A Glutathione Derivative with Chelating and in vitro Neuroprotective Activities: Synthesis, Physicochemical Properties, and Biological Evaluation

Abstract

Metal-ion dysregulation and oxidative stress have been linked to the progressive neurological decline associated with neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Herein we report the synthesis and chelating, antioxidant, and in vitro neuroprotective activities of a novel derivative of glutathione, GS(HQ)H, endowed with an 8-hydroxyquinoline group as a metal-chelating moiety. In vitro results showed that GS(HQ)H may be stable enough to be absorbed unmodified and arrive intact to the blood-brain barrier, that it may be able to remove Cu(II) and Zn(II) from the Aβ peptide without causing any copper or zinc depletion in vivo, and that it protects SHSY-5Y human neuroblastoma cells against H2 O2 - and 6-OHDA-induced damage. Together, these findings suggest that GS(HQ)H could be a potential neuroprotective agent for the treatment of neurodegenerative diseases in which a lack of metal homeostasis has been reported as a key factor.

Improvement of Oxidative and Metabolic Parameters by Cellfood Administration in Patients Affected by Neurodegenerative Diseases on Chelation Treatment

“…Similarly, α -lipoic acid prevented damage induced by 6-hydroxydopamine or by chronic use of L-DOPA in dopaminergic neurons in a PD animal model [29]. A new glutathione derivative, endowed with an 8-hydroxyquinoline group as a metal-chelating moiety, displayed neuroprotective activities in vitro [30]. Some traditional vitamins seem to act as antioxidants on ND [31].…”

Oxidative Stress, Mitochondrial Abnormalities and Proteins Deposition: Multitarget Approaches in Alzheimer's Disease

“…Clearly, being AD a multifactorial disease, the design of new molecular entities, which combine chelating scaffolds with functional moieties able to hit other important disease targets, is a synthetic strategy widely applied in the design of novel combined metal chelating-antioxidant compounds. For instance GS(HQ)H is a hybrid molecule linking the scaffolds of 8-hydroxyquinoline (8HQ) and GSH [102] (Fig. 11).…”

“…The new molecule exhibits affinity for Cu(II) and Zn(II) comparable to that of 8HQ. Moreover, GS(HQ)H seems to be able to reach the BBB, where it displays a good capability in removing Cu(II) and Zn(II) from the Aβ-peptide in vivo, without causing any depletion of these metal ions [102].…”

Metal complexes of amino acids and peptides

“…Cu(II) complexes of disulfide-constrained cyclic tetrapeptides were also studied in order to facilitate the design of sensors for metal ions. 312 Phytochelatins are also thiol contaning peptides with a general formula of ((g-GlyCys) n Gly, n = 2-5) and play an important role in the metal homeostasis of plants. The interaction of Hg(II) ions with some dicysteinyl tripeptides was investigated by isothermal titration calorimetry.…”