Probucol Affords Neuroprotection in a 6-OHDA Mouse Model of Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic nigrostriatal neurons. Although the etiology of the majority of human PD cases is unknown, experimental evidence points to oxidative stress as an early and causal event. Probucol is a lipid-lowering phenolic compound with anti-inflammatory and antioxidant properties that has been recently reported as protective in neurotoxicity and neurodegeneration models. This study was designed to investigate the effects of probucol on the vulnerability of striatal dopaminergic neurons to oxidative stress in a PD in vivo model. Swiss mice were treated with probucol during 21 days (11.8 mg/kg; oral route). Two weeks after the beginning of treatment, mice received a single intracerebroventricular (i.c.v.) infusion of 6-hydroxydopamine (6-OHDA). On the 21st day, locomotor performance, striatal oxidative stress-related parameters, and striatal tyrosine hydroxylase and synaptophysin levels, were measured as outcomes of toxicity. 6-OHDA-infused mice showed hyperlocomotion and a significant decrease in striatal tyrosine hydroxylase (TH) and synaptophysin levels. In addition, 6-OHDA-infused mice showed reduced superoxide dismutase activity and increased lipid peroxidation and catalase activity in the striatum. Notably, probucol protected against 6-OHDA-induced hyperlocomotion and striatal lipid peroxidation, catalase upregulation and decrease of TH levels. Overall, the present results show that probucol protects against 6-OHDA-induced toxicity in mice. These findings may render probucol as a promising molecule for further pharmacological studies on the search for disease-modifying treatment in PD.     

Lithium Fails to Protect Dopaminergic Neurons in the 6-OHDA Model of Parkinson’s Disease

Lithium has been used for the treatment of bipolar mood disorder and is shown to have neuroprotective properties. Since lithium inhibits the activity of glycogen synthase kinase 3 (GSK3) which is implicated in various human diseases, particularly neurodegenerative diseases, the therapeutic potential of lithium receives great attention. Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterized by the pathological loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Intranigral injection of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) causes selective and progressive degeneration of dopaminergic neurons in SNpc, and is a commonly used animal model of PD. The current study was designated to determine whether lithium is effective in alleviating 6-OHDA-induced neurodegeneration in the SNpc of rats. We demonstrated that chronic subcutaneous administration of lithium inhibited GSK3 activity in the SNpc, which was evident by an increase in phosphorylation of GSK3β at serine 9, cyclin D1 expression, and a decrease in tau phosphorylation. 6-OHDA did not affect GSK3 activity in the SNpc. Moreover, lithium was unable to alleviate 6-OHDA-induced degeneration of SNpc dopaminergic neurons. The results suggest that GSK3 is minimally involved in the neurodegeneration in the rat 6-OHDA model of PD.     

Increase in Glutamatergic Terminals in the Striatum Following Dopamine Depletion in a Rat Model of Parkinson’s Disease

Dopaminergic neuron degeneration is known to give rise to dendrite injury and spine loss of striatal neurons, however, changes of intrastriatal glutamatergic terminals and their synapses after 6-hydroxydopamine (6OHDA)-induced dopamine (DA)-depletion remains controversial. To confirm the effect of striatal DA-depletion on the morphology and protein levels of corticostriatal and thalamostriatal glutamatergic terminals and synapses, immunohistochemistry, immuno-electron microscope (EM), western blotting techniques were performed on Parkinson’s disease rat models in this study. The experimental results of this study showed that: (1) 6OHDA-induced DA-depletion resulted in a remarkable increase of Vesicular glutamate transporter 1 (VGlut1) + and Vesicular glutamate transporter 2 (VGlut2)+ terminal densities at both the light microscope (LM) and EM levels, and VGlut1+ and VGlut2+ terminal sizes were shown to be enlarged by immuno-EM; (2) Striatal DA-depletion resulted in a decrease in both the total and axospinous terminal fractions of VGlut1+ terminals, but the axodendritic terminal fraction was not significantly different from the control group. However, total, axospinous and axodendritic terminal fractions for VGlut2+ terminals declined significantly after striatal DA-depletion. (3) Western blotting data showed that striatal DA-depletion up-regulated the expression levels of the VGlut1 and VGlut2 proteins. These results suggest that 6OHDA-induced DA-depletion affects corticostriatal and thalamostriatal glutamatergic synaptic inputs, which are involved in the pathological process of striatal neuron injury induced by DA-depletion.

     

Auricular Vagus Nerve Stimulation Exerts Antiinflammatory Effects and Immune Regulatory Function in a 6-OHDA Model of Parkinson’s Disease

According to epidemiologic studies, smoking appears to downregulate the prevalence of Parkinson’s disease (PD), possibly due to antiinflammatory mechanisms via activation of α7 nicotinic acetylcholine receptors (α7 nAChRs). This receptor also appears to play a role in T-cell differentiation. Recently, it has become apparent that the innate immune system participates in PD pathogenesis. The aim of this study was to evaluate the effects of auricular vagus nerve stimulation (aVNS) on substantia nigra (SN) dopaminergic neurodegeneration and the associated neuroinflammation and immune responses in a rat PD model. Adult male Wistar rats were unilaterally administered 6-hydroxydopamine (6-OHDA) to the medial forebrain bundle, followed by aVNS treatment after surgery. Following motor behavioral tests, the expression of tyrosine hydroxylase (TH) in the SN and the levels of inflammatory cytokines in the ventral midbrain were evaluated. In addition, changes in the trends of subsets of CD4+ T lymphocytes in the SN were measured by immunofluorescence staining. Western blotting was used to evaluate the α7 nAChR protein level. Compared with 6-OHDA treats rats, aVNS treatment significantly improved motor deficits, increased TH and α7 nAChR expression, and reduced the levels of inflammatory cytokines (tumor necrosis factor-a (TNF-α) and interleukin-1β (IL-1β)) (p?<?0.05). Additionally, aVNS increased the numbers of regulatory T (Treg) cells while decreasing T helper (Th)17 cells. aVNS exerted neuroprotective effects against dopaminergic damage, possibly by suppressing the evolution of inflammation and modulating innate immune responses. Thus, aVNS may be a potential promising therapy in the future.     

Loss of Collapsin Response Mediator Protein 4 Attenuates 6-Hydroxydopamine-Induced Impairments in a Mouse Model of Parkinson’s Disease

Neurochemical Research - Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by impaired motor symptoms induced by the degeneration of dopaminergic neurons of the...     

Intranigral LPS Administration Produces Dopamine,Glutathione but not Behavioral Impairment in Comparison to MPTP and 6-OHDA Neurotoxin Models of Parkinson’s Disease

The current investigation compared intranigral lipopolysaccharide (LPS), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) administrations, in the light of neurochemical, behavioral and endogenous antioxidant glutathione alterations. All the results were collected 1, 3 and 7 days after the lesions. LPS produced a delayed reduction of striatal dopamine, whereas homovanillic acid was drastically increased at the first time-point. Comparatively, MPTP promoted dopamine reduction 3 and 7 days with increase of homovanillic acid. Whilst, 6-OHDA generated initial increase of dopamine and homovanillic acid followed by subsequent decrease of this neurotransmitter accompanied by reductions of dopamine metabolites at the same periods. Furthermore, nigral glutathione demonstrated to be a far more sensitive target for LPS than for MPTP or 6-OHDA. Behavioral data indicated impairments induced by MPTP, 6-OHDA but not LPS. In conclusion, it is suggested that intranigral LPS can provide new insights about neuroinflammation, simulating features of the pre-motor phase of Parkinson’s disease.     

Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP

Neurological disorders in humans can be modeled in animals using standardized procedures that recreate specific pathogenic events and their behavioral outcomes. The development of animal models of Parkinsons disease (PD) is important to test new neuroprotective agents and strategies. Such animal models of PD have to mimic, at least partially, a Parkinson-like pathology and should reproduce specific features of the human disease. PD is characterized by massive degeneration of dopaminergic neurons in the substantia nigra, the loss of striatal dopaminergic fibers and a dramatic reduction of the striatal dopamine levels. The formation of cytoplasmic inclusion bodies (Lewy bodies) in surviving dopaminergic neurons represents the most important neuropathological feature of PD. Furthermore, the massive striatal dopamine deficiency causes easily detectable motor deficits in PD patients, including bradykinesia, rigidity, and resting tremor, which are the cardinal symptoms of PD. Over the years, a broad variety of experimental models of PD were developed and applied in diverse species. This review focuses on the two most common classical toxin-induced PD models, the 6-hydroxy-dopamine (6-OHDA model) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, whereas in humans the PD pathogenesis follows a progressive course over decades. This discrepancy reflects one important and principal point of weakness related to most animal models. This review discusses the most important properties of 6-OHDA and MPTP, their modes of administration, and critically examines advantages and limitations of selected animal models. The new genetic and environmental toxin models of PD (e.g. rotenone, paraquat, maneb) are discussed elsewhere in this special issue.This work was supported by grants from the Deutsche Forschungsgemeinschaft.     

Impaired Sense of Smell in a Drosophila Parkinson’s Model

Parkinson’s disease (PD) is one of the most common neurodegenerative disease characterized by the clinical triad: tremor, akinesia and rigidity. Several studies have suggested that PD patients show disturbances in olfaction at the earliest onset of the disease. The fruit fly Drosophila melanogaster is becoming a powerful model organism to study neurodegenerative diseases. We sought to use this system to explore olfactory dysfunction, if any, in PINK1 mutants, which is a model for PD. PINK1 mutants display many important diagnostic symptoms of the disease such as akinetic motor behavior. In the present study, we describe for the first time, to the best of our knowledge, neurophysiological and neuroanatomical results concerning the olfactory function in PINK1 mutant flies. Electroantennograms were recorded in response to synthetic and natural volatiles (essential oils) from groups of PINK1 mutant adults at three different time points in their life cycle: one from 3–5 day-old flies, from 15–20 and from 27–30 days. The results obtained were compared with the same age-groups of wild type flies. We found that mutant adults showed a decrease in the olfactory response to 1-hexanol, α-pinene and essential oil volatiles. This olfactory response in mutant adults decreased even more as the flies aged. Immunohistological analysis of the antennal lobes in these mutants revealed structural abnormalities, especially in the expression of Bruchpilot protein, a marker for synaptic active zones. The combination of electrophysiological and morphological results suggests that the altered synaptic organization may be due to a neurodegenerative process. Our results indicate that this model can be used as a tool for understanding PD pathogensis and pathophysiology. These results help to explore the potential of using olfaction as a means of monitoring PD progression and developing new treatments.     

Reduction in Subventricular Zone-Derived Olfactory Bulb Neurogenesis in a Rat Model of Huntington’s Disease Is Accompanied by Striatal Invasion of Neuroblasts

Huntington’s disease (HD) is an inherited progressive neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the huntingtin gene (HTT). The primary neuropathology of HD has been attributed to the preferential degeneration of medium spiny neurons (MSN) in the striatum. Reports on striatal neurogenesis have been a subject of debate; nevertheless, it should be considered as an endogenous attempt to repair the brain. The subventricular zone (SVZ) might offer a close-by region to supply the degenerated striatum with new cells. Previously, we have demonstrated that R6/2 mice, a widely used preclinical model representing an early onset HD, showed reduced olfactory bulb (OB) neurogenesis but induced striatal migration of neuroblasts without affecting the proliferation of neural progenitor cell (NPCs) in the SVZ. The present study revisits these findings, using a clinically more relevant transgenic rat model of late onset HD (tgHD rats) carrying the human HTT gene with 51 CAG repeats and mimicking many of the neuropathological features of HD seen in patients. We demonstrate that cell proliferation is reduced in the SVZ and OB of tgHD rats compared to WT rats. In the OB of tgHD rats, although cell survival was reduced, the frequency of neuronal differentiation was not altered in the granule cell layer (GCL) compared to the WT rats. However, an increased frequency of dopamenergic neuronal differentiation was noticed in the glomerular layer (GLOM) of tgHD rats. Besides this, we observed a selective proliferation of neuroblasts in the adjacent striatum of tgHD rats. There was no evidence for neuronal maturation and survival of these striatal neuroblasts. Therefore, the functional role of these invading neuroblasts still needs to be determined, but they might offer an endogenous alternative for stem or neuronal cell transplantation strategies.     

Molecular Profiling of a 6-Hydroxydopamine Model of Parkinson’s Disease

Convection enhanced delivery of 6-hydroxydopamine (6-OHDA) to the rat striatum results in a model of Parkinson’s disease. An important feature of this unilateral model is the progressive loss of dopaminergic (DA) neurons over the course of several weeks. To improve the understanding of this model, gene expression changes in the substantia nigra, which contains the DA neuron cell bodies, and the striatum, which contains the DA neuron synaptic terminals, were examined using DNA microarrays. Samples were collected and behavior was analyzed from vehicle and toxin treated animals at 3 days, 1 week, 2 weeks and 4 weeks following 6-OHDA treatment. Tissue DA content was determined and samples from animals which exhibited a substantial depletion of striatal DA were included in the subsequent gene expression analysis. The results of the gene expression analysis indicated that 6-OHDA elicits a vigorous inflammatory response, comprised of several distinct pathways, in the striatum at the earliest time point tested. In contrast, relatively few gene expression changes were observed in the SN at the 3-day time point. In both tissues examined there was evidence for a vigorous inflammatory response at the 1- and 2-week time points, which was substantially diminished by the 4-week time point. Inflammation plays a prominent role in the 6-OHDA model of Parkinson’s disease.     

Weight Loss and Impact on Quality of Life in Parkinson’s Disease

IntroductionWeight loss is common in Parkinson’s Disease (PD) and sometimes may precede the diagnosis. Weight loss is associated with multiple factors but its impact on health-related quality of life (HRQL) in PD remains unknown. We sought to investigate the factors associated with weight change and to quantify its effect on HRQL.MethodsThe National Parkinson Foundation Quality Improvement Initiative (NPF-QII) data was used to analyze PD patients longitudinally between two visits, separated by 12±6 months. Multiple linear regression analyses were used to assess the associations between baseline covariates and body weight change per month, and to evaluate whether, and to what degree, Parkinson’s Disease Questionnaire (PDQ-39) scores were affected.ResultsA higher Hoehn & Yahr stage, higher number of comorbidities, older age, lower MOCA estimate, and higher rate of levodopa usage were observed in patients who lost weight. Multivariate regression analysis indicated that age and levodopa usage were significantly associated with weight loss. Furthermore, monthly body weight loss was significantly associated with HRQL decline in PD patients. Loss of 1 lb (0.45 kg) per month was associated with a decline in QOL: an increase of 0.5% in PDQ-39 Summary Index score (p=0.004), and 1.1% and 1.5% increases in the mobility and ADL dimensions, respectively.ConclusionWeight loss in PD is common and seems to correlate with worsened HRQL. Awareness of factors associated with weight loss and its relation to HRQL may help practitioners improve patient management and expectations.     

Olfactory Deficits in an Alpha-Synuclein Fly Model of Parkinson’s Disease

Parkinson’s disease (PD) is the most common motor neurodegenerative disorder. Olfactory dysfunction is a prevalent feature of PD. It often precedes motor symptoms by several years and is used in assisting PD diagnosis. However, the cellular and molecular bases of olfactory dysfunction in PD are not known. The fruit fly Drosophila melanogaster, expressing human alpha-synuclein protein or its mutant, A30P, captures several hallmarks of PD and has been successfully used to model PD in numerous studies. First, we report olfactory deficits in fly expressing A30P (A30P), showing deficits in two out of three olfactory modalities, tested – olfactory acuity and odor discrimination. The remaining third modality is odor identification/naming. Second, oxidative stress is an important environmental risk factor of PD. We show that oxidative stress exacerbated the two affected olfactory modalities in younger A30P flies. Third, different olfactory receptor neurons are activated differentially by different odors in flies. In a separate experiment, we show that the odor discrimination deficit in A30P flies is general and not restricted to a specific class of chemical structure. Lastly, by restricting A30P expression to dopamine, serotonin or olfactory receptor neurons, we show that A30P expression in dopamine neurons is necessary for development of both acuity and discrimination deficits, while serotonin and olfactory receptor neurons appeared not involved. Our data demonstrate olfactory deficits in a synuclein fly PD model for exploring olfactory pathology and physiology, and for monitoring PD progression and treatment.     

Activin A Protects Midbrain Neurons in the 6-Hydroxydopamine Mouse Model of Parkinson’s Disease

Parkinson’s disease (PD) is a chronic neurodegenerative disease characterized by a significant loss of dopaminergic neurons within the substantia nigra pars compacta (SNpc) and a subsequent loss of dopamine (DA) within the striatum. Despite advances in the development of pharmacological therapies that are effective at alleviating the symptoms of PD, the search for therapeutic treatments that halt or slow the underlying nigral degeneration remains a particular challenge. Activin A, a member of the transforming growth factor β superfamily, has been shown to play a role in the neuroprotection of midbrain neurons against 6-hydroxydopamine (6-OHDA) in vitro, suggesting that activin A may offer similar neuroprotective effects in in vivo models of PD. Using robust stereological methods, we found that intrastriatal injections of 6-OHDA results in a significant loss of both TH positive and NeuN positive populations in the SNpc at 1, 2, and 3 weeks post-lesioning in drug naïve mice. Exogenous application of activin A for 7 days, beginning the day prior to 6-OHDA administration, resulted in a significant survival of both dopaminergic and total neuron numbers in the SNpc against 6-OHDA-induced toxicity. However, we found no corresponding protection of striatal DA or dopamine transporter (DAT) expression levels in animals receiving activin A compared to vehicle controls. These results provide the first evidence that activin A exerts potent neuroprotection in a mouse model of PD, however this neuroprotection may be localized to the midbrain.     

Time-Course of Brain Oxidative Damage Caused by Intrastriatal Administration of 6-Hydroxydopamine in a Rat Model of Parkinson’s Disease

The unilateral and intrastriatal injection of 6-hydroxydopamine is commonly used to provide a partial lesion model of Parkinson’s disease in the investigation of the molecular mechanisms involved in its pathogenesis and to assess new neuroprotective treatments. Its capacity to induce neurodegeneration has been related to its ability to undergo autoxidation in the presence of oxygen and consequently to generate oxidative stress. The aim of the present study was to investigate the time course of brain oxidative damage induced by 6-hydroxydopamine (6 μg in 5 μl of sterile saline containing 0.2% ascorbic acid) injection in the right striatum of the rat. The results of this study show that the indices of both lipid peroxidation (TBARS) and protein oxidation (carbonyl and free thiol contents) increase simultaneously in the ipsilateral striatum and ventral midbrain, reaching a peak value at 48-h post-injection for both TBARS and protein carbonyl content, and at 24 h for protein free thiol content. A lower but significant increase was also observed in the contralateral side (striatum and ventral midbrain). The indices of oxidative stress returned to values close to those found in controls at 7-day post-injection. These data show that the oxidative stress is a possible triggering factor for the neurodegenerative process and the retrograde neurodegeneration observed after 1-week post-injection is a consequence of the cell damage caused during the first days post-injection. The optimal time to assess brain indices of oxidative stress in this model is 48-h post-injection.     

Sodium Butyrate Exacerbates Parkinson’s Disease by Aggravating Neuroinflammation and Colonic Inflammation in MPTP-Induced Mice Model

Neurochemical Research - The abnormal production of short chain fatty acid (SCFAs) caused by gut microbial dysbiosis plays an important role in the pathogenesis and progression of Parkinson’s...     

In Situ Regulated Dopamine Transporter Trafficking: There’s No Place Like Home

Dopamine (DA) is critical for motivation, reward, movement initiation, and learning. Mechanisms that control DA signaling have a profound impact on these important behaviors, and additionally play a role in DA-related neuropathologies. The presynaptic SLC6 DA transporter (DAT) limits extracellular DA levels by clearing released DA, and is potently inhibited by addictive and therapeutic psychostimulants. Decades of evidence support that the DAT is subject to acute regulation by a number of signaling pathways, and that endocytic trafficking strongly regulates DAT availability and function. DAT trafficking studies have been performed in a variety of model systems, including both in vitro and ex vivo preparations. In this review, we focus on the breadth of DAT trafficking studies, with specific attention to, and comparison of, how context may influence DAT’s response to different stimuli. In particular, this overview highlights that stimulated DAT trafficking not only differs between in vitro and ex vivo environments, but also is influenced by both sex and anatomical subregions.

     

Uptake of α-Ketoglutarate by Citrate Transporter CitP Drives Transamination in Lactococcus lactis

Transamination is the first step in the conversion of amino acids into aroma compounds by lactic acid bacteria (LAB) used in food fermentations. The process is limited by the availability of α-ketoglutarate, which is the best α-keto donor for transaminases in LAB. Here, uptake of α-ketoglutarate by the citrate transporter CitP is reported. Cells of Lactococcus lactis IL1403 expressing CitP showed significant levels of transamination activity in the presence of α-ketoglutarate and one of the amino acids Ile, Leu, Val, Phe, or Met, while the same cells lacking CitP showed transamination activity only after permeabilization of the cell membrane. Moreover, the transamination activity of the cells followed the levels of CitP in a controlled expression system. The involvement of CitP in the uptake of the α-keto donor was further demonstrated by the increased consumption rate in the presence of l-lactate, which drives CitP in the fast exchange mode of transport. Transamination is the only active pathway for the conversion of α-ketoglutarate in IL1403; a stoichiometric conversion to glutamate and the corresponding α-keto acid from the amino acids was observed. The transamination activity by both the cells and the cytoplasmic fraction showed a remarkably flat pH profile over the range from pH 5 to pH 8, especially with the branched-chain amino acids. Further metabolism of the produced α-keto acids into α-hydroxy acids and other flavor compounds required the coupling of transamination to glycolysis. The results suggest a much broader role of the citrate transporter CitP in LAB than citrate uptake in the citrate fermentation pathway alone.     

Knockdown of Hsc70-5/mortalin Induces Loss of Synaptic Mitochondria in a Drosophila Parkinson’s Disease Model

Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of dysfunctional, unfolded proteins in aging mitochondria. Mortalin dysfunction associated with Parkinson’s disease (PD) increases the vulnerability of cultured cells to proteolytic stress and leads to changes in mitochondrial function and morphology. To date, Drosophila melanogaster has been successfully used to investigate pathogenesis following the loss of several other PD-associated genes. We generated the first loss-of-Hsc70-5/mortalin-function Drosophila model. The reduction of Mortalin expression recapitulates some of the defects observed in the existing Drosophila PD-models, which include reduced ATP levels, abnormal wing posture, shortened life span, and reduced spontaneous locomotor and climbing ability. Dopaminergic neurons seem to be more sensitive to the loss of mortalin than other neuronal sub-types and non-neuronal tissues. The loss of synaptic mitochondria is an early pathological change that might cause later degenerative events. It precedes both behavioral abnormalities and structural changes at the neuromuscular junction (NMJ) of mortalin-knockdown larvae that exhibit increased mitochondrial fragmentation. Autophagy is concomitantly up-regulated, suggesting that mitochondria are degraded via mitophagy. Ex vivo data from human fibroblasts identifies increased mitophagy as an early pathological change that precedes apoptosis. Given the specificity of the observed defects, we are confident that the loss-of-mortalin model presented in this study will be useful for further dissection of the complex network of pathways that underlie the development of mitochondrial parkinsonism.     

Interleukin-6 Serum Levels in Patients with Parkinson’s Disease

Several lines of evidence suggest that neuroimmune mechanisms may be involved in the neurodegenerative process of Parkinson’s disease (PD). Interleukin-6 (IL-6) is increased in the nigrostriatal region and in the cerebrospinal fluid of patients with PD. IL-6 serum level was evaluated in PD patients. The effects of levodopa treatment and disease severity on IL-6 were also studied. The IL-6 levels were similar between PD patients (treated and not treated) and controls. However, there was a negative correlation of IL-6 levels and the activities of daily living scale (P < 0.05), indicating that patients with more severe disease have higher levels of this cytokine. No correlation involving levodopa treatment and IL-6 serum level was found. The results suggest that only marginal effects of IL-6 occur on the peripheral immune system, and that the role of IL-6 and others neuroimmune factors needs to be well elucidated on PD.