Ellagic Acid Mitigates SNO-PDI Induced Aggregation of Parkinsonian Biomarkers

Abstract

Nitrosative stress mediated S-nitrosylation (SNO) of protein disulfide isomerase (PDI), a housekeeping oxidoreductase, has been implicated in the pathogenesis of sporadic Parkinson's (PD) and Alzheimer's (AD) diseases. Previous cell line studies have indicated that SNO-PDI formation provokes synphilin-1 aggregation, the minor Parkinsonian biomarker protein. Yet no work exists investigating whether SNO-PDI induces α-synuclein aggregation, the major Lewy body constituent associated with Parkinson's pathogenesis. Here, we report that SNO-PDI formation is linked to the aggregation of α-synuclein and also provokes α-synuclein:synphilin-1 deposits (Lewy-body-like debris) normally found in the PD brain. Furthermore, we have examined the ability of a small molecule, 2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione (ellagic acid; EA) to scavenge NOx radicals and to protect cells from SNO-PDI formation via rotenone insult both, cell-based and cell-independent in vitro experiments. Furthermore, EA not only mitigates nitrosative-stress-induced aggregation of synphilin-1 but also α-synuclein and α-synuclein:synphilin-1 composites (Lewy-like neurites) in PC12 cells. Mechanistic analyses of the neuroprotective phenomena revealed that EA lowered rotenone-instigated reactive oxygen species (ROS) and reactive nitrogen species (RNS) in PC12 cells, imparted antiapoptotic tributes, and directly interfered with SNO-PDI formation. Lastly, we demonstrate that EA can bind human serum albumin (HSA). These results collectively indicate that small molecules can provide a therapeutic foothold for overcoming Parkinson's through a prophylactic approach.

Preventive Effects of Ellagic Acid on Nucleus Tractus Solitarius Electrical Activity and Oxidative Stress Altered by Cerebral Global Ischemia/Reperfusion in Rat

“…With respect to numerous reports in antioxidant role of EA on neuodegeneration [47][48][49][50], we can confirm anti-oxidative profile of EA. The SOD enzyme produces substrate for GPx activity in the brain under stressful situations [51,52].…”

“…However, the long-time study in reperfusion phase to show more specific role and perceive mechanism of EA effect should be designed in future studies. Several line of evidences consistently supports the claim that ellagic acid improves antioxidant enzymes and subsequently these enzymes might defend neuronal cells against produced free radicals in brain injuries [47,48,49]. Herein, we detected the two antioxidant enzymes (SOD and GPx) in the present or absence of ellagic acid in ischemic rats' tissues.…”

Neuroprotective Mechanisms of Three Natural Antioxidants on a Rat Model of Parkinson’s Disease: A Comparative Study

“…Pretreatment was done for five days before the surgery. The doses of used compounds were chosen on the basis of our previous studies [25,40,43,57] as well as literature data [12,13,22,26,29,33,49,58,59]. Using the allometric calculation [60,61], a rat dose of 50 mg/kg (weight of 275 g male Wistar rats) of each compound (e.g., EA, LA or Myrt) would correspond to a human dose (human equivalent dose, HED) of approximately 9.8 mg/kg, which is near the clinical dose of amantadine (60 kg middle body human weight).…”

“…Of particular interest for this study is the reported ability of EA to lower the rotenone-induced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in PC12 cells [22] as well as its ability to exhibit a neuroprotective effect against oxidative damage in diabetic rats by suppressing oxidative stress [23]. From cognitive and behavioral points of view, EA prevents scopolamine-and diazepam-induced cognitive impairments [24,25] and may be of potential benefit in brain stroke by alleviating the oxidative stress characteristic for this condition [26].…”

Dual Maleimide Tagging for Relative and Absolute Quantitation of Cysteine‐Containing Peptides by MALDI‐TOF MS

“…Protein disulfide isomerase (PDI) is associated with neurodegenerative diseases . Aberrant modification of PDI by SNO of active cysteine residues has been reported to be correlated closely to neurodegeneration in Parkinson's and Alzheimer's diseases . Therefore, quantitation of CCPs in PDI is fundamentally important for understanding disease development.…”