Dioxopiperidinamide Derivative SKT-36 Alleviates scopolamine-induced Cognitive and Neurobehavioral Impairments in an In-vivo Zebrafish Model.

Dementia, characterized by cognitive decline and synaptic dysfunction, presents significant therapeutic challenges. This study explores the potential of SKT-36, a novel Dioxopiperidinamide (DOPA) derivative, in reversing scopolamine (SCP)-induced cognitive deficits in an in-vivo zebrafish model. SKT-36 exhibits high neuroprotective potential due to its inherent antioxidant and anti-inflammatory properties. Network pharmacology analysis revealed 637 intersecting targets linking SKT-36 with dementia-associated genes such as STAT3, GSK3B, and HSP90AB1 identified as key hubs. Molecular docking also confirmed highly favorable binding affinity of SKT-36 with Danio rerio of AChE, exhibited a binding energy of -6.58 kcal/mol. For in vivo analysis, zebrafish were treated with SKT-36 at 10 µM and 7.5 µM, and the effects were assessed using neurobehavioral, biochemical, and gene expression studies. SKT-36 at 10 µM significantly enhanced locomotor activity, reduced anxiety-like behavior, and improved spatial and recognition memory, as shown by various behavioral tests. Biochemically, SKT-36 reduced oxidative stress markers and restored antioxidant enzyme activities. Also, superior acetylcholinesterase (AChE) inhibitory activity compared to standard treatments was seen suggesting effective cholinergic modulation. Gene expression analysis indicated SKT-36’s anti-inflammatory and neuroprotective effects, normalizing genes related to inflammation and neuronal plasticity. Histological analysis confirmed reduced neuronal damage and amyloid-beta plaque accumulation observed in the optic tectum regions. These findings highlight SKT-36 as a promising therapeutic agent for dementia, offering neuroprotective and cognitive benefits.