Exploring the potential of 4’,5’-dimethyl- 3-chloro-2’-hydroxychalcone on biological targets associated with neurodegenerative diseases

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

Congreso; REUNIÓN CONJUNTA SAIC SAB AAFE AACYTAL 2023; 2023

The complexity of neurodegenerative diseases (NDDs), such asAlzheimer’s disease (AD) and Parkinson’s disease (PD), requiresmultidirectional treatment approaches. The combination of cholinesterases(ChE) and monoamine oxidases (MAO) inhibition, alongwith strategies to counteract amyloid β (Aβ) aggregation, has thepotential to restore neurotransmitter levels and offer a multitargetapproach for NDD treatment. Chalcones, a subgroup of flavonoids,have gained attention in the field of NDDs due to their potential therapeuticproperties. Extensive research has shown that chalconespossess neuroprotective effects by mitigating oxidative stress, reducingneuroinflammation, and modulating key pathways involvedin neurodegeneration. In this study, the synthetic chalcone 4’,5’-Dimetyl-3-chloro-2’-hydroxychalcone (1) was evaluated on biologicaltargets related to NDDs. In vitro experiments were conducted to assessits capacity to inhibit human recombinant monoamine oxidasesA and B (hMAO-A and hMAO-B) (Amplex Red method), murine acetylcholinesterase/butyrylcholinesterase (mAChE/mBChE) (Ellman’smethod), and β-amyloid peptide aggregation (thioflavin T method).In vivo studies on male Swiss mice involved cognitive evaluationswith the Y-maze test and behavioral assessments using a chemicalmodel 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 10μM). Moreover, it demonstrated positive effects on memory in vivoand was able to reverse motor damage induced by rotenone in thePD model. These findings contribute to the existing knowledge onchalcones and highlight the potential of chalcone 1 as a therapeutictool for NDDs