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

Abstract

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 cocultures and primary microglia infected with Cathepsin D (CathD)-overexpressed lentivirus were used to clarify whether the neuroprotective effect of OMT was through a CathDdependent pathway. Results showed that OMT dose-dependently alleviated MPTPinduced 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 downregulated the expression of CathD, and inhibited the activation of the HMGB1/TLR4 signaling pathway as well as the nuclear translocation of NF-kB both in vivo and in vitro. It is worth noting that overexpression of CathD reversed OMT-targeted inhibition of HMGB1/TLR4/NF-kB 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 CathDdependent inhibition of HMGB1/TLR4/NF-kB 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.

Cannabidiol Induces Autophagy to Protects Neural Cells From Mitochondrial Dysfunction by Upregulating SIRT1 to Inhibits NF-κB and NOTCH Pathways

“…Simultaneously, SIRT1 could deacetylate the p65/RELA at lysine 310, leading to NF-κB transcriptional inhibition (Back et al, 2011). Moreover, We also observed that NF-κB and NOTCH signaling pathway participates in the development process of PD (Gan et al, 2020). In this study, we found that Cannabidiol induced cell autophagy by upregulating SIRT1 to inhibits NOTCH1, Hes 1 expression and p65, iκBα phosphorylation.…”

Oxymatrine Induces Autophagy and Apoptosis in Human Poorly Differentiated Gastric Adenocarcinoma Cells via Slit2/Robo1 Signals

“…OMT has a variety of pharmacological properties, including anti-inflammatory, anti-oxidative effects, anti-proliferative effects, and anti-apoptotic activities [3,4] . Recent studies have found that OMT has good anticancer activities.…”

“…Oxymatrine (OMT) is a natural quinoxaline alkaloid and the primary biologically active ingredient extracted from the root of the Chinese herbal medicine Sophora flavescens Ait. OMT has a variety of pharmacological properties, including anti-inflammatory, anti-oxidative effects, anti-proliferative effects, and anti-apoptotic activities [3,4] . Recent studies have found that OMT has good anticancer activities [5] .…”

Potential Therapeutic Applications of Plant-Derived Alkaloids against Inflammatory and Neurodegenerative Diseases

“…Furthermore, by suppressing apoptosis and oxidative stress, it had effective neuroprotection against cerebral hypoxic-ischemic injury, which could be linked to the activation of protein kinase (Akt) and glycogen synthase kinase-3 (GSK3) and modification of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf-2/HO-1) signaling pathway [ 119 ]. Through cathepsin-D-dependent regulation of the Toll-like receptor 4 (TLR4) signaling pathway, oxymatrine significantly attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's diseases, and this provides dopamine-based neuroprotection and reduces microglia-mediated neuroinflammation [ 120 ]. It has been found as a potent anti-inflammatory and neurodegenerative drug, as 12 patients who have psoriasis (a type of skin inflammation) treated by the use of oxymatrine in the duration from 2012 to 2016 showed more significant improvement by inhibiting the excessive secretion of cell proliferation marker in skin surface [ 121 ].…”

“…rough cathepsin-D-dependent regulation of the Toll-like receptor 4 (TLR4) signaling pathway, oxymatrine significantly attenuates 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's diseases, and this provides dopamine-based neuroprotection and reduces microglia-mediated neuroinflammation [120]. It has been found as a potent anti-inflammatory and neurodegenerative drug, as 12 patients who have psoriasis (a type of skin inflammation) treated by the use of oxymatrine in the duration from 2012 to 2016 showed more significant improvement by inhibiting the excessive secretion of cell proliferation marker in skin surface [121].…”