Neuroprotective Potential of Novel Multi-Targeted Isoalloxazine Derivatives in Rodent Models of Alzheimer’s Disease Through Activation of Canonical Wnt/β-Catenin Signalling Pathway

• Published in: Neurotoxicity research 2016-05, Vol.29 (4), p.495-513
• Main Authors: Machhi, Jatin, Sinha, Anshuman, Patel, Pratik, Kanhed, Ashish M., Upadhyay, Pragnesh, Tripathi, Ashutosh, Parikh, Zalak S., Chruvattil, Ragitha, Pillai, Prakash P., Gupta, Sarita, Patel, Kirti, Giridhar, Rajani, Yadav, Mange Ram
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase - metabolism; Alzheimer Disease - chemically induced; Alzheimer Disease - drug therapy; Amyloid beta-Peptides - toxicity; Animals; Apoptosis - drug effects; beta Catenin - metabolism; Biomedical and Life Sciences; Biomedicine; Butyrylcholinesterase - metabolism; Catalase - metabolism; Cell Biology; Cells, Cultured; Cholinesterase Inhibitors - therapeutic use; Disease Models, Animal; Flavins - chemistry; Flavins - pharmacology; Flavins - therapeutic use; Male; Maze Learning - drug effects; Mice; Muscarinic Antagonists - toxicity; Neurobiology; Neurochemistry; Neurology; Neurons - drug effects; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurosciences; Original Article; Peptide Fragments - toxicity; Pharmacology/Toxicology; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; Scopolamine Hydrobromide - toxicity; Wnt Signaling Pathway - drug effects
• ISSN: 1029-8428; 1476-3524
• DOI: 10.1007/s12640-016-9598-4

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 Aβ 1–42 -induced toxicity in rat hippocampal neuronal cells. 7m and 7q were also evaluated using Aβ 1–42 -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 Aβ 1–42 -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 Aβ 1–42 , p -tau, cleaved caspase-3, and cleaved PARP levels in Aβ 1–42 -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 Aβ 1–42 -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.