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Molecular mechanism underlying the cerebral effect of Gly-Pro-Glu tripeptide bound to l-dopa in a Parkinson’s animal model

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Abstract

Oxidative stress is a critical contributing factor to neurodegenerative disorders. Therefore, the inhibition of ROS formation, responsible for chronic detrimental neuroinflammation, is an important strategy for preventing the neurodegenerative disease and for neuroprotective therapy. Gly-Pro-Glu (GPE) is the N-terminal tripeptide of insulin-like growth factor-I, which is naturally cleaved in the plasma and brain tissues. GPE has neuroprotective effects since it crosses the blood–CSF and the functional CSF–brain barriers and binds to glial cells. It has been shown that GPE improves motor behaviour in rats after 6-OHDA lesion, although it does not rescue dopaminergic neurons. Thus, we hypothesized that the GPE therapeutic efficacy in a Parkinson model might be improved by combining GPE to l-dopa. Here, we used an animal model that represents a progressive chronic Parkinson’s disease (PD) model, characterized by high levels of oxidative stress and inflammation. We showed that the co-drug, in which l-dopa is covalently linked to the GPE tripeptide, by down-regulating the expression of inflammatory genes, decreases the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced inflammatory response and, by up-regulating tyrosine hydroxylase, reduces MPTP-induced neurotoxicity. Furthermore, by determining the nuclear translocation/activation of Nrf2 and NF-κB, we showed that systemic administration of the co-drug activates Nrf2-induced antioxidant response while suppressing NF-κB inflammatory pathway. Data suggest that the binding of l-dopa to GPE tripeptide might represent a promising strategy to supply l-dopa to parkinsonian patients.

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Acknowledgments

The authors thank Mary Kerrigan (MA, Cantab) for helpful linguistic suggestions. The study was funded by Fondazione Cassa di Risparmio, Perugia, Italy (Grant 2009-010-0437). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Dipartimento Medicina Sperimentale Scienze Biochimiche, Sezione Biochimica Cellulare, Università di Perugia, Via del Giochetto, 06124, Perugia, Italy

    Alba Minelli & C. Conte

  2. Dipartimento di Scienze del Farmaco, Università “G. D’Annunzio”, Via dei Vestini 31, 66100, Chieti, Italy

    I. Cacciatore, C. Cornacchia & F. Pinnen

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  1. Alba Minelli
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  2. C. Conte
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Correspondence to Alba Minelli.

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Minelli, A., Conte, C., Cacciatore, I. et al. Molecular mechanism underlying the cerebral effect of Gly-Pro-Glu tripeptide bound to l-dopa in a Parkinson’s animal model. Amino Acids 43, 1359–1367 (2012). https://doi.org/10.1007/s00726-011-1210-x

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