Impact of intravenous immunoglobulin on the dopaminergic system and immune response in the acute MPTP mouse model of Parkinson’s disease
© St-Amour et al.; licensee BioMed Central Ltd. 2012
Received: 25 May 2012
Accepted: 16 September 2012
Published: 9 October 2012
Intravenous immunoglobulin (IVIg) is a blood-derived product, used for the treatment of immunodeficiency and autoimmune diseases. Since a range of immunotherapies have recently been proposed as a therapeutic strategy for Parkinson’s disease (PD), we investigated the effects of an IVIg treatment in a neurotoxin-induced animal model of PD. Mice received four injections of MPTP (15 mg/kg) at 2-hour intervals followed by a 14-day IVIg treatment, which induced key immune-related changes such as increased regulatory T-cell population and decreased CD4+/CD8+ ratio. The MPTP treatment induced significant 80% and 84% decreases of striatal dopamine concentrations (P < 0.01), as well as 33% and 40% reductions in the number of nigral dopaminergic neurons (P < 0.001) in controls and IVIg-treated mice, respectively. Two-way analyses of variance further revealed lower striatal tyrosine hydroxylase protein levels, striatal homovanillic acid concentrations and nigral dopaminergic neurons (P < 0.05) in IVIg-treated animals. Collectively, our results fail to support a neurorestorative effect of IVIg on the nigrostriatal system in the MPTP-treated mice and even suggest a trend toward a detrimental effect of IVIg on the dopaminergic system. These preclinical data underscore the need to proceed with caution before initiating clinical trials of IVIg in PD patients.
KeywordsIntravenous immunoglobulin Parkinson’s disease Immunity Neurodegeneration MPTP Dopamine
Central and peripheral activation of the innate and adaptive immune systems have been associated with neurodegenerative diseases such as Parkinson’s disease (PD). Elevated concentrations of cytokines, such as TNFα, IL-1β, IL-6, TGFβ (transforming growth factor-beta) and IFNγ have been reported in mouse models of dopaminergic (DAergic) denervation [1, 2] as well as in the substantia nigra pars compacta (SNpc) and striatum of PD patients [2–6]. Similarly, increased concentrations of macrophage migration inhibition factor, IL-2, IL-6, TNFα and TNFα receptor-1 have been measured in the blood of PD patients [7–13]. Migration of both CD4+ (helper) and CD8+ (cytotoxic) T-lymphocytes have been identified within the SNpc of PD patients and further associated with nigrostriatal denervation in a mouse model of PD through a CD4+ T-cell-dependent Fas/Fas ligand (FasL) cytotoxic pathway . Immunological abnormalities observed in PD patients and animal models suggest an overall disruption of the immune system in the disease, but their causal role is still highly debated. It remains to be demonstrated whether immunological abnormalities are relevant therapeutic targets for neurodegenerative disorders.
Recently, intravenous immunoglobulin (IVIg) has been proposed in the treatment of neurodegenerative diseases. The safety and tolerability profiles of IVIg have justified the initiation of phase II and phase III clinical trials in Alzheimer’s disease (AD) patients and in individuals suffering from mild cognitive impairments (reviewed in ). IVIg is a therapeutic preparation of over 98% human IgG purified from the plasma of thousands of healthy donors [16–19]. Besides its routine use for a growing number of autoimmune diseases, beneficial effects of IVIg have also been reported in immune-mediated neurological diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain–Barré syndrome, multiple sclerosis and multifocal motor neuropathy (reviewed in [20–23]).
Although the mechanisms of action of IVIg remain only partially understood, anti-inflammatory and immunomodulatory effects have been described both in vitro and in vivo[24–28]. In theory, some of these functions could correct key immunologic defects described in PD. For example, in humans, IVIg treatments decrease plasma levels of TGFβ, IL-1β, IL-6, IL-8, IFNγ and TNFα [29, 30], all shown to be upregulated in PD. In vitro, IVIg has also been reported to decrease phagocytosis in microglia, to modulate transendothelial cell migration, adhesion and rolling, and to interfere with the Fas/FasL cytotoxic pathway [31–34]. More recently, increased hippocampal neurogenesis following IVIg treatment has been reported in a mouse model of AD . Furthermore, active and passive immunization against α-synuclein (α-syn), the main component of the neuronal cytoplasmic inclusions found in PD [36, 37], has been shown to reduce neuropathology and behavioral deficits in an α-syn transgenic mouse model [38, 39]. In line with these latter observations, antibodies specific to α-syn have recently been isolated from IVIg , further suggesting a potential clinical application for the use of IVIg to achieve passive immunization in PD.
Current therapies in PD are mainly symptomatic, and no drugs have ever obtained a label of disease modification or neuroprotection from health agencies [41, 42]. In light of the existing data for the benefits of IVIg in autoimmune and neurological diseases, we undertook to investigate whether such an approach could also benefit PD patients. To test this hypothesis, we evaluated whether IVIg could lead to the neurorestoration of the DAergic system after a nigrostriatal lesion. We used a post-MPTP paradigm where the IVIg treatment was delivered after the MPTP insult. This approach avoids unwanted interference of IVIg with MPTP toxicokinetics and is more representative of the typical clinical setting where the treatment is administered after the diagnosis .
Materials and methods
All biochemical reagents were purchased from J.T. Baker (Phillipsburg, NJ, USA) unless otherwise specified.
Animals, MPTP administration and IVIg treatment
Eight-week-old C57BL6J males (22 to 27 g), purchased from Charles River Laboratories (Montréal, QC, Canada) were housed three per cage with free access to food and water. All procedures were approved by the Animal Research Committee of Laval University.
Tissue preparation for postmortem analyses
Terminal intracardiac perfusion was performed under deep anesthesia (ketamine/xylazine). After transcardiac administration of 50 ml PBS buffer (Bioshop Canada Inc., Burlington, ON, Canada) containing protease and phosphatase inhibitors (SigmaFAST Protease Inhibitor Tablets (Sigma-Aldrich) with 50 mM sodium fluoride and 1 mM sodium pyrophosphate), both spleen and brain were collected. Brain hemispheres were separated: the striatum was dissected from the rostral section of the right hemisphere, snap-frozen on dry ice and stored at −80°C. The caudal section was post-fixed in 4% paraformaldehyde pH 7.4 and sliced with a freezing microtome (coronal brain sections of 25 μm). The left hemisphere was snap-frozen in 2-methyl-butane and stored at −80°C for cryostat coronal brain sections (12 μm). Splenocytes were recovered from the spleen following mechanical disaggregation, frozen at −80°C in a cryoprotective medium (Iscove’s Modified Dulbecco’s Medium supplemented with 20% fetal bovine serum and 5% dimethylsulfoxide) and kept in liquid nitrogen until further use.
Cell surface marker expression on splenocytes were analyzed using AF647-conjugated anti-CD3 (clone 17A2; BD Biosciences, Mississauga, ON, Canada), eFluor 780-conjugated anti-B220 (clone RM4-5; BD Biosciences), PE-Cy7-conjugated anti-CD4 (clone GK1.5; eBioscience, San Diego, CA, USA), eFluor 450-conjugated anti-CD8a (clone 53–6.7; eBioscience), APC-conjugated anti-CD11b (clone M1/70; BD Biosciences), FITC-conjugated anti-Gr1 (LY-6 G clone RB6-8C5; eBioscience) or relevant isotypic controls in PBS–1% BSA. For human IgG detection, splenocytes were labeled with PE-conjugated anti-CD45 and FITC-conjugated anti-human IgG. For regulatory T-lymphocyte analyses, splenocytes were stained on ice for 30 minutes with PE-conjugated anti-CD25 (clone PC61.5; eBioscience) and APC-conjugated anti-CD4 (clone RM4-5; BD Bioscience) followed by permeabilization and fixation using the Foxp3 staining buffer (eBioscience) and staining with eFluor450-conjugated anti-Foxp3 (clone FJK-16s; eBioscience) following the manufacturer’s instructions. Cells were acquired and analyzed using a CyFlow ML (Partec, Swedesboro, NJ, USA) cytometer and FCS express software (De Novo Software, Los Angeles, CA, USA).
To determine whether the injection of IVIg triggered an anti-human IgG immune response, an ELISPOT test was performed. Briefly, splenocytes were unfrozen, washed, counted, plated on human IgG-coated wells (Multiscreen® HTS filter plate; Millipore Corporation, Billerica, MA, USA) blocked with 5% fetal bovine serum and left immobile for 16 hours at 37°C, 10% CO2 for antibody secretion. After washing the cells, anti-human specific mouse immunoglobulins were detected using a horseradish peroxidase-conjugated anti-mouse IgG (heavy and light chain specific; Jackson ImmunoResearch Laboratories Inc., West Grove, PA, USA) and TrueBlue™ Peroxydase Substrate (KPL, Mandel Scientific, Gaithersburg, MD, USA). Each spot was counted under a dissection microscope and considered a single anti-human specific B cell. Results from mice treated with IVIg were compared with controls.
ELISA and Western immunoblot analyses
Each striatum was homogenized in 8 volumes of lysis buffer per milligram of tissue (150 mM NaCl, 10 mM Na2HPO4, 0.5% sodium dodecylsulfate, 0.5% sodium deoxycholate, 1% Triton X-100 containing Complete™ protease inhibitors cocktail (Roche, Indianapolis, IN, USA), 10 μg/ml pepstatin A and 1 mM each of sodium fluoride and sodium orthovanadate as phosphatase inhibitors) and was sonicated three times for five 1-second pulses. The solution was centrifuged at 100,000×g for 20 minutes at 4°C, and the supernatant was retrieved and kept at −80°C for ELISA and immunoblotting. The protein concentration was determined using a bicinchoninic acid assay (Pierce, Rockford, IL, USA).
An ELISA specific to human IgG was utilized to determine the striatal concentration of IVIg using goat anti-human IgG Fc-specific antibodies (Jackson ImmunoResearch Laboratories Inc.). For immunoblot analyses, proteins (20 μg/samples) were heated at 95°C for 5 minutes in Laemmli’s loading buffer and separated by SDS-PAGE on a 10% polyacryamide gel, before transferring to a polyvinylidene fluoride membrane (Immobilon-P™; Millipore Corporation) that was blocked in 5% nonfat dry milk, 0.5% BSA, 0.1% Tween 20 in PBS buffer as previously described . Tyrosine hydroxylase (TH) protein was detected using rabbit anti-TH (1:5,000, #P40101; Pel-Freez, Rogers, AR, USA) primary antibody followed by horseradish peroxidase-labeled secondary antibody and chemiluminescence reagents (Lumiglo Reserve; KPL) as previously described . Membranes were also probed for β-actin (1:10,000; Applied Biological Materials Inc., Richmond, BC, Canada) as a control for protein load. Band intensities were quantified using a KODAK Imaging Station 4000 MM Digital Imaging System (Molecular Imaging Software version 4.0.5f7; Carestream Health, Rochester, NY, USA).
Catecholamine and indolamine quantification
Ten slices of 20 μm rostral striata were homogenized in 200 μl of 0.1 N perchloric acid (Mallinckrodt Baker, Phillipsburg, NJ, USA) and centrifuged at 12,000×g for 10 minutes at 4°C. HPLC with electrochemical detection was used to evaluate the concentration of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in striatal supernatant, as previously described . Briefly, 50 μl supernatant were injected into the chromatograph consisting of a Waters 717 plus autosampler automatic injector, a Waters 1525 binary pump equipped with an Atlantis dC18 column, a Waters 2465 electrochemical detector, and a glassy carbon electrode (Waters Ltd, Lachine, QC, Canada). The electrochemical detector was set at 10 nA. The mobile phase consisted of 47.8 mM NaH2PO4, 0.9 m M sodium octyl sulfate, 0.4 mM ethylenediamine tetraacetic acid, 2 mM NaCl and 8% (v/v) methanol at pH 2.9 and was delivered at 0.8 ml/minute. Peaks were identified using Breeze Software (Waters Ltd) and HPLC quantifications were normalized to protein concentrations.
Dopamine transporter quantification
DA transporter (DAT) was evaluated with 3β-(4-125I-iodophenyl) tropane-2-carboxylic acid isopropylester (125I-RTI-121, 2,200 Ci/mmol; NEN-DuPont, Boston, MA, USA), as previously described [45, 49]. Slide-mounted brain sections were preincubated at room temperature for 30 minutes in phosphate buffer pH 7.4 followed by a 90-minute incubation with 20 pM 125I-RTI-121. Nonspecific binding was determined in the presence of 0.1 μM mazindol (Novartis Pharmaceuticals, Dorval, QC, Canada). Sections were then washed with phosphate buffer followed by distilled water, dried overnight and exposed to Kodak BioMax film for 16 hours (Sigma-Aldrich). Densitometry was quantified using the ImageJ Analysis Software (National Institutes of Health, USA). The average labeling for each area was calculated from the mean of six adjacent brain sections from the rostral striatum of a 1/10 series of the same animal.
To visualize TH-positive neurons of the SNpc, sections were first incubated for 30 minutes in 3% H2O2 and blocked with 5% normal goat serum and 0.1% Triton in PBS for 30 minutes. After an overnight incubation with an anti-TH antibody (1:5,000; Pel-Freez), sections were washed three times in PBS and incubated for 1 hour with biotin-conjugated anti-rabbit antibody. After further washing, the sections were placed in a solution containing ABC (Elite kit; Vector Laboratories, Burlington, ON, Canada) for 1 hour at room temperature. The bound peroxidase was revealed with 0.5 mg/ml DAB (Sigma-Aldrich) and 0.01% hydrogen peroxide in 0.05 M Tris (pH 7.6). The reaction was stopped by extensively washing the sections in PBS. The sections were counterstained with cresyl violet, dehydrated and cover slipped. Photomicrographs were taken with a Microfire 1.0 camera (Optronics, Goleta, CA, USA) linked to an E800 Nikon 274 microscope (Nikon Inc., Québec, QC, Canada) using the imaging software Picture Frame.
Stereological counts of TH-positive and cresyl-violet-stained cells
The total number of TH-positive and TH-negative neurons of the SNpc was quantified stereologically on seven sections of a 1/5 series, as previously described [48–50]. Selected sections, at intervals of 125 μm, were counted in a blinded fashion by two independent investigators using Stereo Investigator software (MicroBrightfield, Williston, VT, USA) integrated to an E800 Nikon 274 microscope. After delineating the SNpc at low magnification (4× objective) a point grid was overlaid onto each section. Stained cells (TH-positive or cresyl-violet stained) with a clearly defined and intact nucleus were counted using the optical fractionator method at higher magnification (20× objective). The counting variables were as follows: distance between counting frames, 150 μm×150 μm; counting frame size, 75 μm; guard zone thickness, 1 μm. Cells were counted only if they did not intersect forbidden lines.
Statistical analyses were performed using the JMP software (version 9.0.2; SAS Institute Inc., Cary, IL, USA) and Prism 4.0c (GraphPad Software Inc., La Jolla, CA, USA). A Bartlett test was first performed on all data to verify equal variance. In cases of equal variance, statistical differences were determined using one-way analysis of variance (ANOVA) followed by post-hoc test (Tukey’s or Dunnett’s) for comparison between groups. When variances were unequal, a Welch ANOVA followed with Dunnett’s multiple comparison test was employed. If a Gaussian distribution could not be assumed, the Kruskal–Wallis nonparametric test was used followed by Dunn's post-test. The survival curves were compared using the log-rank test. To evaluate the overall effects of IVIg in both the vehicle and MPTP groups, two-way ANOVAs were also performed.
Health status and IVIg treatment
IVIg administration increases the proportion of the regulatory T cells in the spleen
Bioavailability of IVIg in brain and periphery
IVIg induces a minimal immune response
To determine whether repeated IVIg injections induced an anti-human IgG specific adaptive immune response, ELISPOT analyses were performed (n = 10 per group). With this technique, we were able to assess the number of splenocytes secreting a specific anti-human IgG antibody in control and IVIg groups, 14 days post MPTP. Although there was a significant increase in the number of splenic cells reactive to human IgG following IVIg administration (two-way ANOVA, P < 0.05), it remained very low. The amount of anti-human IgG specific cells was below 4/100,000 splenocytes in all animals. The absolute number of antibody secreting cells per spleen was 445 ± 173 and 154 ± 98 for the vehicle-IVIg and MPTP-IVIg group (mean ± standard error of the mean) versus 34 ± 22 and 23 ± 12 for the vehicle-control and MPTP-control groups. For comparison purposes, in mouse models of autoimmune diseases, the reported absolute number of antibody secreting cells to myeloperoxidase, nucleolin and dsDNA are higher than 11,000, 17,000 and 33,000 specific cells/spleen, respectively [60, 61].
Effects of MPTP and IVIg on the striatal components of the dopaminergic system
Effects of MPTP and IVIg on nigral dopaminergic neuronal loss
Our data clearly show that IVIg treatment has an impact on various immune parameters in mice, confirming the immunomodulatory action of IVIg in the periphery. Indeed, systemic administration of IVIg led to the presence of human IgG at the surface of circulating leukocytes, induced a significant decrease in the CD4+/CD8+ T-cell ratio and increased the Treg percentage. In the present study, we have also assessed the state of the brain DAergic system using a combination of validated markers. However, our results suggest that immunomodulating treatment with IVIg did not translate into neurorestoration of the denervated nigrostriatal DAergic pathway after an acute MPTP insult. Our observations rather suggest potentially negative consequences of IVIg treatment on certain components of the DAergic system, as well as on the health status of the treated animals. The vast majority of preclinical studies aiming to test new compounds for PD are tested in animal models prior to the injury (for example, MPTP treatment), thereby probing the neuroprotective properties of the potential therapeutic agents. We opted instead for a neurorestoration study design, in which the injections of IVIg began 20 hours after the last MPTP injection. MPTP-induced neurodegeneration is still ongoing at that time, as DAergic denervation stabilizes approximately 7 days after initial MPTP insult [63–65]. Nevertheless, such post-MPTP treatment paradigm is more compatible with an eventual clinical use of IVIg in human PD, which would occur after the diagnosis, when neurodegeneration processes are already engaged .
Treg cell adoptive transfer has been previously reported to protect from MPTP-induced nigrostriatal denervation [57–59] in acute MPTP mouse models. In these studies, the amount of Tregs needed to achieve neurorestoration using adoptive transfer ranged between 0.5×106 and 3.5×106 injected into the tail vein 12 hours following the last MPTP injection [57–59]. We also observed a rise in Treg percentage among the CD4+ population, reaching up to 9% in the spleen of IVIg-vehicle mice, after a 14-day treatment. However, this increase in Tregs following IVIg administration did not reach the 16 to 20% CD4+ Treg proportion previously reported [53, 54]. Nevertheless, despite the significant rise in peripheral Tregs, IVIg treatment did not translate into measurable neurorestorative effects. The lack of beneficial effects could be explained by the fact that the rise in Tregs following the initiation of IVIg treatment might have been too slow to allow a sufficient exposure to Tregs to produce any benefits. We also observed a significant increase of Treg percentage after MPTP administration with no additive effects of IVIg. This is in accordance with Rosenkranz and colleagues, who reported a higher suppressive activity of Tregs in PD and AD patients and an increased Treg number associated with aging . Finally, Ramakrishna and colleagues associated the long-term regulation of CNS inflammatory responses to the induction of iCOS+CD4+ T cells , which were left unchanged after the present IVIg treatment. The absence of neurorestorative effects of IVIg could thus also be explained by the lack of expansion of the iCOS+CD4+ T cells or the Treg population in the MPTP-treated groups.
Injections of IVIg resulted in a mild but significant decrease in the CD4+/CD8+ T-cell ratio. Such decreases are also observed in IVIg-treated patients , suggesting it may be a clinically relevant index of IVIg efficacy. Interestingly, a significant decrease in CD4+/CD8+ ratio is observed in PD patients as well [69–71], possibly accounted for by an increased susceptibility to apoptosis observed in CD4+ T cells, consequent of Fas overexpression . IVIg has been reported to modulate the level of expression of Fas and FasL and to inhibit FasL-dependent apoptosis, in both in vivo and in vitro studies [34, 73–75]. This action of IVIg on the Fas/FasL pathway could have been translated into neurorestoration. However, while being consistent with an immunoregulatory action, the effect of IVIg on the CD4+/CD8+ T-cell ratio was not associated with beneficial post-MPTP outcomes on various DAergic markers.
The lack of efficacy of IVIg may also reflect the poor CNS access owing to the presence of the blood–brain barrier. However, our data rather suggest that IVIg displayed significant central bioavailability after systemic administration. Indeed, a fraction of intraperitoneally administered IVIg was detected in the striatum of treated mice using a specific ELISA, consistent with a previous report where peripherally administered IVIg was also detected in APP/PS1 mouse brain using immunohistochemistry . A number of studies have reported data consistent with the penetration of a fraction of systemically administered antibodies into brain tissues leading to central therapeutic effect [38, 77, 78]. Interaction between Fc gamma receptor (FcγR) and immunoglobulins is essential for the initiation of cellular and humoral responses. In the CNS, FcγR are expressed on endothelial cells, neurons, microglia, oligodendrocytes and astrocytes (as reviewed in ) and the IVIg migration to critical regions of the brain, such as the striatum and SNpc in PD, might act as a central immunomodulating agent. A previous report showed that approximately 30% of pigmented SNpc neurons were IgG-positive  in PD patients but not in controls. This suggests that IgG can access the brain during the course of the disease. However, we found no increase in striatal IgG content in MPTP-treated animals. The amount of human IgG detected in the brain of treated mice suggests that low central bioavailability is unlikely to be the sole reason for the lack of efficacy of IVIg in restoring the DAergic pathways.
After systemic injection, MPTP produces a reproducible lesion of the nigrostriatal DAergic pathway by causing oxidative stress, mitochondrial damage and neuronal cell death, as in idiopathic PD. Validation of disease-modifying treatments before clinical trial initiation is therefore often performed in MPTP-treated rodent models [81, 82]. However, these models are not without important limitations . First, the MPTP model used here does not generate a massive degeneration (−30 to 40% of TH-positive cells), which is required for clinically detectable motor symptoms in humans (−50 to 60%) [84, 85]. This explains, at least in part, why motor symptoms in the MPTP mouse model are insufficiently reliable for systematic assessment [83, 86–89] and were not evaluated here after IVIg treatment. To investigate the symptomatic effects of IVIg, the use of the more expensive MPTP monkey model should be considered instead [83, 90]. Second, the acute mouse MPTP model does not replicate α-synucleinopathy or Lewy bodies, which are pathognomonic of PD [91–93]. The use of other models such as the chronic infusion MPTP models or transgenic mice overexpressing human α-syn might be helpful for these purposes [81, 93–95]. Third, the response of a mouse model to human IVIg may differ from humans. Indeed, the absence of positive outcome in our study might be the result of inadequate interactions between human IgG and mouse FcγR, a hypothesis only testable with the use of mouse IgG. However, given that over 2,500 mice would have been required to generate the ~5 g IgG used in this study, murine IgG is scarcely used in preclinical investigations. In a passive model of idiopathic thrombocytopenic purpura, human IVIg and purified mouse IgG shared the same kinetics to restore platelet counts, thus validating the use of human IVIg to study human therapy in mouse models . Since monomeric human IVIg is well tolerated in mice, mouse models of numerous diseases are now routinely used to investigate its efficacy as well as its mechanisms of action [35, 53, 97, 98].
The unexpected deleterious effect of IVIg on TH expression is an intriguing observation that is particularly challenging to explain. On the one hand, a plethora of compounds such as nicotine, cannabinoid agonists and progesterone receptor isoforms [99–101] have been shown to modulate TH expression without obvious harmful effects on the DAergic system. Similarly, our data suggest that IVIg regulates TH expression at the protein or RNA levels. On the other hand, the observed decrease in striatal TH protein levels associated with a trend toward decreased catecholamines, serotonin, nigral TH-positive and total neurons can also be interpreted as a deleterious effect of IVIg on the murine DAergic system. Although acute MPTP administration does not lead to α-syn-positive nigral inclusions [91–93], α-syn-deficient transgenic mouse models are more resistant to MPTP, suggesting a possible implication of α-syn in the MPTP toxicity [102–106]. Increased autoantibodies to α-syn are present in the sera of PD patients [107, 108], and stereotactic injection of human IgG purified from the sera of PD patients into mice SNpc produces a FcγR-dependent microglial activation and a 40% TH-positive cell loss in the SNpc . Since natural anti-α-syn antibodies in IVIg preparations have been recently identified , it is tempting to speculate that IVIg could have modulated the nigrostriatal toxicity of MPTP by binding to α-syn.
Despite the fact that current knowledge of IVIg mechanisms of action holds promising characteristics for the treatment of PD, our results do not provide evidence of a neurorestorative effect of IVIg treatment on the nigrostriatal system of the MPTP-treated mouse. Our data on the general health status, DAergic cell count, TH protein levels and HVA striatal concentrations all suggest that IVIg not only failed to generate beneficial effects, but had a slight detrimental impact on the DAergic system. Such possible harmful consequences flag the need to proceed with caution before initiating clinical trials in PD patients.
analysis of variance
bovine serum albumin
cluster of differentiation
central nervous system
enzyme-linked immunosorbent assay
Fc gamma receptor
high-performance liquid chromatography
3β-(4-125I-iodophenyl) tropane-2-carboxylic acid isopropylester
transforming growth factor-beta
tumor necrosis factor
regulatory T cell
substantia nigra pars compacta
This work was supported by the Canadian Institutes of Health Research (CIHR; grant ISO-102447) and the Héma-Québec foundation. IS-A was supported by an Industrial Innovation PhD scholarship from CRSNG/FQRNT/Héma-Quebec. MB and JD-O were supported by CIHR scholarships. FCa and FCi are supported by salary awards from the Fonds de la recherche en santé du Québec.
- Lofrumento DD, Saponaro C, Cianciulli A, De Nuccio F, Mitolo V, Nicolardi G, Panaro MA: MPTP-induced neuroinflammation increases the expression of pro-inflammatory cytokines and their receptors in mouse brain. Neuroimmunomodulation. 2011, 18: 79-88. 10.1159/000320027.PubMed
- Vroon A, Drukarch B, Bol JGJM, Cras P, Brevé JJP, Allan SM, Relton JK, Hoogland PVJM, Van Dam AM: Neuroinflammation in Parkinson’s patients and MPTP-treated mice is not restricted to the nigrostriatal system: microgliosis and differential expression of interleukin-1 receptors in the olfactory bulb. Exp Gerontol. 2007, 42: 762-771. 10.1016/j.exger.2007.04.010.PubMed
- Boka G, Anglade P, Wallach D, Javoy-Agid F, Agid Y, Hirsch EC: Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson’s disease. Neurosci Lett. 1994, 172: 151-154. 10.1016/0304-3940(94)90684-X.PubMed
- Mogi M, Harada M, Kondo T, Narabayashi H, Riederer P, Nagatsu T: Transforming growth factor-beta 1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson’s disease. Neurosci Lett. 1995, 193: 129-132. 10.1016/0304-3940(95)11686-Q.PubMed
- Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu T: Tumor necrosis factor-alpha (TNF-α) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett. 1994, 165: 208-210. 10.1016/0304-3940(94)90746-3.PubMed
- Mogi M, Kondo T, Mizuno Y, Nagatsu T: p53 protein, interferon-gamma, and NF-Kb levels are elevated in the parkinsonian brain. Neurosci Lett. 2007, 414: 94-97. 10.1016/j.neulet.2006.12.003.PubMed
- Scalzo P, Kummer A, Cardoso F, Teixeira AL: Serum levels of interleukin-6 are elevated in patients with Parkinson’s disease and correlate with physical performance. Neurosci Lett. 2010, 468: 56-58. 10.1016/j.neulet.2009.10.062.PubMed
- Scalzo P, Kummer A, Cardoso F, Teixeira AL: Increased serum levels of soluble tumor necrosis factor-alpha receptor-1 in patients with Parkinson’s disease. J Neuroimmunol. 2009, 216: 122-125. 10.1016/j.jneuroim.2009.08.001.PubMed
- Stypula G, Kunert-Radek J, Stepien H, Zylinska K, Pawlikowski M: Evaluation of interleukins, ACTH, cortisol and prolactin concentrations in the blood of patients with parkinson’s disease. Neuroimmunomodulation. 1996, 3: 131-134. 10.1159/000097237.PubMed
- Dobbs RJ, Charlett A, Purkiss AG, Dobbs SM, Weller C, Peterson DW: Association of circulating TNF-alpha and IL-6 with ageing and parkinsonism. Acta Neurol Scand. 1999, 100: 34-41. 10.1111/j.1600-0404.1999.tb00721.x.PubMed
- Varani K, Vincenzi F, Tosi A, Gessi S, Casetta I, Granieri G, Fazio P, Leung E, MacLennan S, Granieri E, Borea PA: A2A adenosine receptor overexpression and functionality, as well as TNF-alpha levels, correlate with motor symptoms in Parkinson’s disease. FASEB J. 2010, 24: 587-598. 10.1096/fj.09-141044.PubMed
- Nicoletti A, Fagone P, Donzuso G, Mangano K, Dibilio V, Caponnetto S, Bendtzen K, Zappia M, Nicoletti F: Parkinson’s disease is associated with increased serum levels of macrophage migration inhibitory factor. Cytokine. 2011, 55: 165-167. 10.1016/j.cyto.2011.03.027.PubMed
- Hofmann KW, Schuh AFS, Saute J, Townsend R, Fricke D, Leke R, Souza DO, Portela LV, Chaves MLF, Rieder CRM: Interleukin-6 serum levels in patients with Parkinson’s disease. Neurochem Res. 2009, 34: 1401-1404. 10.1007/s11064-009-9921-z.PubMed
- Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay J-M, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S: Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest. 2008, 119: 182-192.PubMed CentralPubMed
- Dodel R, Neff F, Noelker C, Pul R, Du Y, Bacher M, Oertel W: Intravenous immunoglobulins as a treatment for Alzheimer’s disease: rationale and current evidence. Drugs. 2010, 70: 513-528. 10.2165/11533070-000000000-00000.PubMed
- Stein MR, Nelson RP, Church JA, Wasserman RL, Borte M, Vermylen C, Bichler J: Safety and efficacy of Privigen, a novel 10% liquid immunoglobulin preparation for intravenous use, in patients with primary immunodeficiencies. J Clin Immunol. 2009, 29: 137-144. 10.1007/s10875-008-9231-2.PubMed
- Ballow M, Berger M, Bonilla FA, Buckley RH, Cunningham-Rundles CH, Fireman P, Kaliner M, Ochs HD, Skoda-Smith S, Sweetser MT, Taki H, Lathia C: Pharmacokinetics and tolerability of a new intravenous immunoglobulin preparation, IGIV-C, 10% (Gamunex, 10%). Vox Sang. 2003, 84: 202-210. 10.1046/j.1423-0410.2003.00286.x.PubMed
- Roifman CM, Schroeder H, Berger M, Sorensen R, Ballow M, Buckley RH, Gewurz A, Korenblat P, Sussman G, Lemm G: Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency. Int Immunopharmacol. 2003, 3: 1325-1333. 10.1016/S1567-5769(03)00134-6.PubMed
- Lebing W, Remington KM, Schreiner C, Paul HI: Properties of a new intravenous immunoglobulin (IGIV-C, 10%) produced by virus inactivation with caprylate and column chromatography. Vox Sang. 2003, 84: 193-201. 10.1046/j.1423-0410.2003.00285.x.PubMed
- Nimmerjahn F, Ravetch JV: Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol. 2008, 26: 513-533. 10.1146/annurev.immunol.26.021607.090232.PubMed
- Lehmann HC, Hartung HP: Plasma exchange and intravenous immunoglobulins: mechanism of action in immune-mediated neuropathies. J Neuroimmunol. 2011, 231: 61-69. 10.1016/j.jneuroim.2010.09.015.PubMed
- Tackenberg B, Nimmerjahn F, Lunemann JD: Mechanisms of IVIG efficacy in chronic inflammatory demyelinating polyneuropathy. J Clin Immunol. 2010, 30 (Suppl 1): S65-S69.PubMed
- Pigard N, Elovaara I, Kuusisto H, Paalavuo R, Dastidar P, Zimmermann K, Schwarz HP, Reipert B: Therapeutic activities of intravenous immunoglobulins in multiple sclerosis involve modulation of chemokine expression. J Neuroimmunol. 2009, 209: 114-120. 10.1016/j.jneuroim.2009.01.014.PubMed
- Kaveri SV, Maddur MS, Hegde P, Lacroix-Desmazes S, Bayry J: Intravenous immunoglobulins in immunodeficiencies: more than mere replacement therapy. Clin Exp Immunol. 2011, 164: 2-5.PubMed CentralPubMed
- Negi VS, Elluru S, Siberil S, Graff-Dubois S, Mouthon L, Kazatchkine MD, Lacroix-Desmazes S, Bayry J, Kaveri SV: Intravenous immunoglobulin: an update on the clinical use and mechanisms of action. J Clin Immunol. 2007, 27: 233-245. 10.1007/s10875-007-9088-9.PubMed
- Siberil S, Elluru S, Graff-Dubois S, Negi VS, Delignat S, Mouthon L, Lacroix-Desmazes S, Kazatchkine MD, Bayary J, Kaveri SV: Intravenous immunoglobulins in autoimmune and inflammatory diseases: a mechanistic perspective. Ann N Y Acad Sci. 2007, 1110: 497-506. 10.1196/annals.1423.052.PubMed
- Bayary J, Dasgupta S, Misra N, Ephrem A, Van H, Jean-Paul D, Delignat S, Hassan G, Caligiuri G, Nicoletti A, Lacroix-Desmazes S, Kazatchkine MD, Kaveri S: Intravenous immunoglobulin in autoimmune disorders: an insight into the immunoregulatory mechanisms. Int Immunopharmacol. 2006, 6: 528-534. 10.1016/j.intimp.2005.11.013.PubMed
- Vani J, Elluru S, Negi V-S, Lacroix-Desmazes S, Kazatchkine MD, Bayary J, Kaveri SV: Role of natural antibodies in immune homeostasis: IVIg perspective. Autoimmun Rev. 2008, 7: 440-444. 10.1016/j.autrev.2008.04.011.PubMed
- Creange A, Belec L, Clair B, Degos JD, Raphael JC, Gherardi RK: Circulating transforming growth factor beta 1 (TGF-β1) in Guillain–Barre syndrome: decreased concentrations in the early course and increase with motor function. J Neurol Neurosurg Psychiatry. 1998, 64: 162-165. 10.1136/jnnp.64.2.162.PubMed CentralPubMed
- Keskin DB, Stern JNH, Fridkis-Hareli M, Razzaque A: Cytokine profiles in pemphigus vulgaris patients treated with intravenous immunoglobulins as compared to conventional immunosuppressive therapy. Cytokine. 2008, 41: 315-321. 10.1016/j.cyto.2007.12.007.PubMed
- Stangel M, Compston A: Polyclonal immunoglobulins (IVIg) modulate nitric oxide production and microglial functions in vitro via Fc receptors. J Neuroimmunol. 2001, 112: 63-71. 10.1016/S0165-5728(00)00412-4.PubMed
- Issekutz AC, Rowter D, MacMillan HF: Intravenous immunoglobulin G (IVIG) inhibits IL-1- and TNF-alpha-dependent, but not chemotactic-factor-stimulated, neutrophil transendothelial migration. Clin Immunol. 2011, 141: 187-196. 10.1016/j.clim.2011.08.003.PubMed
- Lapointe BM: IVIg therapy in brain inflammation: etiology-dependent differential effects on leucocyte recruitment. Brain. 2004, 127: 2649-2656. 10.1093/brain/awh297.PubMed
- Reipert BM, Stellamor MT, Poell M, Ilas J, Sasgary M, Reipert S, Zimmermann K, Ehrlich H, Schwarz HP: Variation of anti-Fas antibodies in different lots of intravenous immunoglobulin. Vox Sang. 2008, 94: 334-341. 10.1111/j.1423-0410.2008.001036.x.PubMed
- Puli L, Pomeshchik Y, Olas K, Malm T, Koistinaho J, Tanila H: Effects of human intravenous immunoglobulin on amyloid pathology and neuroinflammation in a mouse model of Alzheimer’s disease. J Neuroinflammation. 2012, 9: 105-10.1186/1742-2094-9-105.PubMed CentralPubMed
- Vekrellis K, Xilouri M, Emmanouilidou E, Rideout HJ, Stefanis L: Pathological roles of alpha-synuclein in neurological disorders. Lancet Neurol. 2011, 10: 1015-1025. 10.1016/S1474-4422(11)70213-7.PubMed
- Yasuda T, Mochizuki H: The regulatory role of alpha-synuclein and parkin in neuronal cell apoptosis; possible implications for the pathogenesis of Parkinson’s disease. Apoptosis. 2010, 15: 1312-1321. 10.1007/s10495-010-0486-8.PubMed
- Masliah E, Rockenstein E, Mante M, Crews L, Spencer B, Adame A, Patrick C, Trejo M, Ubhi K, Rohn TT, Mueller-Steiner S, Seubert P, Barbour R, McConlogue L, Buttini M, Games D, Schenk D: Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of lewy body disease. PLoS One. 2011, 6: e19338-10.1371/journal.pone.0019338.PubMed CentralPubMed
- Masliah E, Rockenstein E, Adame A, Alford M, Crews L, Hashimoto M, Seubert P, Lee M, Goldstein J, Chilcote T, Games D, Schenk D: Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. Neuron. 2005, 46: 857-868. 10.1016/j.neuron.2005.05.010.PubMed
- Patrias LM, Klaver AC, Coffey MP, Loeffler DA: Specific antibodies to soluble alpha-synuclein conformations in intravenous immunoglobulin preparations. Clin Exp Immunol. 2010, 161: 527-535. 10.1111/j.1365-2249.2010.04214.x.PubMed CentralPubMed
- Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, Hirsch EC, Farrer M, Schapira AHV, Halliday G: Missing pieces in the Parkinson’s disease puzzle. Nat Med. 2010, 16: 653-661. 10.1038/nm.2165.PubMed
- Nomoto M: Clinical pharmacology and neuroprotection in Parkinson’s disease. Parkinsonism Relat Disord. 2003, 9: 55-58.
- Jackson-Lewis V, Przedborski S: Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc. 2007, 2: 141-151.PubMed
- Yokoyama H, Kuroiwa H, Kasahara J, Araki T: Neuropharmacological approach against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of Parkinson’s disease. Acta Neurobiol Exp. 2011, 71: 269-280.
- Calon F, Lavertu N, Lemieux AM, Morissette M, Goulet M, Grondin R, Blanchet PJ, Bédard PJ, Di Paolo T: Effect of MPTP-induced denervation on basal ganglia GABA(B) receptors: correlation with dopamine concentrations and dopamine transporter. Synapse. 2001, 40: 225-234. 10.1002/syn.1045.PubMed
- Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, Younkin S, Younkin L, Schiff R, Weksler ME: 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging. 2008, 30: 1728-1736.PubMed
- Tremblay C, Pilote M, Phivilay A, Emond V, Bennett DA, Calon F: Biochemical characterization of Abeta and tau pathologies in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis. 2007, 12: 377-390.PubMed
- Bousquet M, St-Amour I, Vandal M, Julien P, Cicchetti F, Calon F: High-fat diet exacerbates MPTP-induced dopaminergic degeneration in mice. Neurobiol Dis. 2012, 45: 529-538. 10.1016/j.nbd.2011.09.009.PubMed
- Bousquet M, Saint-Pierre M, Julien C, Salem N, Cicchetti F, Calon F: Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson’s disease. FASEB J. 2008, 22: 1213-1225.PubMed
- Drouin-Ouellet J, Gibrat C, Bousquet M, Calon F, Kriz J, Cicchetti F: The role of the MYD88-dependent pathway in MPTP-induced brain dopaminergic degeneration. J Neuroinflammation. 2011, 8: 137-10.1186/1742-2094-8-137.PubMed CentralPubMed
- Olivito B, Taddio A, Simonini G, Massai C, Ciullini S, Gambineri E, de Martino M, Azzari C, Cimaz R: Defective FOXP3 expression in patients with acute Kawasaki disease and restoration by intravenous immunoglobulin therapy. Clin Exp Rheumatol. 2010, 28: 93-97.PubMed
- Tsurikisawa N, Saito H, Oshikata C, Tsuburai T, Akiyama K: High-dose intravenous immunoglobulin treatment increases regulatory T cells in patients with eosinophilic granulomatosis with polyangiitis. J Rheumatol. 2012, 39: 1019-1025. 10.3899/jrheum.110981.PubMed
- Ephrem A, Chamat S, Miquel C, Fisson S, Mouthon L, Caligiuri G, Delignat S, Elluru S, Bayry J, Lacroix-Desmazes S, Cohen JL, Salomon BL, Kazatchkine MD, Kaveri SV, Misra N: Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood. 2008, 111: 715-722. 10.1182/blood-2007-03-079947.PubMed
- Ramakrishna C, Newo ANS, Shen Y-W, Cantin E: Passively administered pooled human immunoglobulins exert IL-10 dependent anti-inflammatory effects that protect against fatal HSV encephalitis. PLoS Pathog. 2011, 7: e1002071-10.1371/journal.ppat.1002071.PubMed CentralPubMed
- Sakaguchi S, Miyara M, Costantino CM, Hafler DA: FoxP3(+) regulatory T cells in the human immune system. Nat Rev Immunol. 2010, 10: 490-500. 10.1038/nri2785.PubMed
- Poojary KV, Kong Y-M, Farrar MA: Control of Th2-mediated inflammation by regulatory T cells. Am J Pathol. 2010, 177: 525-531. 10.2353/ajpath.2010.090936.PubMed CentralPubMed
- Reynolds AD, Stone DK, Hutter JAL, Benner EJ, Mosley RL, Gendelman HE: Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J Immunol. 2010, 184: 2261-2271. 10.4049/jimmunol.0901852.PubMed CentralPubMed
- Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL: Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. J Leukoc Biol. 2007, 82: 1083-1094. 10.1189/jlb.0507296.PubMed
- Chi Y, Fan Y, He L, Liu W, Wen X, Zhou S, Wang X, Zhang C, Kong H, Sonoda L, Tripathi P, Li CJ, Yu MS, Su C, Hu G: Novel role of aquaporin-4 in CD4+‚ CD25+ T regulatory cell development and severity of Parkinson’s disease. Aging Cell. 2011, 10: 368-382. 10.1111/j.1474-9726.2011.00677.x.PubMed
- Starke C, Frey S, Wellmann U, Urbonaviciute V, Herrmann M, Amann K, Schett G, Winkler T, Voll RE: High frequency of autoantibody-secreting cells and long-lived plasma cells within inflamed kidneys of NZB/W F1 lupus mice. Eur J Immunol. 2011, 41: 2107-2112. 10.1002/eji.201041315.PubMed
- Bontscho J, Schreiber A, Manz RA, Schneider W, Luft FC, Kettritz R: Myeloperoxidase-specific plasma cell depletion by Bortezomib protects from anti-neutrophil cytoplasmic autoantibodies-induced glomerulonephritis. J Am Soc Nephrol. 2011, 22: 336-348. 10.1681/ASN.2010010034.PubMed CentralPubMed
- Daubner SC, Le T, Wang S: Tyrosine hydroxylase and regulation of dopamine synthesis. Arch Biochem Biophys. 2011, 508: 1-12. 10.1016/j.abb.2010.12.017.PubMed CentralPubMed
- Jakowec MW, Nixon K, Hogg E, McNeill T, Petzinger GM: Tyrosine hydroxylase and dopamine transporter expression following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration of the mouse nigrostriatal pathway. J Neurosci Res. 2004, 76: 539-550. 10.1002/jnr.20114.PubMed
- Jackson-Lewis V, Jakowec M, Burke RE, Przedborski S: Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurodegeneration. 1995, 4: 257-269. 10.1016/1055-8330(95)90015-2.PubMed
- Bezard E, Dovero S, Bioulac B, Gross C: Effects of different schedules of MPTP administration on dopaminergic neurodegeneration in mice. Exp Neurol. 1997, 148: 288-292. 10.1006/exnr.1997.6648.PubMed
- Bezard E: A call for clinically driven experimental design in assessing neuroprotection in experimental Parkinsonism. Behav Pharmacol. 2006, 17: 379-382. 10.1097/00008877-200609000-00003.PubMed
- Rosenkranz D, Weyer S, Tolosa E, Gaenslen A, Berg D, Leyhe T, Gasser T, Stoltze L: Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration. J Neuroimmunol. 2007, 188: 117-127. 10.1016/j.jneuroim.2007.05.011.PubMed
- Aukrust P, Muller F, Nordoy I, Haug CJ, Froland SS: Modulation of lymphocyte and monocyte activity after intravenous immunoglobulin administration in vivo. Clin Exp Immunol. 1997, 107: 50-56. 10.1046/j.1365-2249.1997.d01-904.x.PubMed CentralPubMed
- Baba T, Ishizu A, Iwasaki S, Suzuki A, Tomaru U, Ikeda H, Yoshiki T, Kasahara M: CD4+/CD8+ macrophages infiltrating at inflammatory sites: a population of monocytes/macrophages with a cytotoxic phenotype. Blood. 2006, 107: 2004-2012. 10.1182/blood-2005-06-2345.PubMed
- Bas J, Calopa M, Mestre M, MD G, Cutillas B, Ambrosio S, Buendia E: Lymphocyte populations in Parkinson’s disease and in rat models of parkinsonism. J Neuroimmunol. 2001, 113: 146-152. 10.1016/S0165-5728(00)00422-7.PubMed
- Hisanaga K, Asagi M, Itoyama Y, Iwasaki Y: Increase in peripheral CD4 bright + CD8 dull + T cells in Parkinson disease. Arch Neurol. 2001, 58: 1580-1583. 10.1001/archneur.58.10.1580.PubMed
- Calopa M, Bas J, Callen A, Mestre M: Apoptosis of peripheral blood lymphocytes in Parkinson patients. Neurobiol Dis. 2010, 38: 1-7. 10.1016/j.nbd.2009.12.017.PubMed
- Janke AD, Giuliani F, Yong VW: IVIg attenuates T cell-mediated killing of human neurons. J Neuroimmunol. 2006, 177: 181-188. 10.1016/j.jneuroim.2006.04.023.PubMed
- Ito K, Hara H, Okada T, Shimojima H, Suzuki H: Toxic epidermal necrolysis treated with low-dose intravenous immunoglobulin: immunohistochemical study of Fas and Fas-ligand expression. Clin Exp Dermatol. 2004, 29: 679-680. 10.1111/j.1365-2230.2004.01635.x.PubMed
- Artac H, Kara R, Reisli I: In vivo modulation of the expressions of Fas and CD25 by intravenous immunoglobulin in common variable immunodeficiency. Clin Exp Med. 2009, 10: 27-31.
- Magga J, Puli L, Pihlaja R, Kanninen K, Neulamaa S, Malm T, Hartig W, Grosche J, Goldsteins G, Tanila H, Koistinaho J, Koistinaho M: Human intravenous immunoglobulin provides protection against Abeta toxicity by multiple mechanisms in a mouse model of Alzheimer’s disease. J Neuroinflammation. 2010, 7: 90-10.1186/1742-2094-7-90.PubMed CentralPubMed
- Kitazawa M, Cheng D, Tsukamoto MR, Koike MA, Wes PD, Vasilevko V, Cribbs DH, LaFerla FM: Blocking IL-1 signaling rescues cognition, attenuates Tau pathology, and restores neuronal beta-catenin pathway function in an Alzheimer’s disease model. J Immunol. 2011, 187: 6549.
- Tan J, Town T, Crawford F, Mori T, Delledonne A, Crescentini R, Obregon D, Flavell RA, Mullan MJ: Role of CD40 ligand in amyloidosis in transgenic Alzheimer’s mice. Nat Neurosci. 2002, 5: 1288-1293. 10.1038/nn968.PubMed
- Okun E, Mattson M, Arumugam T: Involvement of Fc receptors in disorders of the central nervous system. Neuromol Med. 2010, 12: 164-178. 10.1007/s12017-009-8099-5.
- Orr CF: A possible role for humoral immunity in the pathogenesis of Parkinson’s disease. Brain. 2005, 128: 2665-2674. 10.1093/brain/awh625.PubMed
- Bezard E, Przedborski S: A tale on animal models of Parkinson’s disease. Mov Disord. 2011, 26: 993-1002. 10.1002/mds.23696.PubMed
- Duty S, Jenner P: Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br J Pharmacol. 2011, 164: 1357-1391. 10.1111/j.1476-5381.2011.01426.x.PubMed CentralPubMed
- Meissner W, Hill MP, Tison F, Gross CE, Bezard E: Neuroprotective strategies for Parkinson’s disease: conceptual limits of animal models and clinical trials. Trends Pharmacol Sci. 2004, 25: 249-253. 10.1016/j.tips.2004.03.003.PubMed
- Riederer P, Wuketich S: Time course of nigrostriatal degeneration in parkinson’s disease. A detailed study of influential factors in human brain amine analysis. J Neural Transm. 1976, 38: 277-301. 10.1007/BF01249445.PubMed
- Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F: Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci. 1973, 20: 415-455. 10.1016/0022-510X(73)90175-5.PubMed
- Meredith GE, Kang UJ: Behavioral models of Parkinson’s disease in rodents: a new look at an old problem. Mov Disord. 2006, 21: 1595-1606. 10.1002/mds.21010.PubMed
- Chagniel L, Robitaille C, Lacharité-Mueller C, Bureau G, Cyr M: Partial dopamine depletion in MPTP-treated mice differentially altered motor skill learning and action control. Behav Brain Res. 2012, 228: 9-15. 10.1016/j.bbr.2011.11.019.PubMed
- Hutter-Saunders JAL, Gendelman HE, Mosley RL: Murine motor and behavior functional evaluations for acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. J Neuroimmune Pharmacol. 2011, 7: 279-288.PubMed CentralPubMed
- Rousselet E, Joubert C, Callebert J, Parain K, Tremblay L, Orieux G, Launay J-M, Cohen-Salmon C, Hirsch EC: Behavioral changes are not directly related to striatal monoamine levels, number of nigral neurons, or dose of parkinsonian toxin MPTP in mice. Neurobiol Dis. 2003, 14: 218-228. 10.1016/S0969-9961(03)00108-6.PubMed
- Jenner P: The contribution of the MPTP-treated primate model to the development of new treatment strategies for Parkinson’s disease. Parkinsonism Relat Disord. 2003, 9: 131-137. 10.1016/S1353-8020(02)00115-3.PubMed
- Shimoji M, Zhang L, Mandir A, Dawson V, Dawson T: Absence of inclusion body formation in the MPTP mouse model of Parkinson’s disease. Mol Brain Res. 2005, 134: 103-108. 10.1016/j.molbrainres.2005.01.012.PubMed
- Vila M, Vukosavic S, Jackson-Lewis V, Neystat M, Jakowec M, Przedborski S: Alpha-synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin MPTP. J Neurochem. 2000, 74: 721-729.PubMed
- Gibrat C, Saint-Pierre M, Bousquet M, Lévesque D, Rouillard C, Cicchetti F: Differences between subacute and chronic MPTP mice models: investigation of dopaminergic neuronal degeneration and alpha-synuclein inclusions. J Neurochem. 2009, 109: 1469-1482. 10.1111/j.1471-4159.2009.06072.x.PubMed
- Fornai F, Schlüer OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, Lazzeri G, Busceti CL, Pontarelli F, Battaglia G, Pellegrini A, Nicoletti F, Ruggieri S, Paparelli A, Südhof TC: Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci USA. 2005, 102: 3413-3418. 10.1073/pnas.0409713102.PubMed CentralPubMed
- Blesa J, Phani S, Jackson-Lewis V, Przedborski S: Classic and new animal models of Parkinson’s disease. J Biomed Biotechnol. 2012, 2012: 10-Article ID 845618, doi:10.1155/2012/845618
- Katsman Y, Foo AH, Leontyev D, Branch DR: Improved mouse models for the study of treatment modalities for immune-mediated platelet destruction. Transfusion. 2010, 50: 1285-1294. 10.1111/j.1537-2995.2009.02558.x.PubMed
- Aubin E, Lemieux R, Bazin R: Indirect inhibition of in vivo and in vitro T-cell responses by intravenous immunoglobulins due to impaired antigen presentation. Blood. 2010, 115: 1727-1734. 10.1182/blood-2009-06-225417.PubMed
- Racz Z, Nagy E, Rosivall L, Szebeni J, Hamar P: Sugar-free, glycine-stabilized intravenous immunoglobulin prevents skin but not renal disease in the MRL/lpr mouse model of systemic lupus. Lupus. 2010, 19: 599-612. 10.1177/0961203309355299.PubMed
- Gonzalez-Flores O, Gomora-Arrati P, Garcia-Juarez M, Miranda-Martinez A, Armengual-Villegas A, Camacho-Arroyo I, Guerra-Araiza C: Progesterone receptor isoforms differentially regulate the expression of tryptophan and tyrosine hydroxylase and glutamic acid decarboxylase in the rat hypothalamus. Neurochem Int. 2011, 59: 671-676. 10.1016/j.neuint.2011.06.013.PubMed
- Bosier B, Muccioli GG, Mertens B, Sarre S, Michotte Y, Lambert DM, Hermans E: Differential modulations of striatal tyrosine hydroxylase and dopamine metabolism by cannabinoid agonists as evidence for functional selectivity in vivo. Neuropharmacology. 2012, 62: 2327-2335.
- Ferrari MFR, Coelho EF, Farizatto KLG, Chadi G, Fior-Chadi DR: Modulation of tyrosine hydroxylase, neuropeptide Y, glutamate, and substance P in ganglia and brain areas involved in cardiovascular control after chronic exposure to nicotine. Int J Hypertens. 2011, 2011: 1-9.
- Dauer W, Kholodilov N, Vila M, Trillat A-C, Goodchild R, Larsen KE, Staal R, Tieu K, Schmitz Y, Yuan CA, Rocha M, Jackson-Lewis V, Hersch S, Sulzer D, Przedborski S, Burke R, Hen R: Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci USA. 2002, 99: 14524-14529. 10.1073/pnas.172514599.PubMed CentralPubMed
- Schluter OM, Fornai F, Alessandri MG, Takamori S, Geppert M, Jahn R, Sudhof TC: Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice. Neuroscience. 2003, 118: 985-1002. 10.1016/S0306-4522(03)00036-8.PubMed
- Drolet RE, Behrouz B, Lookingland KJ, Goudreau JL: Mice lacking alpha-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration. Neurotoxicology. 2004, 25: 761-769. 10.1016/j.neuro.2004.05.002.PubMed
- Robertson DC, Schmidt O, Ninkina N, Jones PA, Sharkey J, Buchman VL: Developmental loss and resistance to MPTP toxicity of dopaminergic neurones in substantia nigra pars compacta of gamma-synuclein, alpha-synuclein and double alpha/gamma-synuclein null mutant mice. Neurochem. 2004, 89: 1126-1136. 10.1111/j.1471-4159.2004.02378.x.
- Klivenyi P, Siwek D, Gardian G, Yang L, Starkov A, Cleren C, Ferrante RJ, Kowall NW, Abeliovich A, Beal MF: Mice lacking alpha-synuclein are resistant to mitochondrial toxins. Neurobiol Dis. 2006, 21: 541-548. 10.1016/j.nbd.2005.08.018.PubMed
- Papachroni KK, Ninkina N, Papapanagiotou A, Hadjigeorgiou GM, Xiromerisiou G, Papadimitriou A, Kalofoutis A, Buchman VL: Autoantibodies to alpha-synuclein in inherited Parkinson’s disease. J Neurochem. 2006, 101: 749-756. 10.1111/j.1471-4159.2006.04365.x.
- Yanamandra K, Gruden MA, Casaite V, Meskys R, Forsgren L, Morozova-Roche LA: Alpha-synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson’s disease patients. PLoS One. 2011, 6: e18513-10.1371/journal.pone.0018513.PubMed CentralPubMed
- He Y, Le W-D, Appel SH: Role of Fcγ receptors in nigral cell injury induced by Parkinson disease immunoglobulin injection into mouse substantia nigra. Exp Neurol. 2002, 176: 322-327. 10.1006/exnr.2002.7946.PubMed
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