Inflammatory Response Modulation by Vitamin C in an MPTP Mouse Model of Parkinson's Disease.

Chiara Porro,Antonia Cianciulli,Alessandro Miraglia,Marianna Kashyrina,Dario Domenico Lofrumento,Giuseppe Nicolardi,Melania Ruggiero,Rosa Calvello,Maria Antonietta Panaro,Francesco De Nuccio

doi:10.3390/biology10111155

Abstract

Simple SummaryVitamin C (Vit C), also called ascorbic acid, is a nutrient present in many foods, particularly citrus fruits and green vegetables. Inadequate dietary Vit C intake causes hypovitaminosis resulting in the risk of developing clinical scurvy, potentially fatal if untreated. Vit C represents one of the safest and most essential nutrients, with antioxidant and anti-inflammatory properties that protect living organisms against oxidative stress; due to this propriety, it is studied for applications in the prevention and management of different pathologies, including neurodegenerative disease. Persistent neuroinflammation is detrimental for the brain and may lead to pathogenesis and progression of neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease. The role of Vit C in the central nervous system is still debated.This study, utilizing a PD mouse model, has demonstrated that Vit C reduces neuroinflammation by the modulation of microglial responses and astrocyte activation, reducing dopaminergic neuronal cell loss involved in PD insurgence.Furthermore, mouse gait and spontaneous locomotor activity were partially ameliorated. In summary, we have demonstrated that the use of Vit C has neuroprotective effects in the brain, alleviating the inflammatory cascade and reducing the progression of PD.Vitamin C (Vit C) is anutrient present in many foods, particularly citrus fruits, green vegetables, tomatoes, and potatoes. Vit C is studied for its applications in the prevention and management of different pathologies, including neurodegenerative diseases. Neuroinflammation is a defense mechanism activated by a stimulus or an insult that is aimed at the preservation of the brain by promoting tissue repair and removing cellular debris; however, persistent inflammatory responses are detrimental and may lead to the pathogenesis and progression of neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease. PD is one of the most common chronic progressive neurodegenerative disorders, and oxidative stress is one of the most important factors involved in its pathogenesis and progression.Due to this, research on antioxidant and anti-inflammatory compounds is an important target for counteracting neurodegenerative diseases, including PD. In the central nervous system, the presence of Vit C in the brain is higher than in other body districts, but why and how this occurs is still unknown. In this research, Vit C, with its anti-inflammatory and anti-oxidative properties, is studied to better understand its contribution to brain protection; in particular, we have investigated the neuroprotective effects of Vit C in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of PD and its role in the modulation of neuroinflammation. First, we observed that Vit C significantly decreased the MPTP-induced loss of tyrosine hydroxylase (TH)-positive dopaminergic neuronal cells in the substantia nigra, as well as microglial cell activation and astrogliosis. Furthermore, gait and spontaneous locomotor activity, evaluated by an automated treadmill and the Open Field test, respectively, were partially ameliorated by Vit C treatment in MPTP-intoxicated animals. In relation to neuroinflammation, results show that Vit C reduced the protein and mRNA expression of inflammatory cytokines such as IL-6, TLR4, TNF-α, iNOS, and CD40, while anti-inflammatory proteins such as IL-10, CD163, TGF-β, and IL-4 increased. Interestingly, we show for the first time that Vit C reduces neuroinflammation by modulating microglial polarization and astrocyte activation. Moreover, Vit C was able to reduce NLRP3 activation, which is linked to the pathogenesis of many inflammatory diseases, including neuroinflammatory disorders. In conclusion, our study provides evidence that Vit C may represent a new promising dietary supplement for the prevention and alleviation of the inflammatory cascade of PD, thus contributing to neuroprotection.

Highlights

Vitamin C (Vit C), called ascorbic acid, is a lactone with six carbon atoms and is water-soluble with a molar mass of 176 Da
MPTP administration induced a decrease in tyrosine hydroxylase (TH) immunoreactivity (Figure 1A) in striatum and substantia nigra parscompacta (SNpc) with respect to controls
In mice treated with MPTP that received Vit C, TH immunoreactivity was more intense compared to animals that received only MPTP, indicating that Vit C reduces dopaminergic neurons loss induced by MPTP

Summary

Introduction

Vitamin C (Vit C), called ascorbic acid, is a lactone with six carbon atoms and is water-soluble with a molar mass of 176 Da. Vit C is a cofactor in many biochemical synthetic reactions, such as the synthesis of hormones and neuropeptides and in non-heme iron absorption.VitC normally circulates in the blood at a concentration of 40–60 μmol/L. Inadequate dietary intake determines hypovitaminosis C (established as a plasma concentration ≤ 23 μmol/L), resulting in the risk of developing clinical scurvy, which is potentially fatal if untreated. The majority of vertebrates and invertebrates can produce Vit C from glucose in the liver; anthropomorphic primates, guinea pigs, bats, and some bird species lost this ability due to mutations in the L-gulono-γ-lactone oxidase (Gulo) gene, which encodes a crucialfor Vit C biosynthesis [3]. Vit C uptake is guaranteed by specific transporter systems and actively guided by a sodium gradient. All cells express members of the transporter family SLC23, the sodium-dependent Vitamin C transporters 1 and 2 (SVCT1 and SVCT2) [4,5]

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