Parkinson's disease (PD) is a neurodegenerative condition characterised by the death of dopaminergic neurons, primarily in the substantia nigra, over time. The gold standard medicine for managing Parkinson's disease (PD) and controlling its symptoms is L-3,4-dihydroxyphenylalanine (LD). However, the formation of pro-oxidant intermediates resulting from LD's autoxidation could produce disease neurotoxicity. To circumvent this constraint, we created a codrug by conjugating LD to the natural antioxidant glutathione (GSH) (GSH-LD). The effect of GSH-LD on H2O2-induced cellular toxicity was investigated in the undifferentiated and differentiated lymphoma U-937 and dopaminergic neuroblastoma SH-SY5Y cell lines, which were used as models to study the involvement of macrophages/microglia and dopaminergic neurons in PD, respectively. We looked studied how GSH-LD affected apoptosis and cellular oxidative stress, two important targets in the prevention and therapy of neurodegenerative disorders. In both cell lines, GSH-LD showed a larger effect than LD and GSH in preventing hydrogen peroxide (H2O2)-induced apoptosis. In a neurotoxicity cellular model, GSH-LD was also able to protect cell viability, cellular redox state, gluthation metabolism, and inhibit reactive oxygen species (ROS) generation in a PI3K/kinase B (Akt)-dependent manner. Our findings suggest that the GSH-LD codrug has benefits derived from the synergistic impact of LD and GSH, and that it could be a good PD treatment candidate. Further research into the neuroprotective benefits of GSH-LD in PD in in vivo animal models and its capacity to permeate the BBB is needed to confirm the importance of our findings.
Author (s) Details
Sara Franceschelli
Department of Psychological, Health and Territorial Sciences, University “G. D’Annunzio”, 66100 Chieti-Pescara, Italy.
Paola Lanuti
Department of Medicine and Science of Aging, University “G. D’Annunzio”, 66100 Chieti-Pescara, Italy.
Alessio Ferrone
Department of Medicine and Science of Aging, University “G. D’Annunzio”, 66100 Chieti-Pescara, Italy.
Daniela Maria Pia Gatta
Department of Medicine and Science of Aging, University “G. D’Annunzio”, 66100 Chieti-Pescara, Italy.
Lorenza Speranza
Department of Medicine and Science of Aging, University “G. D’Annunzio”, 66100 Chieti-Pescara, Italy.
Mirko Pesce
Department of Medicine and Science of Aging, University “G. D’Annunzio”, 66100 Chieti-Pescara, Italy.
Alfredo Grilli
Department of Psychological, Health and Territorial Sciences, University “G. D’Annunzio”, 66100 Chieti-Pescara, Italy.
Ivana Cacciatore
Department of Pharmacy, University “Gabriele D’Annunzio” of Chieti-Pescara, 66100 Chieti-Pescara, Italy.
Emanuela Ricciotti
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
Antonio Di Stefano
Department of Pharmacy, University “Gabriele D’Annunzio” of Chieti-Pescara, 66100 Chieti-Pescara, Italy.
Sebastiano Miscia
Department of Medicine and Science of Aging, University “G. D’Annunzio”, 66100 Chieti-Pescara, Italy.
Mario Felaco
Department of Medicine and Science of Aging, University “G. D’Annunzio”, 66100 Chieti-Pescara, Italy.
Antonia Patruno
Department of Medicine and Science of Aging, University “G. D’Annunzio”, 66100 Chieti-Pescara, Italy.
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