.com (http://www.randomization.com) was used to assign animals into different study groups [25,33]. …”

“…An accelerating rotarod was used to assess motor deficits [25,43]. Animals were adapted to the rotarod for a period of 3 days before randomization.…”

“…HO-1, one of the cytoprotective enzymes activated by the Nrf2 pathway, plays a critical role in maintaining cellular homeostasis by degrading heme [22,23]. Notably, HO-1 may exert beneficial or detrimental effects in the brain after different types and stages of injuries [22–25]. Of course, in addition to HO-1, other antioxidant enzymes are also critical for maintaining cellular redox homeostasis against oxidative insults.…”

An Intersectional Study of LncRNAs and mRNAs Reveals the Potential Therapeutic Targets of Buyang Huanwu Decoction in Experimental Intracerebral Hemorrhage

“…Animals were randomly assigned to the sham-operated group (short for the sham + vehicle group), ICH group (short for the ICH + vehicle group) and BYHWD group (short for the ICH + BYHWD-treated group) (n=3, per group) (for the randomization of animals, refer to Cheng T [25]). The rats were fixed in a prone position on a stereotactic instrument (Stoelting Co., Chicago, IL, USA) after being deeply anesthetized with pentobarbital (65 mg/kg i.p.).…”

Altered Long Noncoding RNA and Messenger RNA Expression in Experimental Intracerebral Hemorrhage - a Preliminary Study

“…Animals were assigned to the sham-operated and ICH groups randomly (randomization of animals referred to Cheng T [22]). After deep intraperitoneal (IP) anesthesia with pentobarbital (65 mg/kg), the right femoral artery of the rat was catheterized for blood glucose, pH, PaO 2 , PaCO 2 , arterial blood pressure, and hematocrit monitoring.…”