Xi-Jin Wang

CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson's disease

BackgroundIncreasing evidence suggests that microglial activation may participate in the aetiology and pathogenesis of Parkinsons disease (PD). CD200-CD200R signalling has been shown to be critical for restraining microglial activation. We have previously shown that expression of CD200R in monocyte-derived macrophages, induced by various stimuli, is impaired in PD patients, implying an intrinsic abnormality of CD200-CD200R signalling in PD brain. Thus, further in vivo evidence is needed to elucidate the role of malfunction of CD200-CD200R signalling in the pathogenesis of PD.Methods6-hydroxydopamine (6-OHDA)-lesioned rats were used as an animal model of PD. CD200R-blocking antibody (BAb) was injected into striatum to block the engagement of CD200 and CD200R. The animals were divided into three groups, which were treated with 6-OHDA/Veh (PBS), 6-OHDA/CAb (isotype control antibody) or 6-OHDA/BAb, respectively. Rotational tests and immunohistochemistry were employed to evaluate motor deficits and dopaminergic neurodegeneration in animals from each group. HPLC analysis was used to measure monoamine levels in striatum. Morphological analysis and quantification of CD11b- (or MHC II-) immunoreactive cells were performed to investigate microglial activation and possible neuroinflammation in the substantia nigra (SN). Finally, ELISA was employed to assay protein levels of proinflammatory cytokines.ResultsCompared with 6-OHDA/CAb or 6-OHDA/Veh groups, rats treated with 6-OHDA/BAb showed a significant increase in counts of contralateral rotation and a significant decrease in TH-immunoreactive (TH-ir) neurons in SN. A marked decrease in monoamine levels was also detected in 6-OHDA/BAb-treated rats, in comparison to 6-OHDA/Veh-treated ones. Furthermore, remarkably increased activation of microglia as well as up-regulation of proinflammatory cytokines was found concomitant with dopaminergic neurodegeneration in 6-OHDA/BAb-treated rats.ConclusionsThis study shows that deficits in the CD200-CD200R system exacerbate microglial activation and dopaminergic neurodegeneration in a 6-OHDA-induced rat model of PD. Our results suggest that dysfunction of CD200-CD200R signalling may be involved in the aetiopathogenesis of PD.

Genistein protects dopaminergic neurons by inhibiting microglial activation

Inflammation participates in the pathogenesis and progression of Parkinsons disease, in which microglia play a key role. Inhibition of microglia activation has been shown to attenuate inflammation-mediated dopaminergic neurodegeneration. In this study, we found that genistein, the primary soybean isoflavone, concentration-dependently attenuated the lipopolysaccharide-induced decrease in dopamine uptake and loss of tyrosine hydroxylase-immunoreactive neurons in rat mesencephalic neuron-glia cultures. Genistein also inhibited lipopolysaccharide-induced microglia activation and production of tumor necrosis factor-&agr;, nitric oxide and superoxide in mesencephalic neuron-glia cultures and microglia-enriched cultures. Our results indicate that genistein may protect dopaminergic neurons from lipopolysaccharide-induced injury and its effective inhibition of microglia activation may be one of the mechanisms.

Luteolin protects dopaminergic neurons from inflammation-induced injury through inhibition of microglial activation.

Parkinsons disease is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra. Accumulating evidence has suggested that inflammation in the brain participates in the pathogenesis of Parkinsons disease. Luteolin, a polyphenolic compound found in foods of plant origin, belongs to the flavone subclass of flavonoids, and has been shown to possess antimutagenic, antitumorigenic, antioxidant and antiinflammatory properties. In this study, we found that luteolin concentration-dependently attenuated the lipopolysaccharide (LPS)-induced decrease in [(3)H]dopamine uptake and loss of tyrosine hydroxylase-immunoreactive neurons in primary mesencephalic neuron-glia cultures. Moreover, luteolin also significantly inhibited LPS-induced activation of microglia and excessive production of tumor necrosis factor-alpha, nitric oxide and superoxide in mesencephalic neuron-glia cultures and microglia-enriched cultures. Our results demonstrate that luteolin may protect dopaminergic neurons from LPS-induced injury and its efficiency in inhibiting microglia activation may underlie the mechanism.

Impaired CD200-CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: roles of aging, superoxide, NADPH oxidase, and p38 MAPK.

CD200-CD200R signaling holds microglia in a quiescent state. Parkinson disease (PD) neurodegeneration may be associated with impairment of CD200-CD200R-mediated microglia silencing in the substantia nigra (SN). In this study, an anti-CD200R blocking antibody (ACDR) selectively and significantly enhanced the susceptibility of dopaminergic neurons to neurotoxicity induced by rotenone (Rot) and iron (Ir) in mesencephalic neuron/glia cultures. Microglia were shown to mediate dopaminergic neurotoxicity induced by ACDR/Rot (combination of ACDR and Rot) and ACDR/Ir (combination of ACDR and Ir). ACDR significantly enhanced the microglial activation induced by Rot and Ir in neuron/glia cultures. NADPH oxidase-mediated superoxide generation was a key contributor to dopaminergic neurotoxicity induced by ACDR/Rot and ACDR/Ir. p38 MAPK contributed to NADPH oxidase activation induced by ACDR/Rot and ACDR/Ir. Interestingly, there were a decrease in CD200 expression (mRNA and protein) and an enhancement of microglial response (MHCII mRNA and ICAM-1 protein) in the rat SN with aging. ICAM-1 expression was significantly inversely correlated with CD200 expression. These results strongly indicate the participation of SN CD200-CD200R dysfunction in the etiopathogenesis of PD and provide a new insight into the molecular mechanisms underlying the involvement of aging in PD and help to elucidate the mechanisms of the combined involvement of immune/inflammatory factors, environmental substances, and aging in PD.

Validation of the Chinese non-motor symptoms scale for Parkinson's disease: results from a Chinese pilot study.

OBJECTIVES To evaluate a Chinese version of the Non-Motor Symptoms Scale (NMSS) in Parkinsons disease (PD) as an instrument for measuring non-motor symptoms (NMSs) in Chinese patients with Parkinsons disease. METHODS We conducted a psychometric analysis of the Chinese version of NMSS using a cross-sectional study of 126 patients with PD. The battery also included the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Mini-Mental State Examination (MMSE), the Geriatric Depression Scale (GDS), and the Hamilton Anxiety Scale (HAMA), and was conducted by neurologists. RESULTS There were significant correlations between the NMSS and PSQI scores (rS=0.63, P<0.001), as well as the NMSS and ESS scores (rS=0.38, P<0.001). Furthermore, significant positive correlations between NMSS and GDS, NMSS and HAMA, and NMSS and disease duration were also observed. Importantly, the sleep/fatigue index of the NMSS significantly correlated with the PSQI and ESS findings, the mood/cognition index of the NMSS significantly correlated with the GDS and HAMA findings, and the attention/memory index of the NMSS significantly correlated with the MMSE findings. CONCLUSION The Chinese version of the NMSS can be considered a comprehensive, useful measure for NMS evaluation in Chinese PD patients.

CD200–CD200R Regulation of Microglia Activation in the Pathogenesis of Parkinson’s Disease

The role of CD200–CD200R signaling in immune regulation of the central nervous system has become a popular field of research in recent years. Many studies have shown that there is a close correlation between CD200–CD200R, microglia activation, and Parkinson’s disease (PD). This review discusses the above relationship, highlighting (1) the gene mapping and molecular structure of CD200 and CD200R, (2) the distribution and expression of CD200 and CD200R in the nervous system, (3) the effect of CD200–CD200R signaling on microglia activation, and (4) the role of microglia activation in the pathogenesis and progression of PD. Finally, we discuss the status of current studies on the regulation of microglia activation in PD and strongly suggest that it is very promising to regulate microglia activation in PD via targeting CD200–CD200R signaling pathways.

Glial cell line-derived neurotrophic factor in bone marrow stromal cells of rat

To investigate the capability of Sprague–Dawley rat bone marrow stromal cells to secrete glial cell line-derived neurotrophic factors (GDNF), we detected expression of GDNF messenger RNA and protein in bone marrow stromal cells of Sprague–Dawley rats by reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA), respectively. The GDNF messenger RNA and protein were detected in culture medium and total cell protein when bone marrow stromal cells were cultured for 3 days. The levels of GDNF in culture medium and total cell protein increased gradually after 3, 7 and 10 days of culture. Rat bone marrow stromal cells have the potential to secrete GDNF. Furthermore, the ability of secretion is determined by the surrounding microenvironment and self-growth status.

Transplantation of bone marrow stromal cells containing the neurturin gene in rat model of Parkinson's disease.

The experiment was to evaluate the therapeutic benefit of transplanted bone marrow stromal cells (BMSCs) transfected with a kind of neurotrophic factor gene, neurturin (NTN) gene, in treating the rat model of Parkinsons disease (PD). The 6-OHDA-lesioned rats were assigned to one of three groups, those receiving BMSCs transfected with NTN gene, those receiving untransfected BMSCs containing a void plasmid and those receiving phosphate buffer solution (PBS). Treatments were injected into the right striatum (6-OHDA-lesioned side). One to six months post-transplantation, apomorphine-induced rotational behavior was observed. One month after transplantation, green fluorescent protein (GFP)/NTN, GFP/glial fibrillary acidic protein (GFAP), GFP/neuron specific enolase (NSE) and GFP/tyrosine hydroxylase (TH) fluorescence determinations of brain sections were carried out. One to six months after transplantation, brain sections containing striatum and substantia nigra were stained for TH. In situ hybridization and Western blots were used to determine NTN mRNA and protein concentration, respectively, in affected brain regions. High performance liquid chromatography (HPLC) was used to measure the dopamine (DA) content in the lesioned striatum 1 and 3 month(s) post-transplantation. The results were shown that: in the first 3 months after transplantation, the number of rotations was lower in NTN-transplant group than the void vector group, and during 1-6 months post-transplantation, the number of rotations was lower in both transplant groups than that in the PBS group (P<0.05). One month after transplantation, we detected GFP/NTN-, GFP/GFAP- and GFP/NSE-labeled cells in the transplantation area of the NTN-transplanted group, but no obvious GFP/TH labeled cells were found. Quantitative analysis of TH-positive cells 1 to 6 months after transplantation indicated that there were no significant differences between groups in survival rates of TH-positive neurons in the lesioned substantia nigra (P>0.05). In situ hybridization and Western blot identified NTN mRNA and protein expression in the transplantation area of the NTN-transplanted group. After transplantation of NTN-expressing cells, DA content in the lesioned striatum was significantly higher in the transgenic group than that in the void vector group or the PBS group (P<0.05). The overall therapeutic effects of the NTN-transplanted group were superior to those of the void plasmid group and the PBS group. The mechanisms by which transgenic therapy treats PD might involve functional enhancement of residual dopaminergic neurons by NTN, which significantly reduces the number of rotations in animals, but not increase the numbers of existing dopaminergic neurons.

Neuroprotective effects of PACAP27 in mice model of Parkinson’s disease involved in the modulation of KATP subunits and D2 receptors in the striatum

Pituitary adenylate cyclase activating polypeptide (PACAP) exhibits a protective effect against neural injury in vitro and in vivo. However, it has not been reported whether peripheral intravenous administration of PACAP could confer benefits in animal models of Parkinsons disease (PD). Furthermore, the underlying molecular mechanisms responsible for these effects are poorly understood. In the present experiments, we determined the effects and mechanism of action of intravenously administered PACAP27 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Our results indicate that intravenous injection of PACAP27 offers neuroprotective effects in the MPTP-induced PD mouse model which may not be directly associated with the expression levels of the monoamine transporters. However, this effect may be correlated with its ability to selectively regulate not only K(ATP) subunits, but D2 receptors in the striatum. Our findings suggest that the benefit of PACAP may accompany with changes not only in dopaminergic neurotransmission, but also in cholinergic neurotransmission that are relatively associated with the K(ATP) subunits and D2 receptors in the striatum.

Four novel mutations in the GCH1 gene of Chinese patients with dopa-responsive dystonia

Mutation detection in the guanosine triphosphate cyclohydrolase I gene (GCH1) was performed from 4 female patients with dopa‐responsive dystonia (DRD). DNA sequencing revealed the presence of four novel mutations including c.2T>C(M1T), c.239G>A(S80N), c.245T>C(L82P), and IVS5+3 del AAGT. These four mutations were not found in 100 genetically unrelated healthy controls with the same ethnic background band. In all 3 childhood‐onset patients, DRD started in the legs, and missense mutations were located in the coding region of GCH1. Deletion mutation in the fifth exon–intron boundary of GCH1 was detected in the adult‐onset patient. Although the data presented here do not provide sufficient evidence to establish a genotype–phenotype correlation of DRD, it is important to know the clinic features and genetic defects of DRD patients, which will help prenatal diagnosis, early diagnosis, evaluate the prognosis, and facilitate causal therapy with levodopa.