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Improving the Efficacy of Quinolylnitrones for Ischemic Stroke Therapy, QN4 and QN15 as New Neuroprotective Agents after Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury.

ABSTRACT: In our search for new neuroprotective agents for stroke therapy to improve the pharmacological profile of the compound quinolylnitrone QN23, we have prepared and studied sixteen new, related and easily available quinolylnitrones. As a result, we have identified compounds QN4 and QN15 as promising candidates showing high neuroprotection power in a cellular experimental model of ischemia. Even though they were found to be less active than our current lead compound QN23, QN4 and QN15 provide an improved potency and, particularly for QN4, an expanded range of tolerability and improved solubility compared to the parent compound. A computational DFT-based analysis has been carried out to understand the antioxidant power of quinolylnitrones QN23, QN4 and QN15. Altogether, these results show that subtle, simple modifications of the quinolylnitrone scaffold are tolerated, providing high neuroprotective activity and optimization of the pharmacological potency required for an improved design and future drug developments in the field.

SUBMITTER: Alonso JM

PROVIDER: S-EPMC9697404 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Improving the Efficacy of Quinolylnitrones for Ischemic Stroke Therapy, QN4 and QN15 as New Neuroprotective Agents after Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury.

Alonso José M JM Escobar-Peso Alejandro A Fernández Israel I Alcázar Alberto A Marco-Contelles José J

Pharmaceuticals (Basel, Switzerland) 20221107 11

In our search for new neuroprotective agents for stroke therapy to improve the pharmacological profile of the compound quinolylnitrone QN23, we have prepared and studied sixteen new, related and easily available quinolylnitrones. As a result, we have identified compounds QN4 and QN15 as promising candidates showing high neuroprotection power in a cellular experimental model of ischemia. Even though they were found to be less active than our current lead compound QN23, QN4 and QN15 provide an imp ...[more]

PMID: 36355534

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Project description:ObjectivesCurcumin (Cur) is a natural polyphenol isolated from turmeric and has potent anti-inflammatory and antioxidant activities. This study aimed to explore the effects and possible mechanisms of curcumin on oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in cultured rat astrocyte primary cells.MethodsAfter screening for effective doses, the cultured rat astrocyte primary cells were divided into three groups: control, OGD/R, and OGD/R + curcumin (10 μM, 20 μM, and 40 μM). Cell viability was detected using CCK8 assays. The level of malondialdehyde and superoxide dismutase activity was determined using commercial kits. The endothelial nitric oxide synthase and adenosine triphosphate concentrations were determined by enzyme-linked immunosorbent assay. The mRNA levels of the inflammatory indexes interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1β were evaluated by quantitative reverse-transcription polymerase chain reaction. Annexin V-fluorescein isothiocyanate/propidium iodide was used to detect apoptosis. JC-1 was used to assess the mitochondrial membrane potential. The protein expression of apoptosis-related proteins (B-cell lymphoma-2 (Bcl-2), BCL-2-associated X (Bax), and cleaved caspase 3), mitochondria-related proteins (dynamin-related protein 1 (DRP1), phosphorylated DRP1 (p-DRP1), and mitofusin 2), and essential proteins of the extracellular signal-regulated kinase (ERK) signaling pathway (ERK1/2, p-ERK1/2) were analyzed by western blot.ResultsOur data indicated that curcumin reversed OGD/R-induced cell viability loss, oxidative stress, inflammatory cytokine production, and cell apoptosis in a dose-dependent manner. Furthermore, curcumin attenuated OGD/R-induced mitochondrial dysfunction and ERK1/2 phosphorylation in a dose-dependent manner.ConclusionsCurcumin protected against OGD/R-induced injury in rat astrocyte primary cells through improving mitochondrial function and regulating the ERK signaling pathway.

Project description:N1-Methyladenosine (m1A) is an abundant modification of transcripts, plays important roles in regulating mRNA structure and translation efficiency, and is dynamically regulated under stress. However, the characteristics and functions of mRNA m1A modification in primary neurons and oxygen glucose deprivation/reoxygenation (OGD/R) induced remain unclear. We first constructed a mouse cortical neuron OGD/R model and then used methylated RNA immunoprecipitation (MeRIP) and sequencing technology to demonstrate that m1A modification is abundant in neuron mRNAs and dynamically regulated during OGD/R induction. Our study suggests that Trmt10c, Alkbh3, and Ythdf3 may be m1A-regulating enzymes in neurons during OGD/R induction. The level and pattern of m1A modification change significantly during OGD/R induction, and differential methylation is closely associated with the nervous system. Our findings show that m1A peaks in cortical neurons aggregate at both the 5' and 3' untranslated regions. m1A modification can regulate gene expression, and peaks in different regions have different effects on gene expression. By analysing m1A-seq and RNA-seq data, we show a positive correlation between differentially methylated m1A peaks and gene expression. The correlation was verified by using qRT-PCR and MeRIP-RT-PCR. Moreover, we selected human tissue samples from Parkinson's disease (PD) and Alzheimer's disease (AD) patients from the Gene Expression Comprehensive (GEO) database to analyse the selected differentially expressed genes (DEGs) and differential methylation modification regulatory enzymes, respectively, and found similar differential expression results. We highlight the potential relationship between m1A modification and neuronal apoptosis following OGD/R induction. Furthermore, by mapping mouse cortical neurons and OGD/R-induced modification characteristics, we reveal the important role of m1A modification in OGD/R and gene expression regulation, providing new ideas for research on neurological damage.

Dataset Information

Improving the Efficacy of Quinolylnitrones for Ischemic Stroke Therapy, QN4 and QN15 as New Neuroprotective Agents after Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury.

Publications

Improving the Efficacy of Quinolylnitrones for Ischemic Stroke Therapy, QN4 and QN15 as New Neuroprotective Agents after Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury.

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