Afridi_2025_Eur.J.Pharmacol__178193

Alzheimer's disease (AD) is the most prevalent form of dementia or amnesia, characterized primarily by loss of acetylcholine (ACh), due to increased activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), both of which accelerate ACh degradation, and exacerbate cholinergic dysfunction. In this regard, the synthetic methyl-substituted monocarbonyl curcumin derivatives (BL1-BL3) were analyzed for AChE and BChE inhibition, followed by molecular docking studies. Scopolamine (1 mg/kg) was used to induce amnesia in mice. The results of BL1-BL3 demonstrated a significant inhibitory effect especially against AChE compared to BChE enzymes, with IC(50) of 128.4, 118.4, 170.9 microg/mL against AChE and 334.3, 1168, 288.2 microg/mL against BChE, respectively. These compounds exhibited strong binding affinities to both target proteins in docking studies. Scopolamine administration induced significant memory deficits in mice, that was significantly (P<0.001) mitigated by pretreatment with BL1-BL3 in the Y-maze test at both 7.5 and 15 mg/kg doses by restoring spontaneous alternation performance (SAP). In the novel object recognition test (NORT), a prominent (P<0.001) improvement in memory retention was seen during the test phase, and enhanced the discrimination index (DI) at both tested doses. Biochemical analyses of hippocampal tissue further supported the behavioral data. Treatment with BL1-BL3 effectively decreases AChE and malondialdehyde (MDA) levels while increasing catalase (CAT) and superoxide dismutase (SOD) levels. Overall, BL2 was found to be most significant. In short, BL1-BL3 emerged as potential therapeutic agents for AD due to significant effects in vitro and in vivo experimental models, and are also equally supported by in silico studies.