Although the etiology of Parkinson’s disease (PD) remains elusive, recent studies suggest that oxidative stress contributes to the cascade leading to dopaminergic (DAergic) neurodegeneration. The ...Nrf2 signaling is the main pathway responsible for cellular defense system against oxidative stress. Nrf2 is a transcription factor that regulates environmental stress response by inducing expression of antioxidant enzyme genes. We have synthesized novel vinyl sulfone derivatives. They exhibited a broad range of activities in inducing HO-1, whose gene expression is under the control of Nrf2. Among them, compound 12g was confirmed to activate Nrf2 and induce expression of the Nrf2-dependent antioxidant enzymes NQO1, GCLC, GLCM, and HO-1, at both mRNA and protein levels in DAergic neuronal cells. This was accompanied by protection of DAergic neurons in both in vitro and MPTP-induced in vivo models of PD. In addition, compound 12g effectively resulted in attenuation of the PD-associated behavioral deficits in the mouse model.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by abnormal movement, including slowed movements, shuffling gait, lack of balance, and tremor. Oxidative stress has been shown ...to play a decisive role in dopaminergic neuronal cell death in PD. The nuclear factor E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) signaling pathway provides the main defense system against oxidative stress by inducing the expression of antioxidant enzyme genes. Direct interference in the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as an effective strategy for Nrf2 activation. Therefore, we searched for novel Nrf2 activators that can disrupt Nrf2-Keap1 interaction by using a virtual screening approach and identified a potent Nrf2 activator, KKPA4026. KKPA4026 was confirmed to induce the expression of the Nrf2-dependent antioxidant enzymes heme oxygenase-1, glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase regulatory subunit, and NAD(P)H:quinone oxidoreductase 1 in BV-2 cells. Furthermore, KKPA4026 showed anti-inflammatory effects in an Nrf2-dependent manner. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, KKPA4026 effectively attenuated PD-associated behavioral deficits and protected dopaminergic neurons. In summary, we identified KKPA4026 as a novel Nrf2 activator and suggested that Nrf2 activation through interference with the Nrf2-Keap1 interaction may be effective for PD treatment.
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•Discovery of KKPA4026, a potent Nrf2 activator via interference with Keap1-Nrf2 interaction.•KKPA4026 induces Nrf2 nuclear translocation and upregulates the expression of Nrf2-dependent antioxidant enzymes.•KKPA4026 reduces the production of inflammatory mediators in an Nrf2-dependent manner.•KKPA4026 attenuates PD-associated motor deficits in MPTP-induced mouse model and protects dopaminergic neurons.
Current pharmacological treatments for Parkinson’s disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible ...dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.
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•Reactive astrocytes in SNpc produce excessive GABA via MAO-B in animal models of PD•Aberrant tonic inhibition causes reduced DA production in neurons and motor deficits•Dormant neurons are rescued by MAO-B inhibition or optogenetic neuronal activation
Heo et al. report that astrocytic GABA-mediated aberrant tonic inhibition of DA neurons leads to a reduction in TH expression and dopamine production, causing dormant DA neurons and motor deficits. Blocking astrocytic GABA synthesis by MAO-B inhibition or optogenetic activation of dormant DA neurons reverses PD pathology.
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We have synthesized three categories of α,β-unsaturated carbonyl derivatives and evaluated their MAO-A and MAO-B inhibitory activities. Among them, compound 10b including ...α,β-unsaturated ketone group showed the most potent and selective MAO-B inhibitory activity (IC50 human MAO-B 16nM, >6000-fold selective vs MAO-A) and compound 10b exhibited good reversibility compared with selegiline, a well-known irreversible MAO-B inhibitor. However, both α,β-unsaturated amide and ester derivatives exhibited weaker MAO-B inhibition potencies. The docking studies provided insights into the possible binding modes and the key interaction sites of the synthesized MAO-B inhibitors.
Monoamine oxidase-B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer's disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in ...reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC
= 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.
Monoamine oxidase-B (MAO-B) is a well-established therapeutic target for Parkinson’s disease (PD); however, previous clinical studies on currently available irreversible MAO-B inhibitors have yielded ...disappointing neuroprotective effects. Here, we tested the therapeutic potential of KDS2010, a recently synthesized potent, selective, and reversible MAO-B inhibitor in multiple animal models of PD. We designed and synthesized a series of α-aminoamide derivatives and found that derivative KDS2010 exhibited the highest potency, specificity, reversibility, and bioavailability (> 100%). In addition, KDS2010 demonstrated significant neuroprotective and anti-neuroinflammatory efficacy against nigrostriatal pathway destruction in the mouse MPTP model of parkinsonism. Treatment with KDS2010 also alleviated parkinsonian motor dysfunction in 6-hydroxydopamine-induced and A53T mutant α-synuclein overexpression rat models of PD. Moreover, KDS2010 showed virtually no toxicity or side effects in non-human primates. KDS2010 could be a next-generation therapeutic candidate for PD.
Accidental vaccination with a live attenuated low-virulence strain of Miyagi (LOM) vaccine led to the reemergence of classical swine fever virus (CSFV) in Jeju province, South Korea in 2014. To ...control the continual outbreaks of LOM-derived CSFV, the provincial government launched a provincial mass vaccination project using a CSF-E2 subunit vaccine. We conducted this study to assess the herd immunity level and outcomes of E2 vaccine-based immunization in breeding and growing herds on Jeju Island during 2020-2021.
A large-scale vaccination trial using the Bayovac CSF-E2 vaccine investigated its efficacy in breeding and growing herds under farm application conditions (10 CSFV-affected and three CSFV-naïve swine farms).
The level of herd immunity in each farm was classified into three (S1-S3) and six (G1-G6) profiles in breeding and growing herds, respectively. Immunity monitoring revealed a remarkable improvement in the herd immunity status in all farms. The majority (10/13) of farms, including CSFV-free farms, showed the S1G1 immunity profile in 2021, indicating the appropriate implementation of the advised vaccination regime. Moreover, there were significant decreases in E
seropositivity from 100% to 50% and 25.9% to 4.3% at farm and pig levels, respectively. In particular, all farms were confirmed as CSFV free in the growing-finishing herds.
Our large-scale trial demonstrated the effectiveness of the E2 subunit vaccine in establishing herd immunity stabilization and eliminating CSFV circulation in the affected farms and highlighted the need for a provincial vaccination policy to regain the CSF-free status on Jeju Island.
Alzheimer’s disease is a common neurodegenerative disease characterized by progressive degeneration and neuronal cell death, resulting in neural network dysfunction. As the underlying mechanisms, ...oxidative damage and neuroinflammation have been reported to contribute to the onset and deterioration of Alzheimer’s disease. The nuclear factor E2-related factor 2-antioxidant responsive element signaling pathway is a pivotal cellular defense mechanism against oxidative stress. Nrf2, a transcription factor, regulates the cellular redox balance and is primarily involved in anti-inflammatory responses. In this study, we synthesized novel chalcone derivatives and found a highly potent Nrf2 activator, compound 20a. Compound 20a confirmed to activate Nrf2 and induce expression of the Nrf2-dependent enzymes HO-1 and GCLC at both mRNA and protein levels. It also suppressed the production of nitric oxide and downregulated inflammatory mediators in BV-2 microglial cells. We found that compound 20a effectively increased the expression level and the activity of superoxide dismutase in both BV-2 microglial cells and brain hippocampus region of the scopolamine-induced mouse model. In addition, compound 20a effectively recovered the learning and memory impairment in a scopolamine-induced mouse model.
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•A novel series of chalcone derivatives were synthesized as Nrf2 activators.•Compound 20a increases antioxidant enzyme expression by nuclear translocation of Nrf2.•20a suppresses reactive oxygen species against oxidative stress in microglia.•20a increases expression level and activity of superoxide dismutase in vitro and in vivo.•20a restores scopolamine-induced memory impairment in mice.
Due to the increased morbidity and mortality by fungal infections and the emergence of severe antifungal resistance, there is an urgent need for new antifungal agents. Here, we screened for ...antifungal activity in our in-house library through the minimum inhibitory concentration test and derived two hit compounds with moderate antifungal activities. The hit compounds’ antifungal activities and drug-like properties were optimized by substituting various aryl ring, alkyl chain, and methyl groups. Among the optimized compounds, 22h was the most promising candidate with good drug-like properties and exhibited potent fast-acting fungicidal antifungal effects against various fungal pathogens and synergistic antifungal activities with some known antifungal drugs. Additionally, 22h was further confirmed to disturb fungal cell wall integrity by activating multiple cell wall integrity pathways. Furthermore, 22h exerted significant antifungal efficacy in both the subcutaneous infection mouse model and ex vivo human nail infection model.
Background and Purpose
Neuroinflammation through microglial activation is involved in the pathogenesis of neurodegenerative diseases including Parkinson's disease (PD), a major neurodegenerative ...disorder characterized by dopaminergic neuronal death in the substantia nigra. We examined our novel synthetic compound VSC2 for its anti‐inflammatory properties towards development of a PD therapy.
Experimental Approach
We tested the effects of VSC2 on production of various NF‐κB‐dependent proinflammatory molecules and Nrf2‐dependent antioxidant enzymes in BV‐2 microglia and in vivo.
Key Results
The vinyl sulfone compound, VSC2, most effectively suppressed the production of NO in LPS‐activated microglia. It also down‐regulated expression of inducible NOS (iNOS), COX‐2, IL‐1β and TNF‐α and inhibited nuclear translocalization and transcriptional activity of NF‐κB. VSC2 increased total and nuclear Nrf2 levels, induced Nrf2 transcriptional activity and was bound to Keap1 with high affinity. Expression of the Nrf2‐regulated antioxidant enzyme genes NAD(P)H quinone oxidoreducase‐1 (NQO‐1), haem oxygenase‐1 (HO‐1) and glutamylcysteine ligase (GCL) were up‐regulated by VSC2. In the MPTP mouse model of PD, oral administration of VSC2 decreased the number of activated microglia in the substantia nigra, lowered the levels of iNOS, COX‐2 and IL‐1β, and protected the dopaminergic neurons. VSC2 also elevated the levels of NQO1, HO‐1, GCL and Nrf2 in the nigrostriatal area.
Conclusions and Implications
VSC2 has both anti‐inflammatory and antioxidant properties and prevented neuroinflammation in microglia and in an animal model of PD. This suggests VSC2 as a potential candidate for PD therapy.
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