Title: Diclofenac derivatives as concomitant inhibitors of cholinesterase, monoamine oxidase, cyclooxygenase-2 and 5-lipoxygenase for the treatment of Alzheimer's disease: synthesis, pharmacology, toxicity and docking studies Javed MA, Bibi S, Jan MS, Ikram M, Zaidi A, Farooq U, Sadiq A, Rashid U Ref: RSC Adv, 12:22503, 2022 : PubMed
Targeting concomitantly cholinesterase (ChEs) and monoamine oxidases (MAO-A and MAO-B) is a key strategy to treat multifactorial Alzheimer's disease (AD). Moreover, it is reported that the expression of cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) is increased significantly in the brain of AD patients. Using the triazole of diclofenac 12 as a lead compound, we synthesized a variety of analogs as multipotent inhibitors concomitantly targeting COX-2, 5-LOX, AChE, BChE, MAO-A and MAO-B. A number of compounds showed excellent in vitro inhibition of the target biological macromolecules in nanomolar concentration. Compound 39 emerged as the most potent multitarget ligand with IC(50) values of 0.03 microM, 0.91 microM, 0.61 microM, 0.01 microM 0.60 microM and 0.98 microM towards AChE, BChE, MAO-A, MAO-B, COX-2 and 5-LOX respectively. All the biologically active compounds were found to be non-neurotoxic and blood-brain barrier penetrant by using PAMPA assay. In a reversibility assay, all the studied active compounds showed reversibility and thus were found to be devoid of side effects. MTT assay results on neuroblastoma SH-SY5Y cells showed that the tested compounds were non-neurotoxic. An in vivo acute toxicity study showed the safety of the synthesized compounds up to a 2000 mg kg(-1) dose. In docking studies three-dimensional construction and interaction with key residues of all the studied biological macromolecules helped us to explain the experimental results.
Organophosphates (OPs) and synthetic pyrethroids (SPs) are the most popular broad spectrum pesticides, used in agriculture as they have a strong pesticidal activity while also being biodegradable in the environment. The present study aimed to demonstrate the effects of these pesticides on the Acetylcholinesterase (AChE) activity in brain, gills and body muscles of Oreochromis niloticus- an important enzyme for the assessment and biomonitoring pollution caused by neurotoxins in the environment. The fish were exposed for 24 and 48h to the LC(0) concentrations of the malathion (1.425mg/L), the chlorpyrifos (0.125mg/L) and the lambda-cyhalothrin (0.0039mg/L), respectively. The activity of the AChE was significantly increased (p < 0.05) at 24hours and decreased at 48hours (except for the chlorpyrifos- treated brain and gills while tissues had shown no activity at 48 hours' exposure) in all pesticides- treated tissues. The maximum increase in the activity and inhibition in the AChE activity were recorded as +92% and -52% in the chlorpyrifos and the lambda -cyhalothrin exposed brain tissues, respectively. Thus, the alterations in the AChE activities indicated that the applied pesticides are highly neurotoxic to fish and the enzyme (AChE) could be used as a useful biomarker for estimation of water pollution.
To obtain a multipotent framework that can target simultaneously COX-2, 5-LOX, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) to treat neuroinflammation, a series of derivatives containing pyrimidine and pyrrolidine cores were rationally synthesized and evaluated. Pyrazoline-pyrimidine hybrid (23g), (3-acetylcoumarin derivative of pyrrolidin-1-yl)benzenesulfonamide (27), and tacrine derivatives of (pyrrolidin-1-yl)benzenesulfonamide (31, 38) displayed excellent in vitro COX-2 inhibition having IC(50) value in the nanomolar range. Tacrine-pyrrolidine hybrids 36 and 38, and tacrine-pyrimidine hybrid (46) emerged as the most potent eeAChE inhibitors with IC(50) values of 23, 16, and 2 nM, respectively. However, compounds 27, 31, and 38 possessed excellent simultaneous and balanced inhibitory activity against all of the four tested targets and thus emerged as optimal multipotent hybrid compounds among all of the synthesized series of the compounds. In the ex vivo, transgenic animal models treated with compounds 36 and 46 displayed a significant decline in both AChE and BChE potentials in the hippocampus and cortical tissues. In anti-inflammatory activities, animals treated with compounds 36 and 46 displayed a significant % inhibition of edema induced by carrageenan and arachidonic acid. Biochemical analysis and histopathological examination of mice liver indicate that tacrine derivatives are devoid of hepatotoxicity and neurotoxicity against SH-SY5Y neuroblastoma cell lines. In vivo acute toxicity study showed the safety of synthesized compounds up to 1000 mg/kg dose. The inhibitory manner of interaction of these potent drugs on all of the studied in vitro targets was confirmed by molecular docking investigations.
Flavonoids are a class of natural substances present in plants, fruits, vegetables, wine, bulbs, bark, stems, roots, and tea. Several attempts are being made to isolate such natural products, which are popular for their health benefits. Flavonoids are now seen as an essential component in a number of cosmetic, pharmaceutical, and medicinal formulations. Quercetin is the major polyphenolic flavonoid found in food products, including berries, apples, cauliflower, tea, cabbage, nuts, and onions that have traditionally been treated as anticancer and antiviral, and used for the treatment of allergic, metabolic, and inflammatory disorders, eye and cardiovascular diseases, and arthritis. Pharmacologically, quercetin has been examined against various microorganisms and parasites, including pathogenic bacteria, viruses, and Plasmodium, Babesia, and Theileria parasites. Additionally, it has shown beneficial effects against Alzheimer's disease (AD), and this activity is due to its inhibitory effect against acetylcholinesterase. It has also been documented to possess antioxidant, antifungal, anti-carcinogenic, hepatoprotective, and cytotoxic activity. Quercetin has been documented to accumulate in the lungs, liver, kidneys, and small intestines, with lower levels seen in the brain, heart, and spleen, and it is extracted through the renal, fecal, and respiratory systems. The current review examines the pharmacokinetics, as well as the toxic and biological activities of quercetin.
Title: Antioxidant and Neuroprotective Effects of Caffeine against Alzheimer's and Parkinson's Disease: Insight into the Role of Nrf-2 and A2AR Signaling Ikram M, Park TJ, Ali T, Kim MO Ref: Antioxidants (Basel), 9:, 2020 : PubMed
This paper reviews the results of studies conducted on the role of caffeine in the management of different neurological disorders, such as Parkinson's disease (PD) and Alzheimer's disease (AD). To highlight the potential role of caffeine in managing different neurodegenerative diseases, we identified studies by searching PubMed, Web of Science, and Google Scholar by scrutinizing the lists of pertinent publications. According to the collected overall findings, caffeine may reduce the elevated oxidative stress; inhibit the activation of adenosine A2A, thereby regulating the accumulation of Abeta; reduce the hyperphosphorylation of tau; and reduce the accumulation of misfolded proteins, such as alpha-synuclein, in Alzheimer's and Parkinson's diseases. The studies have suggested that caffeine has promising protective effects against different neurodegenerative diseases and that these effects may be used to tackle the neurological diseases and/or their consequences. Here, we review the ongoing research on the role of caffeine in the management of different neurodegenerative disorders, focusing on AD and PD. The current findings suggest that caffeine produces potent antioxidant, inflammatory, and anti-apoptotic effects against different models of neurodegenerative disease, including AD, PD, and other neurodegenerative disorders. Caffeine has shown strong antagonistic effects against the adenosine A2A receptor, which is a microglial receptor, and strong agonistic effects against nuclear-related factor-2 (Nrf-2), thereby regulating the cellular homeostasis at the brain by reducing oxidative stress, neuroinflammation, regulating the accumulation of alpha-synuclein in PD and tau hyperphosphorylation, amyloidogenesis, and synaptic deficits in AD, which are the cardinal features of these neurodegenerative diseases.
