Nitrosative stress-induced Parkinsonian Lewy-like aggregates prevented through polyphenolic phytochemical analog intervention.
Nitrosative stress has recently been demonstrated as a causal in a select sporadic variant of Parkinson's (PD) and Alzheimer's (AD) diseases. Specifically, elevated levels of NO disrupt the redox activity of protein-disulfide isomerase, a key endoplasmic reticulum-resident chaperone by S-nitroso modification of its redox-active cysteines. This leads to accumulation of misfolded AD- and PD-specific protein debris. We have recently demonstrated in vitro that polyphenolic phytochemicals, curcumin and masoprocol, can rescue S-nitroso-PDI formation by scavenging NOx. In this study, using dopaminergic SHSY-5Y cells, we have monitored the aggregation of green-fluorescent protein (GFP)-tagged synphilin-1 (a known constituent of PD Lewy neurites) as a function of rotenone-induced nitrosative stress. Importantly, we demonstrate a marked decrease in synphilin-1 aggregation when the cell line is previously incubated with 3,5-bis(2-flurobenzylidene) piperidin-4-one (EF-24), a curcumin analogue, prior to rotenone insult. Furthermore, our data also reveal that rotenone attenuates PDI expression in the same cell line, a phenomenon that can be mitigated through EF-24 intervention. Together, these results suggest that EF-24 can exert neuroprotective effects by ameliorating nitrosative stress-linked damage to PDI and the associated onset of PD and AD. Essentially, EF-24 can serve as a scaffold for the design and development of PD and AD specific prophylactics.
Department of Chemistry, University of Texas at El Paso, El Paso, TX 79968, USA.
Rituraj
R
Pal
Manuel
M
Miranda
Mahesh
M
Narayan
D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology*; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000378:metabolism; D006801:Humans; D016631:Lewy Bodies / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D010881:Piperidones / Q000737:chemistry / Q000494:pharmacology*; D059808:Polyphenols; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological
C524042:3,5-bis(2-fluorobenzylidene)piperidin-4-one; D001597:Benzylidene Compounds; D002352:Carrier Proteins; D005419:Flavonoids; D016166:Free Radical Scavengers; D009419:Nerve Tissue Proteins; D010636:Phenols; D010881:Piperidones; D059808:Polyphenols; D017382:Reactive Oxygen Species; C118958:SNCAIP protein, human; D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; D003474:Curcumin