Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson's Disease.

Oxymatrine (OMT), a natural quinoxaline alkaloid extracted from the root of Sophora flavescens, presents amounts of pharmacological properties including immunomodulation, anti-inflammation, anti-oxidation, and anti-virus. Recent studies tend to focus on its effects on neuroinflammation and neuroprotection in Parkinson's disease (PD) due to its profound anti-inflammatory effect. In this study, the neuroprotective and anti-neuroinflammatory effects of OMT were investigated in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-stimulated mice and 1-methyl-4-phenylpyridinium (MPP+)-induced mice primary microglia. Additionally, mice primary neuron-microglia co-cultures and primary microglia infected with Cathepsin D (CathD)-overexpressed lentivirus were used to clarify whether the neuroprotective effect of OMT was through a CathD-dependent pathway. Results showed that OMT dose-dependently alleviated MPTP-induced motor deficits and conferred significant dopamine (DA) neuroprotection against MPTP/MPP+-induced neurotoxicity. In addition, OMT inhibited MPTP/MPP+-induced microglia activation and the pro-inflammatory cytokines release. Further, OMT down-regulated the expression of CathD, and inhibited the activation of the HMGB1/TLR4 signaling pathway as well as the nuclear translocation of NF-κB both in vivo and in vitro. It is worth noting that overexpression of CathD reversed OMT-targeted inhibition of HMGB1/TLR4/NF-κB signaling and OMT-produced neuroprotection in reconstituted neuron-microglia co-cultures. Our findings indicated that OMT conferred DA neuroprotection and attenuated microglial-mediated neuroinflammation through CathD-dependent inhibition of HMGB1/TLR4/NF-κB signaling pathway. Our study supports a potential role for OMT in ameliorating PD, and proposes that OMT may be useful in the treatment of PD.

Knockdown of cathepsin D protects dopaminergic neurons against neuroinflammation-mediated neurotoxicity through inhibition of NF-κB signalling pathway in Parkinson's disease model.

Parkinson's disease (PD) is a progressive neurodegenerative disorder pathologically characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Cathepsin D (CathD), a soluble aspartic protease, has been reported to play an important role in neurodegenerative diseases such as PD. This research focuses on the role of CathD and the molecular mechanisms involved in the process of neuroinflammation and neurotoxicity. We use 1-methyl-4phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-challenged mice and lipopolysaccharide (LPS)-induced murine microglia BV2 cells as the in vivo and in vitro models, respectively. The effect of CathD on the neuroinflammation, cytotoxicity and the underlying mechanisms associated with NF-κB signalling pathway are investigated. Data showed that MPTP induces motor deficit, inflammation and depletion of dopaminergic neurons in PD model mice. Notably, cathD was overexpressed in the SNpc of MPTP-induced PD mice and was highly expressing in LPS-stimulated primary microglial cells and BV-2 cells. Furthermore, knockdown of CathD with lentiviral transduction inhibited LPS-induced neuroinflammation through inhibition of NF-κB signalling pathway primarily by regulating the NF-κB p65 nuclear translocation both in BV-2 and primary microglial cells. Additionally, knockdown of CathD protected the activated-microglia induced dopaminergic neurons MN9D cells from neurotoxicity as well as apoptosis. Our findings bring a new insight into understanding the complex mechanisms underlying the pathogenesis of PD and provide a novel target to attenuate the excessive neuroinflammatory responses in the treatment of PD.