ALOX5 inhibition protects against dopaminergic neurons undergoing ferroptosis

Li, Kun; Wang, Meng; Huang, Zihan; Wang, Min; Sun, Wanyang; Kojima, Hiroshi; Huang, Rui‐Ting; Wang, Rong; Huang, Feng; Liu, Liang; Li, Yi-Fang; Duan, Wen-Jun; He, Rong‐Rong

doi:10.1016/j.phrs.2023.106779

Cited by 20 publications

(12 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Isaindigotone demonstrated notable affinity for Arachidonate 5-lipoxygenase (ALOX5) and multiple kinases, including IRE1, ERbB-2, ERbB1, and Nek1 (Table ). Its interaction with ALOX5 suggests a potential strategy for treating PD by preventing ferroptosis in dopaminergic neurons …”

Section: Resultsmentioning

confidence: 99%

“…Its interaction with ALOX5 suggests a potential strategy for treating PD by preventing ferroptosis in dopaminergic neurons. 64 …”

Section: Resultsmentioning

confidence: 99%

“…Its interaction with ALOX5 suggests a potential strategy for treating PD by preventing ferroptosis in dopaminergic neurons. 64 The lead compounds displayed diverse interactions with biological targets crucial to the pathophysiology of PD. Their affinity with dopamine and melatonin receptors suggests a potential for modulating dopaminergic neurotransmission and addressing circadian rhythm disturbances commonly observed in PD.…”

Section: Cns-active Drug Criteriamentioning

confidence: 99%

See 2 more Smart Citations

Identification of Novel Quinolone and Quinazoline Alkaloids as Phosphodiesterase 10A Inhibitors for Parkinson’s Disease through a Computational Approach

Ahmad,

Khalid,

Perveen

et al. 2024

ACS Omega

View full text Add to dashboard Cite

Phosphodiesterases (PDEs) are vital in signal transduction, specifically by hydrolyzing cAMP and cGMP. Within the PDE family, PDE10A is notable for its prominence in the striatum and its regulatory function over neurotransmitters in medium-spiny neurons. Given the dopamine deficiency in Parkinson's disease (PD) that affects striatal pathways, PDE10A inhibitors could offer therapeutic benefits by modulating D1 and D2 receptor signaling. This study was motivated by the successful history of quinazoline/ quinazoline scaffolds in the inhibition of PDE10A. This study involved detailed in silico evaluations through docking followed by pharmacological, pharmacophoric, and pharmacokinetic analyses, prioritizing central nervous system (CNS)-active drug criteria. Seven cyclic peptides, those featuring the quinazoline/quinazoline moiety at both termini, exhibited notably enhanced docking scores compared to those of the remaining alkaloids within the screened library. We identified 7 quinolines and 1 quinazoline including Lepadin G, Aspernigerin, CJ-13536, Aurachin A, 2-Undecyl-4(1H)quinolone, Huajiaosimuline 3-Prenyl-4-prenyloxyquinolin-2-one, and Isaindigotone that followed the standard CNS active drug criteria. The dominant quinoline ring in our study and its related quinazoline were central to our evaluations; therefore, the pharmacophoric features of these scaffolds were highlighted. The top alkaloids met all CNS-active drug properties; while nonmutagenic and without PAINS alerts, many indicated potential hepatotoxicity. Among the compounds, Huajiaosimuline was particularly significant due to its alignment with lead-likeness and CNS-active criteria. Aspernigerin demonstrated its affinity for numerous dopamine receptors, which signifies its potential to alter dopaminergic neurotransmission that is directly related to PD. Interestingly, the majority of these alkaloids had biological targets primarily associated with G protein-coupled receptors, critical in PD pathophysiology. They exhibit superior excretion parameters and toxicity end-points compared to the standard. Notably, selected alkaloids demonstrated stability in the binding pocket of PDE10A according to the molecular dynamic simulation results. Our findings emphasize the potential of these alkaloids as PDE10A inhibitors. Further experimental studies may be necessary to confirm their actual potency in inhibiting PDE10A before exploring their therapeutic potential in PD.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Its interaction with ALOX5 suggests a potential strategy for treating PD by preventing ferroptosis in dopaminergic neurons. 64 …”

Section: Resultsmentioning

confidence: 99%

Section: Cns-active Drug Criteriamentioning

confidence: 99%

See 1 more Smart Citation

Identification of Novel Quinolone and Quinazoline Alkaloids as Phosphodiesterase 10A Inhibitors for Parkinson’s Disease through a Computational Approach

Ahmad,

Khalid,

Perveen

et al. 2024

ACS Omega

View full text Add to dashboard Cite

show abstract

“…Earlier studies revealed that ALOX12 played a key role in neuronal cell death [ 22 ] and death of oligodendrocytes caused by glutathione depletion-induced toxicity and accumulation of ROS [ 23 ]. Recent findings have shown that the inhibition of ALOX5 attenuated the accumulation of lipid peroxides and neuronal damage and prevented ferroptosis in a model of Parkinson’s disease [ 24 ]. Another pro-oxidant gene that we found to be upregulated in SP MS, NOX2/CYBB , is proposed to be an important contributor to oxidative stress and subsequent neurotoxicity in the CNS [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Targeted RNAseq Revealed the Gene Expression Signature of Ferroptosis-Related Processes Associated with Disease Severity in Patients with Multiple Sclerosis

Stojkovic,

Jovanovic,

Dincic

et al. 2024

IJMS

View full text Add to dashboard Cite

Detrimental molecular processes in multiple sclerosis (MS) lead to the cellular accumulation of lipid peroxidation products and iron in the CNS, which represents the main driving force for ferroptosis. Ferroptosis is an iron-dependent form of regulated cell death, with proposed roles in neurodegeneration, oligodendrocyte loss and neuroinflammation in the pathogenesis of MS. Ferroptosis-related gene expression signature and molecular markers, which could reflect MS severity and progression, are currently understudied in humans. To tackle these challenges, we have applied a curated approach to create and experimentally analyze a comprehensive panel of ferroptosis-related genes covering a wide range of biological processes associated with ferroptosis. We performed the first ferroptosis-related targeted RNAseq on PBMCs from highly distinctive MS phenotype groups: mild relapsing–remitting (RR) (n = 24) and severe secondary progressive (SP) (n = 24), along with protein detection of GPX4 and products of lipid peroxidation (MDA and 4-HNE). Out of 138 genes, 26 were differentially expressed genes (DEGs), indicating changes in both pro- and anti-ferroptotic genes, representing a molecular signature associated with MS severity. The top three DEGs, as non-core ferroptosis genes, CDKN1A, MAP1B and EGLN2, were replicated by qPCR to validate findings in independent patient groups (16 RR and 16 SP MS). Co-expression and interactions of DEGs were presented as additional valuable assets for deeper understanding of molecular mechanisms and key targets related to MS severity. Our study integrates a wide genetic signature and biochemical markers related to ferroptosis in easily obtainable PBMCs of MS patients with clinical data and disease severity, thus providing novel molecular markers which can complement disease-related changes in the brain and undergo further research as potential therapeutic targets.

show abstract

“…This can lead to diminished adenosine triphosphate (ATP) generation and mitochondrial membrane potential ( Δψm ), as well as increased ROS formation, especially superoxide (O 2 - ), which can induce mitochondrial malfunction and fragmentation, oxidative stress, and even death ( Bloem et al, 2021 ; Dauer & Przedborski, 2003 ). Many cell death-related pathways, such as apoptosis, cell necrosis, and ferroptosis, are associated with oxidative stress ( Callizot et al, 2019 ; Li et al, 2023 ; Qu et al, 2022 ). Among them, apoptosis is considered the predominant programmed cell death mechanism associated with PD ( Tatton et al, 2003 ).…”

Section: Introductionmentioning

confidence: 99%

Cath-KP, a novel peptide derived from frog skin, prevents oxidative stress damage in a Parkinson’s disease model

Lu,

Chai,

et al. 2024

Zoological Research

View full text Add to dashboard Cite

Parkinson’s disease (PD) is a neurodegenerative condition that results in dyskinesia, with oxidative stress playing a pivotal role in its progression. Antioxidant peptides may thus present therapeutic potential for PD. In this study, a novel cathelicidin peptide (Cath-KP; GCSGRFCNLFNNRRPGRLTLIHRPGGDKRTSTGLIYV) was identified from the skin of the Asiatic painted frog ( Kaloula pulchra ). Structural analysis using circular dichroism and homology modeling revealed a unique αββ conformation for Cath-KP. In vitro experiments, including free radical scavenging and ferric-reducing antioxidant analyses, confirmed its antioxidant properties. Using the 1-methyl-4-phenylpyridinium ion (MPP + )-induced dopamine cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, Cath-KP was found to penetrate cells and reach deep brain tissues, resulting in improved MPP + -induced cell viability and reduced oxidative stress-induced damage by promoting antioxidant enzyme expression and alleviating mitochondrial and intracellular reactive oxygen species accumulation through Sirtuin-1 (Sirt1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation. Both focal adhesion kinase (FAK) and p38 were also identified as regulatory elements. In the MPTP-induced PD mice, Cath-KP administration increased the number of tyrosine hydroxylase (TH)-positive neurons, restored TH content, and ameliorated dyskinesia. To the best of our knowledge, this study is the first to report on a cathelicidin peptide demonstrating potent antioxidant and neuroprotective properties in a PD model by targeting oxidative stress. These findings expand the known functions of cathelicidins, and hold promise for the development of therapeutic agents for PD.

show abstract

ALOX5 inhibition protects against dopaminergic neurons undergoing ferroptosis

Cited by 20 publications

References 48 publications

Identification of Novel Quinolone and Quinazoline Alkaloids as Phosphodiesterase 10A Inhibitors for Parkinson’s Disease through a Computational Approach

Identification of Novel Quinolone and Quinazoline Alkaloids as Phosphodiesterase 10A Inhibitors for Parkinson’s Disease through a Computational Approach

Targeted RNAseq Revealed the Gene Expression Signature of Ferroptosis-Related Processes Associated with Disease Severity in Patients with Multiple Sclerosis

Cath-KP, a novel peptide derived from frog skin, prevents oxidative stress damage in a Parkinson’s disease model

Contact Info

Product

Resources

About