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Identification and Kinetic Characterization of Monoamine Oxidase A and B Inhibitors from Psoralea corylifolia Seeds
Başlık:
Identification and Kinetic Characterization of Monoamine Oxidase A and B Inhibitors from Psoralea corylifolia Seeds
Yazar:
Zarmouh, Najla Omar, author.
ISBN:
9780438009097
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (239 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Karam F. A. Soliman Committee members: Selina F. Darling-Reed; Carl B. Goodman; Ebenezer T. Oriaku.
Özet:
Although improved life expectancy, current treatments for Parkinson disease (PD) elucidated multiple adverse effects. The used drugs did not address disease progression and become costly in the long-term use. Chronic therapy is limited by motor complications associated with dyskinesia, psychosis and wearing off complications. The emerging pharmacotherapeutic approaches are focusing on finding novel neuroprotective antiparkinsonian therapeutics that halt, slow, or eliminate the disease progression with the least side effects. The multifunctional monoamine oxidase inhibitors (MAOIs) approach, and particularly MAO-BIs, has captured scientific attention after pharmacological and clinical trials of neuroprotection.
In this research, we hypothesized that phytochemicals have a potential novel strategy to safely inhibit MAOs and maintain dopamine. We investigated the natural plant products for their efficacy against recombinant human (h)MAO-A and MAO-B with the emphasis on disclosing their mechanism of action as an indication of safety and efficacy. Different methods including fluorescent, spectrophotometric, and luminescent techniques were adopted in MAOs assays. A high throughput screening of 132 identified plant ethanolic extracts was conducted for their hMAO-A and hMAO-B inhibitions and selectivities. Psoralea corylifolia L. seeds (PCS) was the plant of choice as a selective h MAO-B inhibitor resource for further studies. Six of PCS benzopyrone phytochemical constituents (biochanin-A (BIO-A), isopsoralen, 6-prenylnaringenin, neobavaisoflavone, psoralen, and psoralidin, compared to PCS ethanolic extract (PCSEE)) were assayed. BIO-A as the most potent and selective hMAO-B inhibitor identified to be in PCSEE using thin layer chromatography (TLC). BIO-A was investigated for its reversibility and enzyme kinetics mode of inhibition. Its underlying molecular mechanisms of action was predicted in silico using docking studies. Further, the BIO-A biological metabolite genistein (GST) in comparison to its analog daidzein (DZ), and the PCS unique flavanone bavachinin (BNN), in comparison to its analog bavachin (BVN), were tested for hMAO-A and hMAO-B isozymes inhibition effects, potency, selectivity, and kinetic mode of inhibition. Furthermore, phytochemicals molecular interactions with both isozymes of active GST and BNN inhibitors, in comparison to the partially active inhibitor analog daidzein and the activator analog BVN, respectively, were interpreted utilizing docking studies.
The obtained results indicated that the most potent and selective hMAO-B inhibitors were the ethanolic extracts (EEs) of PCS, Ferula assafoetida resins (FAR), Glycyrrhiza uralensis roots (GUR), and Phellodendron amurense barks (PAB). With PCS ranking the most potent and selective hMAO-BI, five out of its six investigated benzopyrones against hMAO-A and hMAO-B showed variable inhibitory effects. Notably, BIO-A was identified as the most potent and selective hMAO-BI with a reversible and competitive inhibition on both isozymes. BIO-A docking results specified reversible bonds to be responsible for the selective reversible inhibition and included hydrophobic interactions and two formed hydrogen bonds, one of which is the threonine 201 residue of the MAO-B active site. Its metabolite GST was also a reversible selective hMAOI with higher affinity to hMAO-B. With the very high hydrophobic interactions, the GST molecule was predicted to have stronger hydrogen (H)-bonds with the threonine 201 than its partially active analog DZ that is devoid of its extra C5-OH group. Meanwhile, BNN, detected in PCSEE using TLC and HPLC, inhibited hMAO-A and hMAO-B competitively with a significantly higher affinity to inhibit hMAO-B more than hMAO-A, and consequently reduced its efficiency (Km / Vmax). BNN high affinity and the selective MAO-B inhibition was predicted to be due to BNN C7-methoxy group that contributed to two interactions with threonine 201 residue. Conversely, BVN showed no interactions with a corresponding activation of both isozymes rather than inhibition.
Compared to any screened medicinal plants in this work, our studies indicated that PCSEE possesses a high inhibition of hMAO isozymes with selectivity against hMAO-B. FAR, GUR, and PAB are other plants to be considered as a source of selective MAO-BIs. In this dissertation, BIO-A, GST, and BNN were identified as new or novel compounds that are effective reversible and competitive MAOIs, with MAO-B specific affinity and inhibitions, possibly by their interaction with threonine 201 of MAO-B active site. That mechanism holds an intrinsic self-healing to the isozymes when needed, and thus, least side effects. The results are expected to have a positive translational impact as they support the hypothesis of natural MAO-BIs safe neuroprotection.
Notlar:
School code: 0872
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(677869.1) | 677869-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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