Influence of Umbelliferone on the Anticonvulsant and Neuroprotective Activity of Selected Antiepileptic Drugs: An In Vivo and In Vitro Study

Zagaja, Mirosław; Zagaja, Anna; Szala-Rycaj, Joanna; Szewczyk, Aleksandra; Lemieszek, Marta Kinga; Raszewski, Grzegorz; Andres-Mach, Marta

doi:10.3390/ijms23073492

Cited by 8 publications

(6 citation statements)

References 77 publications

(101 reference statements)

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“…P83 Umbelliferone (Zagaja et al, 2022) and P111 Neohesperidin (Chakraborty et al, 2021) have been reported to exhibit neuroprotective effects. P136 Liquiritigenin (Liu et al, 2022), P116 Tenuifoliside A (Dong et al, 2014), P73 Polygalaxanthone III (Du et al, 2022), P53 Loganin (Pan et al, 2021) and P151 Natsudaidain 3-(4-O-3-Hydroxy-3-Methylglutaroylglucoside) (Okuyama et al, 2017) have been shown to exert their effects through various mechanisms, including changes in neurotransmitter levels, increased cAMP levels and amelioration of locomotor hyperactivity…”

Section: Discussionmentioning

confidence: 99%

Chemical characterization and metabolic profiling of Xiao-Er-An-Shen Decoction by UPLC-QTOF/MS

Yang,

Wei,

Wang

et al. 2023

Front. Pharmacol.

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Background: Xiao-Er-An-Shen decoction (XEASD), a TCM formula composed of sixteen Chinese medicinal herbs, has been used to alleviate tic disorders (TD) in clinical practice for many years. However, the chemical basis underlying the therapeutic effects of XEASD in the treatment of TD remains unknown.Purpose: The present study aimed to determine the major chemical components of XEASD and its prototype compounds and metabolites in mice biological samples.Methods: The chemical constituents in XEASD were identified using ultra-high Performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Following this, XEASD was orally administered to mice, and samples of plasma, urine, feces, bile, and tissue were collected in order to identify effective compounds for the prevention or treatment of TD.Result: Of the total 184 compounds identified to be discriminated in the XEASD, comprising 44 flavonoids, 26 phenylpropanoids, 16 coumarins, 16 triterpenoids, 14 amino acids, 13 organic acids, 13 alkaloids, 13 ketones, 10 cyclic enol ether terpenes, 7 citrullines, 3 steroids, and 5 anthraquinones, and others. Furthermore, we summarized 54 prototype components and 78 metabolic products of XEASD, measured with biological samples, by estimating metabolic principal components, with four prototype compounds detected in plasma, 58 prototypes discriminated in urine, and 40 prototypes identified in feces. These results indicate that the Oroxylin A glucuronide from Citri reticulatae pericarpium (CRP) is a major compound with potential therapeutic effects identified in brain, while operating positive effect in inhibiting oxidative stress in vitro.Conclusion: In summary, our work delineates the chemical basis underlying the complexity of XEASD, providing insights into the therapeutic and metabolic pathways for TD. Various types of chemicals were explored in XEASD, including flavonoids, phenylpropanoids, coumarins, organic acids, triterpenoid saponins, and so on. This study can promote the further pharmacokinetic and pharmacological evaluation of XEASD.

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Section: Discussionmentioning

confidence: 99%

Chemical characterization and metabolic profiling of Xiao-Er-An-Shen Decoction by UPLC-QTOF/MS

Yang,

Wei,

Wang

et al. 2023

Front. Pharmacol.

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“…The animals were administered with increasing doses of KA-228 and KA-232, and the anticonvulsant activity of each drug was evaluated as the ED 50 . This experimental procedure has been described in detail in our previous studies [19,35].…”

Section: -Hz (32 Ma) Seizure Modelmentioning

confidence: 99%

“…The results for KA-11 were used from Kaminski et al[6]; see compound 11. ED 50 and TD 50 of valproic acid (VPA) were used from Zagaja et al[8,19] and Kaminski et al[20].…”

mentioning

confidence: 99%

In Vivo and In Vitro Characterization of Close Analogs of Compound KA-11, a New Antiseizure Drug Candidate

Andres-Mach

Zagaja

Szala-Rycaj

et al. 2023

IJMS

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Epilepsy is a neurological disorder involving a number of disease syndromes with a complex etiology. A properly matched antiseizure drug (ASD) gives remission in up to 70% of patients. Nevertheless, there is still a group of about 30% of patients suffering from drug-resistant epilepsy. Consequently, the development of new more effective and/or safer ASDs is still an unmet clinical need. Thus, our current studies were focused on the structural optimization/modifications of one of the leading compounds, KA-11, aiming at the improvement of its antiseizure activity. As a result, we designed and synthesized two close analogs with highly pronounced drug-like physicochemical properties according to in silico predictions, namely KA-228 and KA-232, which were subsequently tested in a panel of animal seizure models, i.e., MES, 6 Hz (32 mA), scPTZ and ivPTZ. Among these compounds, KA-232, which was designed as a water-soluble salt, was distinctly more effective than KA-228 and assured similar antiseizure protection as its chemical prototype KA-11. With the aim of a more detailed characterization of both new molecules, in vitro binding tests were performed to evaluate the potential mechanisms of action. Furthermore, KA-232 was also evaluated in several ADME-Tox studies, and the results obtained strongly supported its drug-like potential. The proposed chemical modification of KA-11 enabled the identification of new pharmacologically active chemotypes, particularly water-soluble KA-232, which, despite the lack of better efficacy than the leading compound, may be used as a chemical prototype for the development of new ASDs, as well as substances potentially active in other neurological or neurodegenerative conditions.

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“…Coumarins are phenolic compounds produced in plants as secondary metabolites. Most known coumarins include coumarin, umbelliferone, scopoletin and esculetin and have several interesting biological activities, including anti-inflammatory, anticancer, neuroprotective, antifungal, antibacterial, antidiabetic, antiepileptic, cardiovascular protective, antiulcerogenic, and antidiarrheal, among others [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. For example, several coumarins have been studied in clinical trials and demonstrated potential in the treatment of leukemia, renal, and prostate cancers, among others [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Challenges in the Heterologous Production of Furanocoumarins in Escherichia coli

2022

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Coumarins and furanocoumarins are plant secondary metabolites with known biological activities. As they are present in low amounts in plants, their heterologous production emerged as a more sustainable and efficient approach to plant extraction. Although coumarins biosynthesis has been positively established, furanocoumarin biosynthesis has been far more challenging. This study aims to evaluate if Escherichia coli could be a suitable host for furanocoumarin biosynthesis. The biosynthetic pathway for coumarins biosynthesis in E. coli was effectively constructed, leading to the production of umbelliferone, esculetin and scopoletin (128.7, 17.6, and 15.7 µM, respectively, from tyrosine). However, it was not possible to complete the pathway with the enzymes that ultimately lead to furanocoumarins production. Prenyltransferase, psoralen synthase, and marmesin synthase did not show any activity when expressed in E. coli. Several strategies were tested to improve the enzymes solubility and activity with no success, including removing potential N-terminal transit peptides and expression of cytochrome P450 reductases, chaperones and/or enzymes to increase dimethylallylpyrophosphate availability. Considering the results herein obtained, E. coli does not seem to be an appropriate host to express these enzymes. However, new alternative microbial enzymes may be a suitable option for reconstituting the furanocoumarins pathway in E. coli. Nevertheless, until further microbial enzymes are identified, Saccharomyces cerevisiae may be considered a preferred host as it has already been proven to successfully express some of these plant enzymes.

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Influence of Umbelliferone on the Anticonvulsant and Neuroprotective Activity of Selected Antiepileptic Drugs: An In Vivo and In Vitro Study

Cited by 8 publications

References 77 publications

Chemical characterization and metabolic profiling of Xiao-Er-An-Shen Decoction by UPLC-QTOF/MS

Chemical characterization and metabolic profiling of Xiao-Er-An-Shen Decoction by UPLC-QTOF/MS

In Vivo and In Vitro Characterization of Close Analogs of Compound KA-11, a New Antiseizure Drug Candidate

Challenges in the Heterologous Production of Furanocoumarins in Escherichia coli

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