2ʹ,4ʹ,6ʹ-Trimethoxyacetophenone

Depressive amnesia, involving memory impairment and mood dysregulation, frequently co-occurs with depression and neurodegenerative diseases. Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to depressive-like behaviors and cognitive deficits. This study evaluated the therapeutic potential of 2',4',6'-trimethoxyacetophenone (TMA), a bioactive compound from Lycoris sanguinea var. koreana, in a mouse model of MGO-induced depressive amnesia. Mice received MGO (60 mg/kg) followed by TMA (5 or 20 mg/kg), and behavioral tests were conducted to assess mood, cognition, and locomotor activity. TMA significantly reduced immobility in tail suspension and forced swim tests, improved locomotion and exploration in the open field, and restored memory in novel object recognition and Y-maze tests. Histological analysis showed that TMA preserved hippocampal integrity, modulated glucocorticoid receptor expression, and reduced cortisol levels, indicating involvement in stress regulation. TMA also attenuated neuroinflammation by lowering IL-1β and microglial activation while increasing IL-10. Additionally, it reduced amyloidogenic markers, including oligomeric Aβ and amyloid precursor protein. These findings highlight the neuroprotective and antidepressant potential of TMA and support its use as a natural therapeutic candidate for treating depression-related cognitive impairment.