PAMAM dendrimers of generation 4.5 and its complexes with curcumin prevent the α-synuclein aggregation

IGARTUA DE; GONZÁLEZ LIZARRAGA F; MARTINEZ CS; ÁVILA CL; CHEHÍN R; CHIARAMONI NS; PRIETO MJ

Congreso; SAB 2020; 2020

Parkinson´s disease (PD) is a neurodegenerative disease characterized by α-synucleinaggregation in dopaminergic neurons, increased levels of oxidative stress, andneuroinflammation. To date, there is no pharmacological treatment to stop theprogression of the disease. For this reason, it is imperative to develop disease-modifyingtherapies that prevent or delay disease progression. Furthermore, due to themultifactorial characteristics of PD, these treatments must be multitarget and effectiveboth against α-synuclein aggregation, as well as against oxidative stress andneuroinflammation.Curcumin (CUR) is a natural polyphenol that could modulate the PD progression since itsantioxidant and anti-inflammatory properties might reduce the levels of oxidative stressand neuroinflammation. However, clinical studies did not have positive results, whichcould be due to CUR insolubility in aqueous solutions, short half-life, and lowbioavailability. For these, CUR is a good candidate to be used in nanocarriers. Dendrimersare used as nanocarriers due to the possibility of encapsulating drug molecules in theirinterior or anchoring drug molecules to their surface groups. Moreover, it has beenrecently shown that dendrimers could have intrinsic activity and act as nanodrugs perse, exhibiting anti-protein aggregation, anti-viral, anti-bacterial, and anti-inflammatoryproperties.Using a combination of biophysical techniques together with in vitro and in vivo models,we demonstrated: (i) the dendrimer DG4.5 increase the solubility and stability of CURforming DG4.5-CUR complexes; (ii) the DG4.5-CUR complexes result biocompatible invitro; and (iii) both the DG4.5 and DG4.5-CUR complexes impact on the α-synucleinaggregation. In conclusion, this work proposes the use of dendrimers as nanodrugscapable of inhibiting α-synuclein aggregation. Furthermore, this work proposes theincorporation of curcumin into dendrimers as a drug capable of reducing oxidative stressand neuroinflammation