Development of 2-Methoxyhuprine as Novel Lead for Alzheimer’s Disease Therapy

Mezeiová, Eva; Korábečný, Jan; Šepsová, Vendula; Hrabinová, Martina; Jost, Philipp J.; Múčková, Lubica; Kučera, Tomáš; Doležal, Rafael; Mišík, Ján; Špilovská, Katarína; Pham, Ngoc Lam; Pokrievkova, Lucia; Roh, Jaroslav; Jun, Daniel; Soukup, Ondřej; Kaping, Daniel; Kuča, Kamil

doi:10.3390/molecules22081265

Cited by 28 publications

(12 citation statements)

References 77 publications

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“…The currently available drug therapies for neurodegenerative diseases are palliative with limited effectiveness and adverse side effects [ 7 – 9 ]. The major challenge for the researchers is to develop a therapy that addresses the underlying cause/mechanism of degeneration with improved effectiveness and least side effects.…”

Section: Introductionmentioning

confidence: 99%

Tinospora cordifolia as a potential neuroregenerative candidate against glutamate induced excitotoxicity: an in vitro perspective

Sharma

Kaur

2018

BMC Complement Altern Med

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BackgroundGlutamate, the major excitatory neurotransmitter of CNS acts as a neurotoxin at higher concentrations. Prolonged activation of glutamate receptors results in progressive neuronal damage by aggravating calcium influx, inducing mitochondrial damage and oxidative stress. Excitotoxic cell death is associated with the pathogenesis of various neurodegenerative disorders such as trauma, brain injury and neurodegenerative diseases. The current study was designed to investigate the neuroprotective and neuroregenerative potential of Tinospora cordifolia against glutamate-induced excitotoxicity using primary cerebellar neuronal cultures as a model system.MethodsMonosodium salt of glutamate was used to induce neurotoxic injury in primary cerebellar neurons. Four extracts including Hexane extract, Chloroform extract, Ethyl acetate, and Butanol extract were obtained from fractionation of previously reported aqueous ethanolic extract of T. cordifolia and tested for neuroprotective activity. Out of the four fractions, Butanol extract of T. cordifolia (B-TCE) exhibited neuroprotective potential by preventing degeneration of neurons induced by glutamate. Expression of different neuronal, apoptotic, inflammatory, cell cycle regulatory and plasticity markers was studied by immunostaining and Western blotting. Neurite outgrowth and migration were also studied using primary explant cultures, wound scratch and gelatin zymogram assay.ResultsAt molecular level, B-TCE pretreatment of glutamate-treated cultures normalized the stress-induced downregulation in the expression of neuronal markers (MAP-2, GAP-43, NF200) and anti-apoptotic marker (Bcl-xL). Further, cells exposed to glutamate showed enhanced expression of inflammatory (NF-κB, AP-1) and senescence markers (HSP70, Mortalin) as well as the extent of mitochondrial damage. However, B-TCE pretreatment prevented this increase and inhibited glutamate-induced onset of inflammation, stress and mitochondrial membrane damage. Furthermore, B-TCE was observed to promote regeneration, migration and plasticity of cerebellar neurons, which was otherwise significantly inhibited by glutamate treatment.ConclusionThese results suggest that B-TCE may have neuroprotective and neuroregenerative potential against catastrophic consequences of glutamate-mediated excitotoxicity and could be a potential therapeutic candidate for neurodegenerative diseases.Electronic supplementary materialThe online version of this article (10.1186/s12906-018-2330-6) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Tinospora cordifolia as a potential neuroregenerative candidate against glutamate induced excitotoxicity: an in vitro perspective

Sharma

Kaur

2018

BMC Complement Altern Med

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“…7-MEOTA was prepared at the University of Defense (Faculty of Military Health Sciences, Hradec Kralove, Czech Republic) by the previously described method 39 , 97 , 98 . Other reagents were obtained from Sigma-Aldrich (Prague, Czech Republic) in reagent grade quality.…”

Section: Methodsmentioning

confidence: 99%

In vitro investigating of anticancer activity of new 7-MEOTA-tacrine heterodimers

Janočková

Korábečný

Plsikova

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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A combination of biochemical, biophysical and biological techniques was used to study calf thymus DNA interaction with newly synthesized 7-MEOTA-tacrine thiourea 12 – 17 and urea heterodimers 18 – 22 , and to measure interference with type I and II topoisomerases. Their biological profile was also inspected in vitro on the HL-60 cell line using different flow cytometric techniques (cell cycle distribution, detection of mitochondrial membrane potential dissipation, and analysis of metabolic activity/viability). The compounds exhibited a profound inhibitory effect on topoisomerase activity (e.g. compound 22 inhibited type I topoisomerase at 1 µM concentration). The treatment of HL-60 cells with the studied compounds showed inhibition of cell growth especially with hybrids containing thiourea ( 14–17 ) and urea moieties ( 21 and 22 ). Moreover, treatment of human dermal fibroblasts with the studied compounds did not indicate significant cytotoxicity. The observed results suggest beneficial selectivity of the heterodimers as potential drugs to target cancer cells.

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“…The cholinesterase enzymes have approved drugs for AD treatment. [11,21] The use of acetylcholinesterase inhibitors (AChEIs) has gained popularity in the quest to find a cure for Alzheimer. There are three AChEIs namely, donepezil, rivastigmine, and galantamine, approved by the FDA for the treatment of mild to moderate AD.…”

Section: Dr Hezekiel M Kumalo Is a Principal Investigator And Seniomentioning

confidence: 99%

Design and Development of Cholinesterase Dual Inhibitors towards Alzheimer's Disease Treatment: A Focus on Recent Contributions from Computational and Theoretical Perspective

2020

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In recent times, review topics on Alzheimer's disease (AD) have received massive attention, especially on drug design and development of potent inhibitors targeting specific pathway(s) of this multifaceted disease. Drug design and development through the use of computer has taken an intriguing dimension over the last two decades, and AD drug design is not an exception. Computational approaches have found usage in identifying potentially active molecules targeting specific enzyme or gene in the pathological pathway of a disease such as AD. Herein, we present an overview of research contributions over the last ten years from different authors who had used computational approaches to explore potent dual inhibitors of the cholinesterase enzymes linked with AD patho-genesis. We gave an introductory background of the disease, highlight challenges of in silico approach to drug design, and discuss its pros and cons. The overview also covers previously reported review works which are related to the topic. We proposed that continued research efforts to unravel more effective dual acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors through computational tools could plausibly be a successful approach to AD cure. Computational researchers should leverage on the available cost-effective resources to identify lead compounds and work in collaboration with experimental personnel to push their discovery forward.

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Development of 2-Methoxyhuprine as Novel Lead for Alzheimer’s Disease Therapy

Cited by 28 publications

References 77 publications

Tinospora cordifolia as a potential neuroregenerative candidate against glutamate induced excitotoxicity: an in vitro perspective

Tinospora cordifolia as a potential neuroregenerative candidate against glutamate induced excitotoxicity: an in vitro perspective

In vitro investigating of anticancer activity of new 7-MEOTA-tacrine heterodimers

Design and Development of Cholinesterase Dual Inhibitors towards Alzheimer's Disease Treatment: A Focus on Recent Contributions from Computational and Theoretical Perspective

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