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Investigation of Dithiolethione 59 as Potential Neuroprotective Antiparkinsonian Agent
Author(s) -
Betharia Swati,
Brown Dennis,
Fuentes Steven,
Aoude Iman
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.708.3
Subject(s) - gclc , gclm , neuroprotection , glutathione , chemistry , buthionine sulfoximine , dopaminergic , pharmacology , oxidative stress , biochemistry , gstp1 , dopamine , biology , enzyme , endocrinology
Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder characterized by the disintegration of nigrostriatal dopaminergic neurons. The resulting loss of dopamine gives rise to the cardinal symptoms of the disease, including resting tremor, rigidity, and bradykinesia. Oxidative stress and depletion of the ubiquitous antioxidant glutathione (GSH) have been implicated in the pathophysiology of PD. Towards the development of novel neuroprotective antiparkinsonian agents, we report the pharmacological characterization of the sulfur‐containing dithiolethone (DTT) 59 in the dopaminergic neuroblastoma SH‐SY5Y cell line. DTTs are known activators of the transcription factor nuclear factor erythroid‐2 factor (Nrf2). Activation of Nrf2 is associated with the induction of various cytoprotective antioxidants such as GSH, the catalytic unit of enzyme glutamate cysteine ligase (GCLC), the cytosolic isoform of glutathione S‐transferase (GSTP1), the light chain subunit of the cysteine‐glutamate transporter (xCT), and the phase II enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1). Compound 59 was found to dose‐dependently increase cellular levels of total GSH. 59 also provided significant neuroprotection in the 6‐hydroxydopamine (6‐OHDA) model of neurotoxicity at concentrations as low as 10 μM. Mechanistic studies showed a concentration‐ and time‐dependent increase in NQO1 at both the message and protein levels; however, GCLC, GSTP1 and xCT levels remained unchanged. Pretreatment of SH‐SY5Y cells with the GCLC inhibitor buthionine sulfoximine (BSO) was found to block 59 ‐mediated GSH induction. BSO treatment also abolished the protective properties of 59 , indicating that GSH induction is important for neuroprotection. While the Nrf2 pathway did not appear to be involved in this induction, these data suggest that 59 is a potential neuroprotective antiparkinsonian agent and warrants additional exploration. Support or Funding Information This research was supported by Manchester University College of Pharmacy, Natural and Health Sciences.