Sinomenine Hydrochloride Impedes Memory Impairments via Nrf2/HO-1-Mediated Inhibition of Oxidative Stress, Neuroinflammation and Apoptosis in Mice Brain.

Abstract

Oxidative stress is a key factor in the progression of Alzheimer's disease (AD) and other neurodegenerative disorders. We evaluated whether sinomenine hydrochloride (SH) exhibits antioxidant and anti-inflammatory effects against cadmium chloride (CdCl2)-induced neurodegeneration and synaptic impairment in mouse brains. The mice were allowed to undergo Cd injection for two weeks. SH was administered orally for eight consecutive weeks (100 mg/kg/bw/mouse, p.o.). The heavy metal cadmium (Cd) disrupts cellular metabolism in the brain, increasing levels of reactive oxygen species (ROS) and lipid peroxidation (LPO), which affects glutathione (GSH) and the production of regulatory enzymes, such as glutathione reductase (GSH-R). An imbalance in this homeostatic system may lead to the downregulation of nuclear factor erythroid-2-related factor 2 (Nrf2) and the enzyme heme oxygenase 1 (HO-1) expression in the Cd-injected mouse brain. Interestingly, the levels of both Nrf2 and HO-1 increased in the Cd + SH-treated mice. Additionally, toll-like receptor 4 (TLR4), phospho-nuclear factor kappa B (p-NF-kB), and phospho-c-Jun N-terminal kinase (p-JNK) expressions were elevated in the Cd-treated group, but significantly downregulated in the Cd + SH-treated mice brains. Similarly, SH inhibits Cd-induced apoptotic markers in mouse hippocampal tissues. These results suggest that SH may mitigate Cd-induced mitochondrial oxidative stress and inflammatory responses in wild-type mice brain hippocampus by regulating the NRF-2/HO-1 signaling pathways.