Retinoic acid-loaded polymeric nanoparticles induce neuroprotection in a mouse model for Parkinson's disease.

Marta Esteves,Sandra M Rocha,Graça Baltazar,Tatiana Saraiva,Ana C Cristóvão,Liliana Bernardino,Lino Ferreira

doi:10.3389/fnagi.2015.00020

Abstract

Retinoic acid (RA) plays an important role in the commitment, maturation and survival of neural cells. Recently, RA was pointed as a therapeutic option for some neurodegenerative diseases, including Parkinson's disease (PD). The administration of RA has been defying, and in this sense we have previously developed novel RA-loaded polymeric nanoparticles (RA-NPs) that ensure the efficient intracellular transport and controlled release of RA. Herein, we show that nanoformulation as an efficient neuroprotective effect on dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induced mouse model for PD. The results showed that the RA-NPs administration induced a significant reduction of DA neuron loss in the substantia nigra (SN) as well as their neuronal fiber/axonal innervations in the striatum. Furthermore, we observed an increase in the expression levels of the transcription factors Pitx3 and Nurr1 induced by RA-NPs, showing its supportive effect on the development and functional maintenance of DA neurons in PD. This is the first study showing that RA-NPs can be an innovative strategy to halt the progression of PD pathogenesis, suggesting that this nanoformulation could be of particular interest for the development of new approaches for PD therapeutics.

Highlights

Retinoic acid (RA) is a metabolic product of vitamin A which plays important roles in the development of mammalian nervous system (Maden, 2007)
RA-loaded polymeric nanoparticles (RA-NPs) Induce Neuroprotection of the substantia nigra (SN) Dopaminergic Neurons Against the MPTP-Induced Lesion In this work we evaluated the putative neuroprotective effect of RA-NPs on a MPTP-induced mouse Parkinson’s disease (PD) model
No statistical difference was found in the intensity and area occupied by Tyrosine Hydroxylase (TH)+ fibers in the contralateral striatum of saline-treated animals as compared to the ipsilateral side of the same animals injected with RA- or blank-NPs (Figure 3A)

Summary

Introduction

Retinoic acid (RA) is a metabolic product of vitamin A (retinol) which plays important roles in the development of mammalian nervous system (Maden, 2007). The RA signal is transduced by specific nuclear receptors: retinoic acid receptors (RAR) and retinoid X receptors (RXR), which are members of the nuclear receptor superfamily (Kastner et al, 1997). These receptors heterodimerize and bind to a DNA sequence called retinoic acid-response element (RARE) and induce gene transcription (Bastien and Rochette-Egly, 2004). It was shown that stimulation of RAR with RAR agonist AM80, prevented DA cell loss induced by lipopolysaccharide (LPS) in the substantia nigra (SN) (Katsuki et al, 2009). Mutations in the gene coding for this enzyme was shown to represent a genetic risk factor for human PD either alone or in conjunction with other environmental risk factors (Buervenich et al, 2005)

Methods

Results

Discussion

Conclusion