Unveiling the Therapeutic Potential of D2AAK1 and Its Derivatives: Mechanistic Insights and Applications in Neurodegenerative Disease Treatment

ABSTRACT The global rise in life expectancy has been accompanied by a growing prevalence of neurodegenerative diseases, such as Alzheimer's disease (AD). These complex disorders arise from multiple pathogenic factors and biological pathways, necessitating the development of multi‐target therapeutic strategies. D2AAK1, discovered by our group, has emerged as a promising candidate due to its cytoprotective, antioxidant, and procognitive properties. This study aimed to further elucidate the mechanisms underlying the action of D2AAK1 and its derivatives, with a focus on their potential for neuroprotection and cognitive enhancement. The effect of D2AAK1 on cell viability was evaluated under normal conditions and during H 2 O 2 ‐induced oxidative stress using the resazurin assay. p38 MAPK activity was measured through cell‐based ELISA. mRNA expression was analyzed using a two‐step quantitative PCR method, and enzymatic effects were assessed via photometric, fluorescence, and luminescence techniques. Behavioral studies in murine models were performed to investigate the influence of the compounds on memory processes. It was found that D2AAK1 and its derivatives significantly enhanced cell viability, with some derivatives exhibiting greater potency than D2AAK1. In vivo, one derivative notably improved memory performance and reversed scopolamine‐induced memory impairment in the novel object recognition test in male Swiss mice. Mechanistic studies revealed that D2AAK1 increased the expression of cytoprotective proteins such as Bcl‐2 and HO‐1, while concurrently reducing the expression and activity of pro‐apoptotic factors, including caspase‐3, p38 MAPK, and MAO‐B. These dual actions culminated in enhanced cellular resilience and viability, translating into improved cognitive outcomes. The findings suggest that D2AAK1 and its derivatives, through their multi‐factor mechanism of action, hold promise as therapeutic agents for the treatment of neurodegenerative diseases. image