Cycloastragenol Reduced BBB Disruption and Ameliorated Neuroinflammation of Intracerebral Hemorrhage in Mice by Modulating the p38 MAPK/Nrf2/HO-1 Signaling Pathway

Background: Intracerebral hemorrhage (ICH) is a prevalent cerebrovascular disorder in clinical practice. Secondary brain in-jury (SBI) is observed in the perihematomal tissue following ICH. A traditional Chinese herb astragalus membranaceus (AM) has been reported to treat cerebrovascular disease. The study aimed to explore the function and mechanism of cycloastragenol (CAG), a hydrolysis product of astragaloside IV isolated from AM, on ICH. Methods: Male Sprague-Dawley rats weighing 300 +/- 20 g were randomly assigned to the sham group, ICH group, CAG-low group (CAG-L), CAG-medium group (CAG-M), and CAG-high group (CAG-H). Rats were used to establish an ICH model by intrastriatal injection of collagenase type IV. Different concentrations of CAG (2.5, 5, and 10 mg/kg) were intraperitoneally in-jected at 1 h and 6 h after immunohistochemistry (IHC) induction. Rats were necropsied on the 3 days after ICH induction. Neurobehavioral assessments (daily), blood-brain barrier (BBB) permeability, brain water content (BWC), immunofluorescence staining, and western blot were performed. HT22 cells were treated with different concentrations of CAG (1, 10, and 20 mu M). Cell proliferation was assessed using the Cell Counting Kit-8 (CCK-8), while cell apoptosis was evaluated via flow cytometry. Results: CAG improves ICH-induced neurological deficits and neuronal apoptosis in a dose-dependent manner. CAG also de-creases BBB permeability and BWC during continuous testing. Enzyme-linked immunosorbent assay (ELISA) of brain tissues from the peri-hematoma area shows CAG dose-dependently inhibited oxidative stress and inflammation of ICH rats. These functional improvements are correlated with reductions in inducible nitric oxide synthase (iNOS), interleukin (IL)-1 beta, IL-6, tumour necrosis factor (TNF)-alpha, and reactive oxygen species (ROS) levels as well as microglial deactivation. Mechanistically, CAG dose-dependently inhibits the p38 mitogen-activated protein kinase (MAPK)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling in neurons and astrocytes. In vitro, hemin induces apoptosis and inhibits proliferation of HT22 cells. In addition, CAG inhibits hemin-induced apoptosis and promotes proliferation of HT22 cells. Conclusions: Taken together, these data indicate that CAG may provide therapeutic benefits for ICH patients.