EXPLORING THE POTENTIAL OF 4’,5’-DIMETHYL-3-CHLORO-2’-HYDROXYCHALCONE ON BIOLOGICALTARGETS ASSOCIATED WITH NEURODEGENERATIVE DISEASES

FABIOLA KAMECKI; CAROLINA MARCUCCI; MARINA RADEMACHER; VALENTINA PASTORE; NATALIA COLETTIS; MARIEL MARDER.

MEDICINA (BUENOS AIRES)

MEDICINA (BUENOS AIRES)

Lugar: Buenos Aires; Año: 2023

0025-7680

The complexity of neurodegenerative diseases (NDDs), such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), requires multidirectional treatment approaches. The combination of cholinesterases (ChE) and monoamine oxidases (MAO) inhibition, along with strategies to counteract amyloid β (Aβ) aggregation, has the potential to restore neurotransmitter levels and offer a multitarget approach for NDD treatment. Chalcones, a subgroup of flavonoids, have gained attention in the field of NDDs due to their potential therapeutic properties. Extensive research has shown that chalcones possess neuroprotective effects by mitigating oxidative stress, reducing neuroinflammation, and modulating key pathways involved in neurodegeneration. In this study, the synthetic chalcone 4’,5’-Dimetyl-3-chloro-2’-hydroxychalcone (1) was evaluated on biological targets related to NDDs. In vitro experiments were conducted to assess its capacity to inhibit human recombinant monoamine oxidases A and B (hMAO-A and hMAO-B) (Amplex Red method), murine acetylcholinesterase/butyrylcholinesterase (mAChE/mBChE) (Ellman’s method), and β-amyloid peptide aggregation (thioflavin T method). In vivo studies on male Swiss mice involved cognitive evaluations with the Y-maze test and behavioral assessments using a chemical model of PD (administering 1.5 mg/kg/day of rotenone for 7 days). Chalcone 1 exhibited selective and reversible inhibition of hMAO-B (IC50= 0,354 ± 0,084 μM), selective inhibition of mAChE (IC50= 4,37 ± 0,83 μM), and inhibition of Aβ aggregation (51,6 ± 11,3% at 10 μM). Moreover, it demonstrated positive effects on memory in vivo and was able to reverse motor damage induced by rotenone in the PD model. These findings contribute to the existing knowledge on chalcones and highlight the potential of chalcone 1 as a therapeutic tool for NDDs.