Modulation of Apoptotic Cell Death and Neuroprotective Effects of Glutathione—L-Dopa Codrug Against H2O2-Induced Cellular Toxicity

Sara Franceschelli,Emanuela Ricciotti,Lorenza Speranza,Antonia Patruno,Paola Lanuti,Ivana Cacciatore,Sebastiano Miscia,Mario Felaco,Mirko Pesce,Alessio Ferrone,Daniela Maria Pia Gatta,Antonio Di Stefano,Alfredo Grilli

doi:10.3390/antiox8080319

Abstract

The L-3,4-dihydroxyphenylalanine (LD) is the gold standard drug currently used to manage Parkinson’s disease (PD) and to control its symptoms. However, LD could cause disease neurotoxicity due to the generation of pro-oxidant intermediates deriving from its autoxidation. In order to overcome this limitation, we have conjugated LD to the natural antioxidant glutathione (GSH) to form a codrug (GSH-LD). Here we investigated the effect of GSH-LD on H2O2-induced cellular toxicity in undifferentiated and differentiated lymphoma U-937 and dopaminergic neuroblastoma SH-SY5Y cell lines, used respectively as models to study the involvement of macrophages/microglia and dopaminergic neurons in PD. We analyzed the effect of GSH-LD on apoptosis and cellular oxidative stress, both considered strategic targets for the prevention and treatment of neurodegenerative diseases. Compared to LD and GSH, GSH-LD had a stronger effect in preventing hydrogen peroxide (H2O2) induced apoptosis in both cell lines. Moreover, GSH-LD was able to preserve cell viability, cellular redox status, gluthation metabolism and prevent reactive oxygen species (ROS) formation, in a phosphinositide 3-kinase (PI3K)/kinase B (Akt)-dependent manner, in a neurotoxicity cellular model. Our findings indicate that the GSH-LD codrug offers advantages deriving from the additive effect of LD and GSH and it could represent a promising candidate for PD treatment.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons mainly in the substantia nigra
The neuro-inflammation process is characterized by the presence of reactive astrocytes and activated microglia that produce cytokines, chemokines, prostaglandins, and reactive oxygen and nitrogen species (ROS/RNS), which can be responsible for the disruption of the blood-brain barrier (BBB) [27]
During the progression of PD, the initial neuro-protective action guaranteed by microglia becomes toxic to dopaminergic neurons as a result of the overproduction of reactive oxygen species (ROS)/RNS and cytokines

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons mainly in the substantia nigra. Recent studies have indicated a possible involvement of LD to disease progression due to the generation of pro-oxidant intermediates deriving from its autoxidation [2]. For these reasons, new therapeutic strategies based on DA replacement therapy, are needed to reduce the inexorable progression of PD. DA metabolism, mitochondrial dysfunction, and neuro-inflammation, which cause free radical/reactive oxygen species (ROS) generation in dopaminergic neurons and consequent oxidative stress-triggered neuronal death in the substantia nigra, have been greatly

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