Neuroprotective Role of Novel Triazine Derivatives by Activating Wnt/[beta] Catenin Signaling Pathway in Rodent Models of Alzheimer's Disease

• Published in: Molecular neurobiology Vol. 52; no. 1; p. 638
• Main Authors: Sinha, Anshuman, Tamboli, Riyaj S, Seth, Brashket, Kanhed, Ashish M, Tiwari, Shashi Kant, Agarwal, Swati, Nair, Saumya, Giridhar, Rajani, Chaturvedi, Rajnish Kumar, Yadav, Mange Ram
• Format: Journal Article
• Language: English
• Published: Totowa Springer Nature B.V 01.08.2015
• Subjects: Alzheimer's disease; Neurobiology; Rodents
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-014-8899-y

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 A[beta]^sub 1-42^-induced neurotoxicity in rat hippocampal cells. Their neuroprotective role was assessed using A[beta]^sub 1-42^-induced Alzheimer's-like phenotype in rats. Further, the role of compounds on the activation of the Wnt/[beta]-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 A[beta]^sub 1-42^ 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/[beta]-catenin pathway. Immunoblot and immunofluorescence data suggested that ratio of pGSK3/GSK3 and [beta]-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 A[beta]^sub 1-42^-induced Alzheimer's rat model and also activate the Wnt/[beta]-catenin signaling pathway. These findings conclude that TRZ-15 and TRZ-20 could be a therapeutic approach to treat AD.