Animal Models Of Parkinson's Disease Research Articles

Induction of Parkinsonian-Like Changes via Targeted Downregulation of Astrocytic Glutamate Transporter GLT-1 in the Striatum.

Previous investigations have suggested that decreased expression of glutamate transporter-1 (GLT-1) is involved in glutamate excitotoxicity and contribute to the development of Parkinson's disease (PD), GLT-1 is decreased in animal models of PD. GLT-1 is mainly expressed in astrocytes, and the striatum is a GLT-1-rich brain area. The aim was to explore the function and mechanism of astrocytic GLT-1 in PD-like changes. In the study, PD-like changes and their molecular mechanism in rodents were tested by a behavioral assessment, micro-positron emission tomography/computed tomography (PET/CT), western blotting, immunohistochemical and immunofluorescence staining, and high performance liquid chromatography pre-column derivatization with O-pthaldialdehida after downregulating astrocytic GLT-1 in vivo and in vitro. In vivo, after 6 weeks of brain stereotactic injection of adeno-associated virus into the striatum, rats in the astrocytic GLT-1 knockdown group showed poorer motor performance, abnormal gait, and depression-like feature; but no olfactory disorders. The results of micro-PET/CT and western blotting indicated that the dopaminergic system was impaired in astrocytic GLT-1 knockdown rats. Similarly, tyrosine hydroxylase (TH) positive immune-staining in neurons of astrocytic GLT-1 knockdown rats showed deficit in cell count. In vitro, knockdown of astrocytic GLT-1 via RNA interference led to morphological injury of TH-positive neurons, which may be related to the abnormal calcium signal induced by glutamate accumulation after GLT-1 knockdown. Furthermore, the GLT-1 agonist ceftriaxone showed a protective effect on TH-positive neuron impairment. The present findings may shed new light in the future prevention and treatment of PD based on blocking glutamate excitotoxicity.

Levodopa-induced dyskinesia: a historical review of Parkinson's disease, dopamine, and modern advancements in research and treatment.

Over the past two decades, animal models of Parkinson's disease (PD) have helped to determine the plausible underlying mechanism of levo-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia following L-DOPA treatment. However, our understanding of the mechanisms related to this phenomenon remains incomplete. The purpose of this manuscript is to provide a comprehensive review of treatment protocols used for assessing the occurrence of L-DOPA-induced dyskinesia, L-DOPA absorption, distribution, drug/food interaction, and discuss current strategies and future directions. This review offers a historical perspective using L-DOPA in animal models of PD and the occurrence of L-DOPA-induced dyskinesia.

Dopaminergic neuronal death in the substantia nigra associates with change in serum levels of TNF-α and IL-1β; evidence from early experimental model of Parkinson’s disease

ABSTRACT Purpose Studies have shown that inflammation plays a key role in etiology of Parkinson’s disease (PD). However, human studies which have evaluated association between PD and serum levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) have reported conflicting results. In this study, serum and striatum levels of these cytokines were evaluated in 6-hydroxydopamine (6-OHDA) animal model of PD. Method The neurotoxin of 6-OHDA was injected into medial forebrain bundle of right hemisphere and behavioral tests were carried out to eight weeks thereafter to evaluate severity of PD and its progress. Blood was collected before the toxin and in second and eight weeks after that. Survival of dopaminergic (DAergic) neurons in substantia nigra was assessed by immunohistochemistry. TNF-α and IL-1β levels were determined using ELISA kits. Result Severity of behavioral symptoms was gradually increased in 6-OHDA-treated rats. They showed a decrease in serum TNF-α level in the eight week and increase in IL-1β both in the second and eight weeks. They were divided into two subgroups, symptomatic and asymptomatic with severe and moderate degrees in DAergic neuronal death. Significant decrease in serum TNF-α was only observed in the symptomatic subgroup but IL-1β increased in both subgroups. Also, striatal levels of both cytokines were higher in the lesioned hemisphere. Conclusion Increase in serum IL-1β level can reflect moderate degree of lesion in substantia nigra and thereby is used for prognosis of PD before its clinical symptoms are appeared. On the other hand, an increase in serum TNF-α is appeared in advanced stage of PD.

L-Theanine Ameliorated Rotenone-Induced Parkinsonism-like Symptoms in Rats.

Rotenone (RO)-induced neurotoxicity exhibits pathophysiological features similar to those reported in patients with Parkinson's disease (PD), such as nitrosative and oxidative stress, mitochondrial dysfunction, and neural cytoarchitecture alterations in the substantia nigra pars compacta (SNpc)/striatum (ST), which has been used for decades as an animal model of PD in humans. L-Theanine (LT), a major amino acid component of green tea, exhibits potent antioxidant and anti-inflammatory activities and protects against various neural injuries. We investigated the potential therapeutic effects of LT on RO-induced behavioral and neurochemical dysfunction in rats and the neuroprotective mechanisms underlying these effects. Unilateral stereotaxic intranigral infusion of RO into the SNpc to induce PD-like manifestations induced significant behavioral impairment as evaluated using an open field test, rotarod test, grip strength measurement, and beam-crossing task in rats. LT treatment (300mg/kg i.p., 21days) ameliorated most RO-induced behavioral impairments. In addition, LT treatment reduced nitric oxide level and lipid peroxidation production, increased mitochondrial function and integrity, as well as the activities of mitochondrial complexes I, II, IV, and V, and reduced the levels of neuroinflammatory and apoptotic markers in the SNpc and ameliorated the levels of catecholamines, GABA and glutamate in the ST induced by RO. These results demonstrate the possible therapeutic effects of LT against RO-induced behavioral impairments, including antioxidative effects, prevention of mitochondrial dysfunction, prevention of neurochemical deficiency, anti-neuroinflammatory effects, and anti-apoptotic effects. This is the first report on the neuroprotective effect of LT against RO-induced behavioral impairments, and the above evidence provides a potential clinically relevant role for LT in the management of human PD.

Targeting the epigenome to treat neurodegenerative diseases or delay their onset: a perspective

Targeting the epigenome to treat neurodegenerative diseases or delay their onset: a perspective

Chapter 10 - Alpha-synuclein and cortico-striatal plasticity in animal models of Parkinson disease

Alpha-synuclein (α-synuclein) is a small, acidic protein containing 140 amino acids, highly expressed in the brain and primarily localized in the presynaptic terminals. It is found in high concentrations in Lewy Bodies, proteinaceous aggregates that constitute a typical histopathologic hallmark of Parkinson's disease. Altered environmental conditions, genetic mutations and post-translational changes can trigger abnormal aggregation processes with the increased frequency of oligomers, protofibrils, and fibrils formation that perturbs the neuronal homeostasis leading to cell death. Relevant to neuronal activity, a function of α-synuclein that has been extensively detailed is its regulatory actions in the trafficking of synaptic vesicles, including the processes of exocytosis, endocytosis and neurotransmitter release. Most recently, increasing attention has been paid to the possible role that α-synuclein plays at a postsynaptic level by interacting with selective subunits of the glutamate N-methyl-d-aspartate receptor, altering the corticostriatal plasticity of distinct neuronal populations.

Modeling Mechanisms and Applications of Parkinson's Disease Animal Models

Modeling Mechanisms and Applications of Parkinson's Disease Animal Models

Animal models of action control and cognitive dysfunction in Parkinson's disease.

Parkinson's disease (PD) has historically been considered a motor disorder induced by a loss of dopaminergic neurons in the substantia nigra pars compacta. More recently, it has been recognized to have significant non-motor symptoms, most prominently cognitive symptoms associated with a dysexecutive syndrome. It is common in the literature to see motor and cognitive symptoms treated separately and, indeed, there has been a general call for specialized treatment of the latter, particularly in the more severe cases of PD with mild cognitive impairment and dementia. Animal studies have similarly been developed to model the motor or non-motor symptoms. Nevertheless, considerable research has established that segregating consideration of cognition from the precursors to motor movement, particularly movement associated with goal-directed action, is difficult if not impossible. Indeed, on some contemporary views cognition is embodied in action control, something that is particularly prevalent in theory and evidence relating to the integration of goal-directed and habitual control processes. The current paper addresses these issues within the literature detailing animal models of cognitive dysfunction in PD and their neural and neurochemical bases. Generally, studies using animal models of PD provide some of the clearest evidence for the integration of these action control processes at multiple levels of analysis and imply that consideration of this integrative process may have significant benefits for developing new approaches to the treatment of PD.

Assessment of Dopaminergic Neurodegeneration in Mice.

Neuron death is a key feature of neurological disorders like Alzheimer's or Parkinson's disease (PD). As a result, analysis of neurodegeneration is often considered a central experiment in the postmortem characterization of preclinical PD animal models. Stereology provides a precise estimate of particles, like neurons, in three-dimensional objects, like the brain, and is the gold standard quantification approach for the assessment of neuron survival in neurodegenerative disease research. Here, we provide a detailed step-by-step guide for the quantification of dopaminergic neurons in the substantia nigra pars compacta, a brain area prone to neuron loss in PD. In addition, we outline the protocol for the analysis of the dopaminergic terminals in the striatum, the projection area of midbrain dopaminergic neurons, as a readout for the integrity of the nigrostriatal projections.

FUNCTIONAL CHANGES IN PERIPHERAL PHAGOCYTES IN RATS WITH LPS-INDUCED PARKINSON'S DISEASE

Sustained neuroinflammation is considered to be a leading contributor to progressive neuron damage of the substantia nigra, leading to the development of Parkinson’s disease (PD). Systemic inflammation (SI) correlates with neuroinflammation as PD progresses, and exacerbates neurodegeneration. Phagocytes are key players in both neuroinflammation and SI. SI manifestation in commonly used animal models of PD is an unexplored question.LPS-induced PD is usually used for the study of the inflammation in the PD pathophysiology. The aim of this study was to examine metabolic profile of peripheral phagocytes in rats with LPS-induced PD. LPS-induced PD was accompanied by the neutrophilia, the decrease of circulating lymphocyte proportion, and as a result - by doubling the neutrophil-to-lymphocytes ratio. Reactive oxygen species generation was higher in circulating phagocytes from rats with PD (by 1.3 times in neutrophils and by more than 5 times - in monocytes) as compared to control animals. Wherein, phagocytic activity was lower in neutrophils by 1.2 times and in monocytes - by 2.6 times as compared to the control. These data indicate systemic inflammatory process in LPS lesioned rats. Thus, LPS-induced PD reproduces systemic inflammation spread, which is inherent for progressive PD.

Inhibition of anandamide hydrolysis does not rescue respiratory abnormalities observed in an animal model of Parkinson's disease.

What is the central question of this study? The respiratory frequency to hypercapnia is attenuated in an animal model of Parkinson's disease (PD): what is the therapeutic potential of inhibition of anandamide hydrolysis for this respiratory deficit? What is the main finding and its importance? In an animal model of PD there is an increased variability in resting respiratory frequency and an impaired tachypnoeic response to hypercapnia, which is accompanied by diminished expression of Phox2b immunoreactivity in the retrotrapezoid nucleus (RTN). Inhibition of anandamide hydrolysis also impaired the response to hypercapnia and decreased the number of Phox2b immunoreactive cells in the RTN. This strategy does not reverse the respiratory deficits observed in an animal model of PD. Parkinson's disease (PD) is characterized by severe classic motor symptoms along with various non-classic symptoms. Among the non-classic symptoms, respiratory dysfunctions are increasingly recognized as contributory factors to complications in PD. The endocannabinoid system has been proposed as a target to treat PD and other neurodegenerative disorders. Since symptom management of PD is mainly focused on the classic motor symptoms, in this work we aimed to test the hypothesis that increasing the actions of the endocannabinoid anandamide by inhibiting its hydrolysis with URB597 reverses the respiratory deficits observed in an animal model of PD. Results show that bilateral injection of 6-hydroxydopamine hydrochloride (6-OHDA) in the dorsal striatum leads to neurodegeneration of the substantia nigra, accompanied by reduced expression of Phox2b in the retrotrapezoid nucleus (RTN), an increase in resting respiratory frequency variability and an impaired tachypnoeic response to hypercapnia. URB597 treatment in control animals was associated with an impaired tachypnoeic response to hypercapnia and a reduced expression of Phox2b in the RTN, whereas treatment of 6-OHDA-lesioned animals with URB597 was not able to reverse the deficits observed. These results suggest that targeting anandamide may not be a suitable strategy to treat PD since this treatment mimics the respiratory deficits observed in the 6-OHDA model of PD.

Exosomes isolated during dopaminergic neuron differentiation suppressed neuronal inflammation in a rodent model of Parkinson’s disease

Our previous investigation showed Wnt signal pathway was significantly activated during DA neuron differentiation of epiblast-derived stem cells. In this study, we next attempt to examine the therapeutic potential of the purified exosomes derived bone marrow mesenchymal stem cells (BMSCs) by administrating exosomes into the rat striatum of parkinson's disease (PD) animal model. Results revealed that the protein levels of interleukin (IL)-6, IL-1β, tumor necrosis factor-alpha (TNF-α), and reactive oxygen species (ROS) in the substantia nigra of PD rats were down regulated after injection of BMSC induced-Exosomes into the striatum of PD model compared to BMSC quiescent-Exosomes. In addition, the expression of ionized calcium binding adaptor molecule 1 (Iba1) mRNA was significantly decreased, while the expression of tyrosine hydroxylase (TH) mRNA was increased after injection of BMSC induced-Exosomes. Injection of BMSC induced-Exosomes into the striatum rescued the rotation behavior and climbing speed in the PD rats. More importantly, Wnt5a was found to be enriched in BMSC induced Exosomes, which could be effectively transferred to the substantia nigra of PD rats. In conclusion, these findings demonstrated that exosomes isolated during dopaminergic neuron differentiation could rescue the pathogenic features of Parkinson’s disease by reshaping the inflammatory microenvironment in the substantia nigra and repairing the injury to DA nerves.

Reduction of tyrosine hydroxylase expression and increase of α-synuclein in the substantia nigra in a rat model of benign prostatic hyperplasia

Parkinson's disease (PD) occurs when dopaminergic cells in the substantia nigra (SN) region are destroyed; however, the cause of the destruction of dopamine cells has not yet been determined. This study was performed to investigate whether changes in the hormones that cause benign prostatic hyperplasia (BPH) are related to pathological changes in PD. The pathological findings were examined by observing the lesion sites related to PD in a BPH rat model. BPH was induced in rats by subcutaneous injection of testosterone propionate for 4 weeks after castration. To investigate the changes in the SN regions, tyrosine hydroxylase (TH) and α-synuclein (α-syn) expression were analyzed by western blotting. TH expression, expressed in dopaminergic cells and used as a dopaminergic cell detection marker, decreased, whereas α-syn expression increased at the SN site. These results are quite similar to the pathological changes observed in patients with PD and Parkinsonism animal models. Our results showed an increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in the SN regions in the BPH group. Additionally, a decreased expression of B-cell lymphoma protein 2 and an increased expression of B-cell lymphoma protein 2-associated X, suggesting increased apoptosis, were observed in the BPH group. These results suggest that the pathological changes associated with PD may be caused by BPH or factors related to BPH. Thus, this study has presented a new avenue for an approach related to hormonal changes as a method to determine the cause of PD, for which the exact cause is not yet known.

Androgens and Parkinson's Disease: A Review of Human Studies and Animal Models.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A greater prevalence and incidence of PD are reported in men than in women, suggesting a potential contribution of sex, genetic difference and/or sex hormones. This review presents an overview of epidemiological and clinical studies investigating sex differences in the incidence and symptoms of PD. This sex difference is replicated in animal models of PD showing an important neuroprotective role of sex steroids. Therefore, although gender and genetic factors likely contribute to the sex difference in PD, focus here will be on sex hormones because of their neuroprotective role. Androgens receive less attention than estrogen. It is well known that endogenous androgens are more abundant in healthy men than in women and decrease with aging; lower levels are reported in PD men than in healthy male subjects. Drug treatments with androgens, androgen precursors, antiandrogens, and drugs modifying androgen metabolism are available to treat various endocrine conditions, thus having translational value for PD but none have yet given sufficient positive effects for PD. Variability in the androgen receptor is reported in humans and is an additional factor in the response to androgens. In animal models of PD used to study neuroprotective activity, the androgens testosterone and dihydrotestosterone have given inconsistent results. 5α-Reductase inhibitors have shown neuroprotective activity in animal models of PD and antidyskinetic activity. Hence, androgens have not consistently shown beneficial or deleterious effects in PD but numerous androgen-related drugs are available that could be repurposed for PD.

Real-time removal of stimulation artifacts in closed-loop deep brain stimulation

Objective. Closed-loop deep brain stimulation (DBS) with neural feedback has shown great potential in improving the therapeutic effect and reducing side effects. However, the amplitude of stimulation artifacts is much larger than the local field potentials, which remains a bottleneck in developing a closed-loop stimulation strategy with varied parameters. Approach. We proposed an irregular sampling method for the real-time removal of stimulation artifacts. The artifact peaks were detected by applying a threshold to the raw recordings, and the samples within the contaminated period of the stimulation pulses were excluded and replaced with the interpolation of the samples prior to and after the stimulation artifact duration. This method was evaluated with both simulation signals and in vivo closed-loop DBS applications in Parkinsonian animal models. Main results. The irregular sampling method was able to remove the stimulation artifacts effectively with the simulation signals. The relative errors between the power spectral density of the recovered and true signals within a wide frequency band (2–150 Hz) were 2.14%, 3.93%, 7.22%, 7.97% and 6.25% for stimulation at 20 Hz, 60 Hz, 130 Hz, 180 Hz, and stimulation with variable low and high frequencies, respectively. This stimulation artifact removal method was verified in real-time closed-loop DBS applications in vivo, and the artifacts were effectively removed during stimulation with frequency continuously changing from 130 Hz to 1 Hz and stimulation adaptive to beta oscillations. Significance. The proposed method provides an approach for real-time removal in closed-loop DBS applications, which is effective in stimulation with low frequency, high frequency, and variable frequency. This method can facilitate the development of more advanced closed-loop DBS strategies.

The Neuroprotective Effects of Cannabis-Derived Phytocannabinoids and Resveratrol in Parkinson's Disease: A Systematic Literature Review of Pre-Clinical Studies.

Currently, there are no pharmacological treatments able to reverse nigral degeneration in Parkinson’s disease (PD), hence the unmet need for the provision of neuroprotective agents. Cannabis-derived phytocannabinoids (CDCs) and resveratrol (RSV) may be useful neuroprotective agents for PD due to their anti-oxidative and anti-inflammatory properties. To evaluate this, we undertook a systematic review of the scientific literature to assess the neuroprotective effects of CDCs and RSV treatments in pre-clinical in vivo animal models of PD. The literature databases MEDLINE, EMBASE, PsychINFO, PubMed, and Web of Science core collection were systematically searched to cover relevant studies. A total of 1034 publications were analyzed, of which 18 met the eligibility criteria for this review. Collectively, the majority of PD rodent studies demonstrated that treatment with CDCs or RSV produced a significant improvement in motor function and mitigated the loss of dopaminergic neurons. Biochemical analysis of rodent brain tissue suggested that neuroprotection was mediated by anti-oxidative, anti-inflammatory, and anti-apoptotic mechanisms. This review highlights the neuroprotective potential of CDCs and RSV for in vivo models of PD and therefore suggests their potential translation to human clinical trials to either ameliorate PD progression and/or be implemented as a prophylactic means to reduce the risk of development of PD.

Cardiac and Autonomic Dysfunctions Assessed Through Recurrence Quantitative Analysis of Electrocardiogram Signals and an Application to the 6-Hydroxydopamine Parkinson's Disease Animal Model.

A classic method to evaluate autonomic dysfunction is through the evaluation of heart rate variability (HRV). HRV provides a series of coefficients, such as Standard Deviation of n-n intervals (SDNN) and Root Mean Square of Successive Differences (RMSSD), which have well-established physiological associations. However, using only electrocardiogram (ECG) signals, it is difficult to identify proper autonomic activity, and the standard techniques are not sensitive and robust enough to distinguish pure autonomic modulation in heart dynamics from cardiac dysfunctions. In this proof-of-concept study we propose the use of Poincaré mapping and Recurrence Quantification Analysis (RQA) to identify and characterize stochasticity and chaoticity dynamics in ECG recordings. By applying these non-linear techniques in the ECG signals recorded from a set of Parkinson’s disease (PD) animal model 6-hydroxydopamine (6-OHDA), we showed that they present less variability in long time epochs and more stochasticity in short-time epochs, in their autonomic dynamics, when compared with those of the sham group. These results suggest that PD animal models present more “rigid heart rate” associated with “trembling ECG” and bradycardia, which are direct expressions of Parkinsonian symptoms. We also compared the RQA factors calculated from the ECG of animal models using four computational ECG signals under different noise and autonomic modulatory conditions, emulating the main ECG features of atrial fibrillation and QT-long syndrome.

Parkinson's Disease Modification Through Abl Kinase Inhibition: An Opportunity.

ABSTRACTParkinson's disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5 000 000 cases worldwide. Historically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, PD pathology is now known to be widespread and to affect serotonin, cholinergic and norepinephrine neurons as well as nerve cells in the olfactory system, cerebral hemisphere, brain stem, spinal cord, and peripheral autonomic nervous system. PD pathology is characterized by the accumulation of misfolded α‐synuclein, which is thought to play a critical role in the etiopathogenesis of the disease. Animal models of PD suggest that activation of the Abelson tyrosine kinase (c‐Abl) plays an essential role in the initiation and progression of α‐synuclein pathology and neurodegeneration. These studies demonstrate that internalization of misfolded α‐synuclein activates c‐Abl, which phosphorylates α‐synuclein and promotes α‐synuclein pathology within the affected neurons. Additionally, c‐Abl inactivates parkin, disrupting mitochondrial quality control and biogenesis, promoting neurodegeneration. Post‐mortem studies of PD patients demonstrate increased levels of tyrosine phosphorylated α‐synuclein, consistent with the activation of c‐Abl in human disease. Although the c‐Abl inhibitor nilotinib failed to demonstrate clinical benefit in two double‐blind trials, novel c‐Abl inhibitors have been developed that accumulate in the brain and may inhibit c‐Abl at saturating levels. These novel inhibitors have demonstrated benefits in animal models of PD and have now entered clinical development. Here, we review the role of c‐Abl in the neurodegenerative disease process and consider the translational potential of c‐Abl inhibitors from model studies to disease‐modifying therapies for Parkinson's disease. © 2021 Inhibikase Therapeutics, Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Chronic and progressive dopaminergic neuronal death in substantia nigra associates with a decrease in serum levels of glucose and free fatty acids, the role of interlokin-1 beta.

Human studies indicate that Parkinson's disease (PD) associates with disruption in metabolism of glucose and free fatty acids (FFA). Studies have shown that interlukin-1beta (IL-1β) causes hypoglycemia through insulin- independent mechanisms. Here, we investigated association between dopaminergic neuronal death, as the main pathophysiological mechanism underlying PD, and serum levels of glucose, FFA and IL-1β in 6-hydroxydopamine (6-OHDA) animal model of PD. Neurotoxin of 6-OHDA was injected into medial forebrain bundle and multiple behavioral testes were carried out during eight weeks thereafter. Blood was collected before the toxin and in second and eight weeks thereafter. Then, brain of the animals was perfused to assess survival of dopaminergic (DAergic) neurons in substantia nigra by tyrosine hydroxylase (TH) immunohistochemistry. Glucose, FFA and IL-1β levels were determined using calorimetric method and specific ELISA kits. In compare to control, 6-OHDA- treated rats had less glucose and FFA levels in the eight week and higher IL-1β level in the both second and eight weeks. Based on severity of behavioral symptoms, 6-OHDA- treated rats were divided into two subgroups of severe and mild. Number of TH- positive cells in these subgroups was 83 and 45% less than that in control. Also, both subgroups showed less weight gain, lower glucose and FFA and higher IL-1β in eight week. Our data indicate that moderate to severe progressive DAergic neuronal death in substantia nigra associates with a decrease in serum levels of glucose and FFA. Increase in IL-1β production following neuronal death possibly mediated this decrease.

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

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.