title: Polyphenols in combination with β-cyclodextrin can inhibit and disaggregate α-synuclein amyloids under cell mimicking conditions: A promising therapeutic alternative.
abstract: Parkinson's disease is characterized by the presence of insoluble and neurotoxic aggregates (amyloid fibrils) of an intrinsically disordered protein α-synuclein. In this study we have examined the effects of four naturally occurring polyphenols in combination with β-cyclodextrin (β-CD) on the aggregation of α-synuclein in the presence of macromolecular crowding agents. Our results reveal that even at sub-stoichiometric concentrations of the individual components, the polyphenol-β-CD combination(s) not only inhibited the aggregation of the proteins but was also effective in disaggregating preformed fibrils. Curcumin was found to be the most efficient, followed by baicalein with (-)-epigallocatechin gallate and resveratrol coming in next, the latter two exhibiting very similar effects. Our results suggest that the efficiency of curcumin results from a balanced composition of the phenolic OH groups, benzene rings and flexibility. The latter ensures proper positioning of the functional groups to maximize the underlying interactions with both the monomeric form of α-synuclein and its aggregates. The uniqueness of β-CD was reinforced by the observation that none of the other cyclodextrin variants [α-CD and HP-β-CD] used was as effective, in spite of these possessing better water solubility. Moreover, the fact that the combinations remained effective under conditions of macromolecular crowding suggests that these have the potential to be developed into viable drug compositions in the near future. MTT assays on cell viability independently confirmed this hypothesis wherein these combinations (and the polyphenols alone too) appreciably impeded the toxicity of the prefibrillar α-synuclein aggregates on the mouse neuroblastoma cell lines (N2a cells).
authors.affiliation: Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Gautam
authors.affiliation: Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
authors.forename: Sandip
authors.initials: S
authors.lastname: Karmakar
authors.affiliation: Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
authors.forename: Radhika
authors.initials: R
authors.lastname: Batra
authors.affiliation: Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Pradhan
authors.affiliation: Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India.
authors.forename: Jasdeep
authors.initials: J
authors.lastname: Singh
authors.affiliation: Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India. Electronic address: bkundu@bioschool.iitd.ac.in.
authors.forename: Bishwajit
authors.initials: B
authors.lastname: Kundu
authors.affiliation: Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India. Electronic address: pramitc@chemistry.iitd.ac.in.
authors.forename: Pramit K
authors.initials: PK
authors.lastname: Chowdhury
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002392:Catechin / Q000031:analogs & derivatives / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival; D002942:Circular Dichroism; D003474:Curcumin / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D051379:Mice; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059808:Polyphenols / Q000008:administration & dosage* / Q000737:chemistry; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000473:pathology; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000682:Amyloid; D058227:Amyloidogenic Proteins; D059808:Polyphenols; D051844:alpha-Synuclein; D047392:beta-Cyclodextrins; D002392:Catechin; C045651:epigallocatechin gallate; D003474:Curcumin; C031215:betadex
keywords: Amyloid inhibition and disaggregation; Parkinson's disease; Polyphenols; α-Synuclein; β-cyclodextrin