title: Neuroprotective Potential of Novel Multi-Targeted Isoalloxazine Derivatives in Rodent Models of Alzheimer's Disease Through Activation of Canonical Wnt/β-Catenin Signalling Pathway.
abstract: Previous reports suggest that Alzheimer's disease is protected by cholinesterase inhibitors. We synthesized some isoalloxazine derivatives and evaluated them using in vitro cholinesterase inhibition assay. Two of the compounds (7m and 7q) were figured out as potent cholinesterase inhibitors. They further showed anti-Aβ aggregatory activity in the in vitro assay. The current study deals with the evaluation of neuroprotective potentials of the potent compounds (7m and 7q) using different in vitro and in vivo experiments. The compounds were first assessed for their tendency to cross blood-brain barrier using in vitro permeation assay. They were evaluated using scopolamine-induced amnesic mice model. Additionally, ROS scavenging and anti-apoptotic properties of 7m and 7q were established against Aβ1-42-induced toxicity in rat hippocampal neuronal cells. 7m and 7q were also evaluated using Aβ1-42-induced Alzheimer's rat model. Lastly, their involvement in Wnt/β-catenin pathway was also demonstrated. The results indicated good CNS penetration for 7m and 7q. The neuroprotective effects of 7m and 7q were evidenced by improved cognitive ability in both scopolamine and Aβ1-42-induced Alzheimer's-like condition in rodents. The in vivo results also confirmed their anti-cholinesterase and anti-oxidant potential. Immunoblot results showed that treatment with 7m and 7q decreased Aβ1-42, p-tau, cleaved caspase-3, and cleaved PARP levels in Aβ1-42-induced Alzheimer's rat brain. Additionally, immunoblot results demonstrated that 7m and 7q activated the Wnt/β-catenin pathway as evidenced by increased p-GSK-3, β-catenin, and neuroD1 levels in Aβ1-42-induced Alzheimer's rat brain. These findings have shown that isoalloxazine derivatives (7m and 7q) could be the potential leads for developing effective drugs for the treatment of AD.
authors.affiliation: Faculty of Pharmacy, Kalabhavan, The M. S. University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Jatin
authors.initials: J
authors.lastname: Machhi
authors.affiliation: Faculty of Pharmacy, Kalabhavan, The M. S. University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Anshuman
authors.initials: A
authors.lastname: Sinha
authors.affiliation: Faculty of Pharmacy, Kalabhavan, The M. S. University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Pratik
authors.initials: P
authors.lastname: Patel
authors.affiliation: Faculty of Pharmacy, Kalabhavan, The M. S. University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kanhed
authors.affiliation: Faculty of Pharmacy, Kalabhavan, The M. S. University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Pragnesh
authors.initials: P
authors.lastname: Upadhyay
authors.affiliation: Division of Neurobiology, Department of Zoology, Faculty of Science, The M. S. University of Baroda, Vadodara, Gujarat, 390002, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tripathi
authors.affiliation: Division of Neurobiology, Department of Zoology, Faculty of Science, The M. S. University of Baroda, Vadodara, Gujarat, 390002, India.
authors.forename: Zalak S
authors.initials: ZS
authors.lastname: Parikh
authors.affiliation: Department of Biochemistry, Faculty of Science, The M. S. University of Baroda, Vadodara, Gujarat, 390002, India.
authors.forename: Ragitha
authors.initials: R
authors.lastname: Chruvattil
authors.affiliation: Division of Neurobiology, Department of Zoology, Faculty of Science, The M. S. University of Baroda, Vadodara, Gujarat, 390002, India.
authors.forename: Prakash P
authors.initials: PP
authors.lastname: Pillai
authors.affiliation: Department of Biochemistry, Faculty of Science, The M. S. University of Baroda, Vadodara, Gujarat, 390002, India.
authors.forename: Sarita
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Faculty of Pharmacy, Kalabhavan, The M. S. University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Kirti
authors.initials: K
authors.lastname: Patel
authors.affiliation: Faculty of Pharmacy, Kalabhavan, The M. S. University of Baroda, Vadodara, Gujarat, 390001, India.
authors.forename: Rajani
authors.initials: R
authors.lastname: Giridhar
authors.affiliation: Faculty of Pharmacy, Kalabhavan, The M. S. University of Baroda, Vadodara, Gujarat, 390001, India. mryadav11@yahoo.co.in.
authors.forename: Mange Ram
authors.initials: MR
authors.lastname: Yadav
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D005415:Flavins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018727:Muscarinic Antagonists / Q000633:toxicity; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010446:Peptide Fragments / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012601:Scopolamine / Q000633:toxicity; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D005415:Flavins; D018727:Muscarinic Antagonists; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D051176:beta Catenin; C008173:isoalloxazine; D012601:Scopolamine; D002374:Catalase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer’s disease; Aβ1–42; Isoalloxazine; Wnt pathway; p-GSK-3