Neuroprotection by Nrf2 via modulating microglial phenotype and phagocytosis after intracerebral hemorrhage.

Activated microglia are divided into pro-inflammatory and anti-inflammatory functional states. In anti-inflammatory state, activated microglia contribute to phagocytosis, neural repair and anti-inflammation. Nrf2 as a major endogenous regulator in hematoma clearance after intracerebral hemorrhage (ICH) has received much attention. This study aims to investigate the mechanism underlying Nrf2-mediated regulation of microglial phenotype and phagocytosis in hematoma clearance after ICH. In vitro experiments, BV-2 cells were assigned to normal group and administration group (Nrf2-siRNA, Nrf2 agonists Monascin and Xuezhikang). In vivo experiments, mice were divided into 5 groups: sham, ICH + vehicle, ICH + Nrf2-/-, ICH + Monascin and ICH + Xuezhikang. In vitro and in vivo, 72 h after administration of Monascin and Xuezhikang, the expression of Nrf2, inflammatory-associated factors such as Trem1, TNF-α and CD80, anti-inflammatory, neural repair and phagocytic associated factors such as Trem2, CD206 and BDNF were analyzed by the Western blot method. In vitro, fluorescent latex beads or erythrocytes were uptaken by BV-2 cells in order to study microglial phagocytic ability. In vivo, hemoglobin levels reflect the hematoma volume. In this study, Nrf2 agonists (Monascin and Xuezhikang) upregulated the expression of Trem2, CD206 and BDNF while decreased the expression of Trem1, TNF-α and CD80 both in vivo and in vitro. At the same time, after Monascin and Xuezhikang treatment, the phagocytic capacity of microglia increased in vitro, neurological deficits improved and hematoma volume lessened in vivo. These results were reversed in the Nrf2-siRNA or the Nrf2-/- mice. All these results indicated that Nrf2 enhanced hematoma clearance and neural repair, improved neurological outcomes through enhancing microglial phagocytosis and alleviating neuroinflammation.

Mechanisms of Oxidative Stress and Therapeutic Targets following Intracerebral Hemorrhage.

Oxidative stress (OS) is induced by the accumulation of reactive oxygen species (ROS) following intracerebral hemorrhage (ICH) and plays an important role in secondary brain injury caused by the inflammatory response, apoptosis, autophagy, and blood-brain barrier (BBB) disruption. This review summarizes the current state of knowledge regarding the pathogenic mechanisms of brain injury after ICH, markers for detecting OS, and therapeutic strategies that target OS to mitigate brain injury.

Long-term outcomes of monascin - a novel dual peroxisome proliferator-activated receptor γ/nuclear factor-erythroid 2 related factor-2 agonist in experimental intracerebral hemorrhage.

BACKGROUND: Hematoma is the chief culprit in brain injury following intracranial cerebral hemorrhage (ICH). Noninvasive hematoma clearance could be an option to prevent and alleviate early brain injury after ICH. Peroxisome proliferator-activated receptor γ (PPAR-γ) and nuclear factor-erythroid 2 related factor-2 (Nrf2) facilitate removal of hematoma in ICH. Monascin acts as the natural Nrf2 activator with PPAR-γ agonist, and the long-term effects of monascin following ICH have not been elucidated. METHODS: ICH in rats was induced by stereotactic, intrastriatal injection of type IV collagenase. Monascin was administered twice daily by gastric perfusion for 14 days after ICH induction. Long-term neurological scores (T maze, Garcia scales, rotor rod test, and Morris water maze), hematoma volume, as well as iron overload around hematoma and brain atrophy were evaluated at 7, 14, and 28 days after ICH. RESULTS: The results showed that monascin improved long-term neurological deficits, spatial memory performance, learning ability, and brain shrinkage after ICH. Monascin also reduced hematoma volume at 7 days and iron content at 7 and 14 days after ICH. CONCLUSION: PPAR γ and Nrf2 play a crucial role in hematoma clearance after ICH in rat. As a dual agonist of PPAR γ and Nrf2, monascin improved long-term outcomes by facilitating hematoma clearance, and by attenuating iron overload and brain atrophy after experimental ICH.