Bruceine D elevates Nrf2 activation to restrain Parkinson's disease in mice through suppressing oxidative stress and inflammatory response.

Parkinson's disease (PD) is neurodegenerative disease, featured by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), characteristic motor symptoms and cognitive impairment. Development of effective therapeutic drugs for PD is necessary. In this study, we investigated the potential of Bruceine D (BD) during PD progression. After establishment of PD mouse models, we found that BD markedly improved the motor function of mice and alleviated chemically induced dopaminergic neuron loss of tyrosine hydroxylase (TH) in the SNpc area. BD treatments markedly repressed the neuroinflammation in SNpc by restricting nuclear factor κB (NF-κB) activation, accompanied with the reduced activity of astrocytes and microglial. BD also improved the antioxidant system in MPTP-challenged mice, as proved by the up-regulated superoxide dismutase (SOD) and glutathione (GSH), and down-regulated malondialdehyde (MDA) in SNpc and striatum (STR). The anti-oxidant effects of BD were regulated by the activation of nuclear factor E2-related factor 2 (Nrf2) signaling, contributing to the expression of Nrf2 down-streaming signals such as heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutathione cysteine ligase modulatory subunit (GCLM). In MPP+-challenged mouse neurons, BD exhibited cytoprotective effects by improving the Nrf2-meditated antioxidant system and abolished the MPP+-triggered inflammatory response through hindering the activation of the NF-κB signal. The pharmacokinetic parameters and organ distribution findings demonstrated that BD showed a brain tissue targeting function. Moreover, both in vivo and in vitro analysis indicated that BD had few side effects. Collectively, results here demonstrated that BD was effective for the inhibition of dopaminergic neuronal loss and PD progression by activating Nrf2 without toxicity.

Yang Y ，Kong F ，Ding Q ，Cai Y ，Hao Y ，Tang B ... -  《-》

Benfotiamine protects MPTP-induced Parkinson's disease mouse model via activating Nrf2 signaling pathway.

The pursuit of drugs and methods to safeguard dopaminergic neurons holds paramount importance in Parkinson's disease (PD) research. Benfotiamine (BFT) has demonstrated neuroprotective properties, yet its precise mechanisms in PD remain elusive. This study investigated BFT's potential protective effects against dopamine neuron damage in a PD animal model and the underlying mechanisms. The PD mouse model was induced by 5 consecutive MPTP injections, followed by BFT intervention for 28 days. Motor deficits were assessed via pole test, hang test, gait analysis, and open field test, while dopaminergic neuron damage was evaluated through Immunofluorescence, Nissl staining, and Western blot analysis of Tyrosine Hydroxylase (TH) in the substantia nigra and striatum. High Performance Liquid Chromatography quantified dopamine (DA) levels and its metabolites. Genetic pathways were explored using RNA-seq and bioinformatics analysis on substantia nigra tissues, confirmed by qPCR. Activation of the Nrf2 pathway was examined through nuclear translocation and expression of downstream antioxidant enzymes HO-1, GCLM, and NQO1 at mRNA and protein levels. Additionally, measurements of MDA content, GSH activity, and SOD activity were taken in the substantia nigra and striatum. BFT administration improved motor function and protected against dopaminergic neuron degeneration in MPTP mice, with partial recovery in TH expression and DA levels. RNA-seq analysis revealed distinct effects of BFT and the NLRP3 inhibitor MCC950 on Parkinson-related pathways and genes. Control of Nrf2 proved crucial for BFT, as it facilitated Nrf2 movement to the nucleus, upregulating antioxidant genes and enzymes while mitigating oxidative damage. This study elucidates BFT's neuroprotective effects in a PD mouse model via Nrf2-mediated antioxidant mechanisms and gene expression modulation, underscoring its potential as a therapeutic agent for PD.

Wang K ，Han C ，Yang J ，Xu W ，Wang L ，Li H ，Wang Y ... -  《PLoS One》

5-(3,4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole (DDO-7263), a novel Nrf2 activator targeting brain tissue, protects against MPTP-induced subacute Parkinson's disease in mice by inhibiting the NLRP3 inflammasome and protects PC12 cells aga

Parkinson's disease (PD) is the second most common aging-related neurodegenerative disease worldwide. Oxidative stress and neuroinflammation are critical events in the degeneration of dopaminergic neurons in PD. In this study, we found that DDO-7263, a novel Nrf2-ARE activator reported by us, has ideal therapeutic effects on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice. DDO-7263 improved the behavioral abnormalities induced by MPTP in mice, significantly attenuated chemically induced dopaminergic neuron loss of tyrosine hydroxylase (TH) in the substantia nigra (SN) and striatum of the mouse brain and inhibited the secretion of inflammatory factors. In addition, DDO-7263 protected PC12 neurons from H2O2-induced oxidative damage. The neuroprotective effects of DDO-7263 were confirmed both in vitro and in vivo models. Further studies showed that the neuroprotective effect of DDO-7263 was mediated by the activation of Nrf2-ARE signaling pathway and the inhibition of NLRP3 inflammasome activation. DDO-7263 induced NLRP3 inflammasome inhibition is dependent on Nrf2 activation. This conclusion was also verified in THP-1-derived macrophages (THP-Ms). DDO-7263 significantly inhibited NLRP3 activation, cleaved caspase-1 production and IL-1β protein expression in ATP-LPS-exposed THP-Ms cells. The pharmacokinetic parameters and tissue distribution results indicated that DDO-7263 has a brain tissue targeting function. All these lines of evidence show that DDO-7263 has ideal therapeutic effects on neurodegenerative diseases such as PD.

Xu LL ，Wu YF ，Yan F ，Li CC ，Dai Z ，You QD ，Jiang ZY ，Di B ... -  《-》

Gintonin Mitigates MPTP-Induced Loss of Nigrostriatal Dopaminergic Neurons and Accumulation of α-Synuclein via the Nrf2/HO-1 Pathway.

Jo MG ，Ikram M ，Jo MH ，Yoo L ，Chung KC ，Nah SY ，Hwang H ，Rhim H ，Kim MO ... -  《-》

Preferential Heme Oxygenase-1 Activation in Striatal Astrocytes Antagonizes Dopaminergic Neuron Degeneration in MPTP-Intoxicated Mice.

Xu X ，Song N ，Wang R ，Jiang H ，Xie J ... -  《-》