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.

Cerebral mTOR signal and pro-inflammatory cytokines in Alzheimer’s disease rats

“…Caspases, a family of thiol proteases, are activated during the neurodegenerative process of AD and play an important regulating role in the apoptotic cascade [37, 38]. A feature of caspases in the cell is that they exist as zymogens, termed pro-caspases, which are inactive until a biochemical change causes their activation [39].…”

Design, green synthesis and pharmacological evaluation of novel 5,6-diaryl-1,2,4-triazines bearing 3-morpholinoethylamine moiety as potential antithrombotic agents

“…Recent studies on 5,6-diaryl triazines showed neuropharmacological applications of this moiety, such as adenosine A 2A antagonism, in Parkinson's disease 31 , anti-neuroinflammatory activity in Alzheimer's disease 32 and as neuroprotectants 33 . More recently, potent neuroprotective action of some 1,2,4-triazines by activating Wnt/b-catenin signaling pathway has been demonstrated by our research group 34 . Some patents have also disclosed the topical anti-inflammatory 35 and antithrombotic activity of diaryl triazines 35 .…”

“…Our earlier study has shown that this type of compounds does not exhibit any cytotoxicity rather show protective role in Malondialdehyde (MDA), catalase and intracellular reactive oxygen species (ROS) generation assays 34 . The whole human blood aggregation study was done as per our previously reported procedure 37 .…”

“…The changing paradigm to use alternative reaction media rather than volatile organic solvents emphasizes on the use of ionic liquids and solvent-free solid-phase syntheses. As per our interest in developing green synthetic methodologies for biologically active small molecules 34,38 , first step of the synthesis was carried out in ionic liquid and the latter one in solvent-less condition. The ionic liquid 1,3-dibutylimidazolium bromide [Bbim +…”

Design, Synthesis, and Cholinesterase Inhibition Assay of Coumarin‐3‐carboxamide‐N‐morpholine Hybrids as New Anti‐Alzheimer Agents

“…[24,25] On the other hands, N-morpholine moiety was recently used in design and synthesis of new AChE inhibitors (Figure 1, C). [26] Hence, in continuation to our interest in the development of potent anti-Alzheimer agents by molecular hybridization, in this work, a novel series of coumarin-3-carboxamide-N-morpholine hybrids 5a-5l has been presented ( Figure 1). [27] Herein, the synthesis, AChE/BuChE inhibitory effects, kinetic, and docking studies of these hybrids as new dual binding site ChE inhibitors are reported.…”