Exploring the molecular approach of COX and LOX in Alzheimer’s and Parkinson’s disorder

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 IC50 value in the nanomolar range. Tacrine–pyrrolidine hybrids 36 and 38, and tacrine–pyrimidine hybrid (46) emerged as the most potent eeAChE inhibitors with IC50 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.

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“…AA is metabolized into prostaglandins and leukotrienes by enzymes LOX and COX. Both enzymes accompany neurodegeneration and aging. ,− …”

Section: Introductionmentioning

confidence: 99%

Structural Modification, In Vitro, In Vivo, Ex Vivo, and In Silico Exploration of Pyrimidine and Pyrrolidine Cores for Targeting Enzymes Associated with Neuroinflammation and Cholinergic Deficit in Alzheimer’s Disease

Javed

Ashraf

Jan

et al. 2021

ACS Chem. Neurosci.

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“…GPs mainly function as amphipathic molecules that form the backbone of biological membranes and as reservoirs for the generation of multiple bioactive mediators. Moreover, GPs serve as precursors for the synthesis of diacylglycerol, which favors membrane fusion, participates in neurotransmitter release, and modulates the activities of diverse kinases, such as 5-lipoxygenase. − In this study, cefepime treatment resulted in abnormalities in neurites, mitochondria, and synaptic vesicles, which are biological membrane-enriched structures in neurons. We speculated that cefepime-mediated dysregulation of GPs in the striatum may at least partially contribute to the aberrant membrane structure, which eventually leads to abnormal neurobehaviors.…”

Section: Discussionmentioning

confidence: 64%

Lipidomics Reveals Dysregulated Glycerophospholipid Metabolism in the Corpus Striatum of Mice Treated with Cefepime

Liu

Wei

Yang

et al. 2021

ACS Chem. Neurosci.

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Cefepime exhibits a broad spectrum of antimicrobial activity and thus is a widely used treatment for severe bacterial infections. Adverse effects on the central nervous system (CNS) have been reported in patients treated with cefepime. Current explanation for the adverse neurobehavioral effect of cefepime is mainly attributed to its ability to cross the blood–brain barrier and competitively bind to the GABAergic receptor; however, the underlying mechanism is largely unknown. In this study, mice were intraperitoneally administered 80 mg/kg cefepime for different periods, followed by neurobehavioral tests and a brain lipidomic analysis. LC/MS–MS-based metabolomics was used to investigate the effect of cefepime on the brain lipidomic profile and metabolic pathways. Repeated cefepime treatment time-dependently caused anxiety-like behaviors, which were accompanied by reduced locomotor activity in the open field test. Cefepime profoundly altered the lipid profile, acyl chain length, and unsaturation of fatty acids in the corpus striatum, and glycerophospholipids accounted for a large proportion of those significantly modified lipids. In addition, cefepime treatment caused obvious alteration in the lipid-enriched membrane structure, neurites, mitochondria, and synaptic vesicles of primary cultured striatal neurons; moreover, the spontaneous electrical activity of striatal neurons was significantly reduced. Collectively, cefepime reprograms glycerophospholipid metabolism in the corpus striatum, which may interfere with neuronal structure and activity, eventually leading to aberrant neurobehaviors in mice.

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“…Since that time, there has been little work reported specifically on sPLA 2 -IIA or hGIIA function in the CNS. Studies have concentrated on characterizing lipid mediator profiles in neuroinflammation [ 88 , 89 , 90 ]. While the evidence cited above suggests further investigation of the role of hGIIA in neuroinflammation is warranted, the tools needed to robustly evaluate hGIIA in the setting of neuroinflammation are lacking.…”

Section: Hgiia Functionmentioning

confidence: 99%

Human Group IIA Phospholipase A2—Three Decades on from Its Discovery

et al. 2021

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Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA2, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA2 field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Functionally-selective inhibitors together with isoform-selective inhibitors are necessary to limit the apparent toxicity of previous drugs. There is also a need to define the relevance of the catalytic function of hGIIA to human inflammatory pathology relative to its recently-discovered catalysis-independent function.

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Exploring the molecular approach of COX and LOX in Alzheimer’s and Parkinson’s disorder

Cited by 39 publications

References 94 publications

Structural Modification, In Vitro, In Vivo, Ex Vivo, and In Silico Exploration of Pyrimidine and Pyrrolidine Cores for Targeting Enzymes Associated with Neuroinflammation and Cholinergic Deficit in Alzheimer’s Disease

Structural Modification, In Vitro, In Vivo, Ex Vivo, and In Silico Exploration of Pyrimidine and Pyrrolidine Cores for Targeting Enzymes Associated with Neuroinflammation and Cholinergic Deficit in Alzheimer’s Disease

Lipidomics Reveals Dysregulated Glycerophospholipid Metabolism in the Corpus Striatum of Mice Treated with Cefepime

Human Group IIA Phospholipase A2—Three Decades on from Its Discovery

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