title: Neuroprotective Role of Novel Triazine Derivatives by Activating Wnt/β Catenin Signaling Pathway in Rodent Models of Alzheimer's Disease.
abstract: It has been reported in the literature that cholinesterase inhibitors provide protection in Alzheimer's disease (AD). Recent reports have implicated triazine derivatives as cholinesterase inhibitors. These findings led us to investigate anti-cholinestrase property of some novel triazine derivatives synthesized in this laboratory. In vitro cholinesterase inhibition assay was performed using Ellman method. The potent compounds screened out from in vitro assay were further evaluated using scopolamine-induced amnesic mice model. Further, in vitro reactive oxygen species (ROS) scavenging and anti-apoptotic property of the potent compounds were demonstrated against Aβ1-42-induced neurotoxicity in rat hippocampal cells. Their neuroprotective role was assessed using Aβ1-42-induced Alzheimer's-like phenotype in rats. Further, the role of compounds on the activation of the Wnt/β-catenin pathway was studied. The results showed that the chosen compounds are having protective effect in Alzheimer's-like condition; the ex vivo results advocated their anti-cholinestrase and anti-oxidant activities. Treatment with TRZ-15 and TRZ-20 showed neuroprotective ability of the compounds as evidenced from the improved cognitive ability in the animals, and decrease in Aβ1-42 burden and cytochrome c and cleaved caspase-3 levels in the brain. This study also demonstrates positive involvement of the novel triazine derivatives in the Wnt/β-catenin pathway. Immunoblot and immunofluorescence data suggested that ratio of pGSK3/GSK3 and β-catenin got dramatically improved after treatment with TRZ-15 and TRZ-20. TRZ-15 and TRZ-20 showed neuroprotection in scopolamine-induced amnesic mice and Aβ1-42-induced Alzheimer's rat model and also activate the Wnt/β-catenin signaling pathway. These findings conclude that TRZ-15 and TRZ-20 could be a therapeutic approach to treat AD.
authors.affiliation: Pharmacy Department, Faculty of Technology & Engineering, Kalabhavan, The MS University of Baroda, Vadodara, 390001, Gujarat, India.
authors.forename: Anshuman
authors.initials: A
authors.lastname: Sinha
authors.forename: Riyaj S
authors.initials: RS
authors.lastname: Tamboli
authors.forename: Brashket
authors.initials: B
authors.lastname: Seth
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kanhed
authors.forename: Shashi Kant
authors.initials: SK
authors.lastname: Tiwari
authors.forename: Swati
authors.initials: S
authors.lastname: Agarwal
authors.forename: Saumya
authors.initials: S
authors.lastname: Nair
authors.forename: Rajani
authors.initials: R
authors.lastname: Giridhar
authors.forename: Rajnish Kumar
authors.initials: RK
authors.lastname: Chaturvedi
authors.forename: Mange Ram
authors.initials: MR
authors.lastname: Yadav
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D062105:Molecular Docking Simulation; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D017208:Rats, Wistar; D012601:Scopolamine; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D014227:Triazines; D051176:beta Catenin; D045304:Cytochromes c; D012601:Scopolamine; D038362:Glycogen Synthase Kinase 3; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D053148:Caspase 3