Atractylenolide-I Attenuates MPTP/MPP(+)‑Mediated Oxidative Stress in Parkinson's Disease Through SIRT1/PGC‑1α/Nrf2 Axis.

Parkinson's disease (PD) is typically marked by motor dysfunction accompanied by loss of dopaminergic (DA) neurons and aggravated oxidative stress in the substantia nigra pars compacta (SNpc). Atractylenolide-I (ATR-I) is a potent antioxidant sesquiterpene with neuroprotective properties. However, whether ATR-I plays a neuroprotective role against oxidative stress in PD remains unclear. The objective of this study was to explore the mechanism of antioxidant action of ATR-I in PD models both in vivo and in vitro. Here, we show that ATR-I alleviated motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice. Moreover, ATR-I treatment effectively reduced DA neuron loss and increased tyrosine hydroxylase expression in the SNpc of MPTP-induced mice. Additionally, ATR-I inhibited oxidative stress (as manifested by elevated superoxide dismutase and glutathione peroxidase activities, and reduced malondialdehyde content) in MPTP-induced mice and attenuated reactive oxygen species levels in 1-methyl-4-phenylpyridinum (MPP+)-treated SH-SY5Y cells. Finally, ATR-I upregulated expressions of silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), NF-E2-related factor-2 (Nrf2), and heme oxygenase-1 in MPTP-induced mice and MPP+-treated SH-SY5Y cells, but had little effect on these factors in the presence of the SIRT1 inhibitor EX527. Taken together, these findings indicated that the important antioxidant role of ATR-I in MPTP/MPP+-mediated oxidative stress and the pathogenesis of PD through the SIRT1/PGC-1α/Nrf2 axis, highlighting its potential as a therapeutic option for PD.

Gao Y ，Li S ，Zhang S ，Zhang Y ，Zhang J ，Zhao Y ，Chang C ，Gao X ，Chen L ，Yang G ... -  《-》

Neuroprotective Role of Transchalcone in Parkinson's Disease through AMP-activated Protein Kinase-mediated Signaling Pathway.

Parkinson's disease (PD) is a gradually worsening neurodegenerative condition marked by the deterioration of dopaminergic neurons, motor dysfunction, and mitochondrial dysfunction. Trans-chalcone, a natural flavonoid, has shown promise in various disease models because of its antioxidant and anti-inflammatory features. This study investigates the neuroprotective effects of transchalcone in a rat model of PD, focusing on its impact on the activation levels of AMP-activated protein kinase (AMPK) signaling pathway, sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) proteins, and mitochondrial-inflammatory responses. Male Sprague Dawley rats were allocated into five groups Control, Control plus transchalcone, PD, PD plus transchalcone, PD plus compound-C, and PD plus Compound-C and trans-chalcone. PD was induced using intranigral 6-hydroxydopamine injection. Trans-chalcone (100 μg/kg) and compound-C (20 mg/kg) were intraperitoneally administered daily for 4 weeks in PD rats. Motor function was assessed using rota-rod and grid tests. Striatal dopamine and cytokines (interleukin 1-beta [IL-1 β], IL-10) and p65-nuclear factor kappa-B (NF-κB) levels were measured with enzyme-linked immunosorbent assay. Mitochondrial function was evaluated by fluorometric techniques. The expression of phosphorylated AMPK, PGC-1α, and SIRT1 was analyzed by Western blotting. Trans-chalcone treatment significantly improved motor function, evidenced by increased latency to fall in the rota-rod test and recovered traversal time in the grid test. It also restored dopamine levels, enhanced mitochondrial function (reduced reactive oxygen species levels, increased membrane potential, and adenosine triphosphate production), normalized cytokines (IL-1 β, IL-10) and p65-NF-κB, and upregulated the proteins expression in rats with PD. Inhibition of AMPK activity with compound-C suppressed the neuroprotective impacts of trans-chalcone, highlighting the contribution of AMPK signaling pathway in its mechanism of action. Neuroprotective and mitoprotective impacts of trans-chalcone were mostly mediated through the activation of AMPK-SIRT1-PGC1α pathway. These results indicate that trans-chalcone could be a promising therapeutic agent for PD, warranting further investigation to assess its efficacy and safety in human patients.

Cheng Y ，Hussain SA ，Alrubie TM ，Zhang X ... -  《-》

HDAC4/5 Inhibitor, LMK-235 Improves Animal Voluntary Movement in MPTP-Induced Parkinson's Disease Model.

Oxidation of dopamine can cause various side effects, which ultimately leads to cell death and contributes to Parkinson's disease (PD). To counteract dopamine oxidation, newly synthesized dopamine is quickly transported into vesicles via vesicular monoamine transporter 2 (VMAT2) for storage. VMAT2 expression is reduced in patients with PD, and studies have shown increased accumulation of dopamine oxidation byproducts and α-synuclein in animals with low VMAT2 expression. Conversely, animals that overexpress VMAT2 show better protection for dopamine neurons. Based on these findings, this study used histone deacetylase inhibitors (HDACi) to increase VMAT2 expression, reduce dopamine-induced oxidative stress, and evaluate the resulting behavioral improvements in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model. LMK-235 not only increased VMAT2 expression at various concentrations in the SH-SY5Y cell line differentiated into dopaminergic cells but also demonstrated effective cytoprotective properties in several toxicity assays. It significantly raised VMAT2 expression in both the striatum and the ventral tegmental area of an MPTP-induced PD model, supporting its role in reversing behavioral abnormalities linked to PD. In addition to these results, coadministration of LMK-235 with L-DOPA, a standard therapy for PD, restored typical behavioral patterns, highlighting the potential of HDACi in alleviating PD symptoms. The expression of VMAT2 induced by LMK-235, an inhibitor of Class IIa histone deacetylases primarily found in the nervous system, aids in sequestering dopamine into vesicles, potentially enhancing cell survival by inhibiting dopamine oxidation. Additionally, upregulation of VMAT2 has been shown to offer effective protection against MPTP-induced toxicity and significantly improve behavioral abnormalities associated with PD. Coadministration with L-DOPA produced the most notable improvement in behavioral outcomes. Altogether, these findings suggest that the overexpression of VMAT2 may offer a promising strategy for developing treatments for PD by mitigating dopaminergic neuron death resulting from dopamine oxidation.

Lee H ，Kim HJ ，Min JS ，Lee E ，Choi DK ，Choi JH ，Seo Y ，Lee S ，Im CY ，Bae GH ，Oh Y ，Ko EA ，Jung SC ，Kim SH ，Kwon OB ... -  《-》

Electroacupuncture ameliorated locomotor symptoms in MPTP-induced mice model of Parkinson's disease by regulating autophagy via Nrf2 signaling.

Parkinson's disease (PD) is a prevalent and challenging neurodegenerative disorder, and may involve impaired autophagy. Nuclear factor erythroid-2-related factor 2 (Nrf2) is crucial for regulating autophagy-related genes and maintaining cellular homeostasis. Electroacupuncture (EA), a complementary and alternative therapy for PD, has gained widespread clinical application. In this study, we investigate whether EA at Baihui (GV20) and Taichong (LR3) acupoints modulates autophagy through the Nrf2 pathway, providing neuroprotection in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. Using wild-type and Nrf2 knockout (KO) mice, we examined EA's effects on dopaminergic neuron survival, α-synuclein expression, motor function and the underlying mechanisms. Results showed that EA treatment significantly reduced dopaminergic neuron loss and α-synuclein expression, and improved motor deficits while restoring autophagy, as evidenced by increased autophagy markers (Atg7, LC3II) and decreased p62 levels. Transmission electron microscopy confirmed a rise in autophagosomes and lysosomes in the MPTP + EA group. EA also enhanced nuclear Nrf2 expression and activated Nrf2 signaling. Importantly, Nrf2 KO mice did not exhibit neuroprotection or increased autophagy-related proteins following EA treatment. In conclusion, our research demonstrated that EA ameliorated defective autophagy and activated the Nrf2 signaling pathway, which collectively contribute to its neuroprotective effects against MPTP-induced neurotoxicity.NEW & NOTEWORTHY In this study, we explored the potential mechanism of electroacupuncture (EA) therapy at the GV20 and LR3 acupoints of Parkinson's disease (PD). We demonstrated EA therapy's neuroprotective effect on PD, through ameliorating defective autophagy and activating the nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway whereas the regulation of EA on autophagy was absent in Nrf2 knockout (KO) mice. Our study not only provides new insights into the therapeutic mechanisms of EA but also suggests a promising strategy for PD treatment.

Zhang J ，Fu Z ，Wen F ，Lyu P ，Huang S ，Cai X ，Zhang Z ，Zhang Y ，Fan C ，Man W ，Sun X ，Huang Y ... -  《-》

Neuroprotective and anti-inflammatory effects of the RIPK3 inhibitor GSK872 in an MPTP-induced mouse model of Parkinson's disease.

Park JS ，Leem YH ，Kim DY ，Park JM ，Kim SE ，Kim HS ... -  《-》