Neuroprotective Potential of Novel Multi-Targeted Isoalloxazine Derivatives in Rodent Models of Alzheimer's Disease Through Activation of Canonical Wnt/β-Catenin Signalling Pathway.
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.
['Machhi|Jatin|J|', 'Sinha|Anshuman|A|', 'Patel|Pratik|P|', 'Kanhed|Ashish M|AM|', 'Upadhyay|Pragnesh|P|', 'Tripathi|Ashutosh|A|', 'Parikh|Zalak S|ZS|', 'Chruvattil|Ragitha|R|', 'Pillai|Prakash P|PP|', 'Gupta|Sarita|S|', 'Patel|Kirti|K|', 'Giridhar|Rajani|R|', 'Yadav|Mange Ram|MR|']
D000110:Acetylcholinesterase D000544:Alzheimer Disease D016229:Amyloid beta-Peptides D000818:Animals D017209:Apoptosis D002091:Butyrylcholinesterase D002374:Catalase D002478:Cells, Cultured D002800:Cholinesterase Inhibitors D004195:Disease Models, Animal D005415:Flavins D008297:Male D018782:Maze Learning D051379:Mice D018727:Muscarinic Antagonists D009474:Neurons D018696:Neuroprotective Agents D010446:Peptide Fragments D051381:Rats D017208:Rats, Wistar D017382:Reactive Oxygen Species D012601:Scopolamine D060449:Wnt Signaling Pathway D051176:beta Catenin
Isoalloxazine p-GSK-3 Alzheimer’s disease Aβ1–42 Wnt pathway