-
Nian Xiong,
Jing Xiong,
Min Jia,
Ling Liu,
Xiaowei Zhang,
Zhenzhen Chen, Jinsha Huang,
Zhentao Zhang,
Lingling Hou,
Devina Ghoorah,
Zhicheng Lin,
Tao Wang
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Autophagy-mediated self-digestion of cytoplasmic inclusions may be protective against neurodegenerative diseases such as Parkinson's disease (PD). However, excessive autophagic activation evokes autophagic programmed cell death. METHODS: In this study, we aimed at exploring the role of autophagy in the pathogenesis of rotenone-induced cellular and animal models for PD. RESULTS: Reactive oxygen species over-generation, mitochondrial membrane potential reduction or apoptosis rate elevation occurred in a dose-dependent fashion in rotenone-treated human neuroblastoma cell line SH-SY5Y. The time- and dose-dependent increases in autophagic marker microtubule-associated protein1 light chain 3 (LC3) expression and decreases in autophagic adaptor protein P62 were observed in this cellular model. LC3-positive autophagic vacuoles were colocalized with alpha-synuclein-overexpressed aggregations. Moreover, the number of autophagic vacuoles was increased in rotenone-based PD models in vitro and in vivo. CONCLUSIONS: These data, along with our previous finding showing rotenone-induced toxicity was prevented by the autophagy enhancers and was aggravated by the autophagy inhibitors in SH-SY5Y, suggest that autophagy contributes to the pathogenesis of PD, attenuates the rotenone toxicity and possibly represents a new subcellular target for treating PD.
Behavioral and Brain Functions 03/2013; 9(1):13. · 2.13 Impact Factor
-
Youpei Wang,
Ling Liu,
Jing Xiong,
Xiaowei Zhang,
Zhenzhen Chen,
Lan Yu,
Chunnuan Chen, Jinsha Huang,
Zhentao Zhang,
Asrah A Mohmed,
Zhicheng Lin,
Nian Xiong,
Tao Wang
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Mutations of the glucocerebrosidase (GBA) gene have reportedly been associated with Parkinson disease (PD) in various ethnic populations such as Singaporean, Japanese, Formosan, Canadian, American, Portuguese, Greek, Brazilian, British, Italian, Ashkenazi Jewish, southern and southwestern Chinese. The purpose of this study is to determine in central China whether or not the reported GBA mutations remain associated with PD. METHODS: In this project, we conducted a controlled study in a cohort of 208 central Chinese PD patients and 298 controls for three known GBA mutations (L444P, N370S and R120W). RESULTS: Our data reveals a significantly higher frequency of L444P mutation in GBA gene of PD cases (3.4 %) compared with the controls (0.3 %) (P = 0.007, OR = 10.34, 95% CI = 1.26 - 84.71). Specifically, the frequency of L444P mutation was higher in the late onset PD (LOPD) cases compared with that in control subjects. The N370S and R120W mutations were detected in neither the PD group nor the control subjects. CONCLUSIONS: Our observations demonstrated that the GBA L444P mutation confers genetic risk for PD, especially LOPD, among the population in the central China area.
Behavioral and Brain Functions 12/2012; 8(1):57. · 2.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cerebral venous sinus thrombosis (CVST) is a relatively rare cerebrovascular condition which accounts for 0.5% of all strokes. Risk of CVST has been documented in patients with numerous conditions including central nervous system infections, however, Japanese encephalitis (JE, epidemic encephalitis type B) with CVST has not been reported previously.
Here, we present a case of JE with CVST in a 17-year-old man. On admission, the patient was initially diagnosed as intracranial infection, and soon after, brain magnetic resonance (MR) imaging (MRI) and MR Venography (MRV) confirmed the diagnosis of CVST. Moreover, the blood JE-specific IgM antibody which proved weakly positive at first, turned positive one week later. Consequently, our patient was diagnosed as CVST accompanied by JE. Anticoagulant and anti-infective therapy were initiated, which eventually lead to gradual recovery of the patient.
To our knowledge, this is the first case report of CVST associated with JE. MRI and MRV represent a prime method for the diagnosis of CVST, while the positivity of JE virus IgM antibody, especially increased antibody levels within a short period, is of great significance to diagnose JE. The early diagnosis and timely treatment of this potentially lethal condition would improve its prognosis significantly.
BMC Neurology 06/2012; 12:43. · 2.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The etiology of Parkinson's disease (PD) is attributed to both environmental and genetic factors. The development of PD reportedly involves mitochondrial impairment, oxidative stress, α-synuclein aggregation, dysfunctional protein degradation, glutamate toxicity, calcium overloading, inflammation and loss of neurotrophic factors. Based on a link between mitochondrial dysfunction and pesticide exposure, many laboratories, including ours, have recently developed parkinsonian models by utilization of rotenone, a well-known mitochondrial complex I inhibitor. Rotenone models for PD appear to mimic most clinical features of idiopathic PD and recapitulate the slow and progressive loss of dopaminergic (DA) neurons and the Lewy body formation in the nigral-striatal system. Notably, potential human parkinsonian pathogenetic and pathophysiological mechanisms have been revealed through these models. In this review, we summarized various rotenone-based models for PD and discussed the implied etiology of and treatment for PD.
Critical Reviews in Toxicology 05/2012; 42(7):613-32. · 5.16 Impact Factor
-
Nian Xiong, Jinsha Huang,
Chunnuan Chen,
Ying Zhao,
Zhaowen Zhang,
Min Jia,
Zhentao Zhang,
Lingling Hou,
Hecheng Yang,
Xuebing Cao,
Zhihou Liang,
Yongxue Zhang,
Shenggang Sun,
Zhicheng Lin,
Tao Wang
[show abstract]
[hide abstract]
ABSTRACT: In the absence of a cure for Parkinson's disease, development of preventive medications for this devastating disease is particularly encouraged. Dl-3-n-butylphthalide (NBP), an established natural antioxidant for clinical stroke treatment in China, can reportedly reduce beta-amyloid-induced neuronal toxicity in cultured neuronal cells, and attenuate neurodegenerative changes in aged rats. However, whether or not NBP confers neuroprotection in parkinsonian models is still unknown. In this study, we investigated the effects of NBP in rotenone models for Parkinson's diseases. In a cellular model, pretreatment with NBP enhanced cell viability by decreasing nuclear fragmentation, retaining mitochondrial membrane potential, and preventing reactive oxygen species (ROS) from generation. In a rodent model, 2-week treatment with NBP was able to ameliorate apomorphine-evoked rotations by 48% and rescue dopaminergic (DA) neurons by 30% and striatal DA terminal by 49%. Furthermore, NBP upregulated the vesicular monoamine transporter 2 gene expression in vitro and in vivo. Together, NBP protects DA neurons likely by reducing oxidative stress, offering an alternative neuroprotective medication for Parkinson's disease.
Neurobiology of aging 04/2011; 33(8):1777-91. · 5.94 Impact Factor
-
Nian Xiong,
Jing Xiong,
Ghanshyam Khare,
Chunnuan Chen, Jinsha Huang,
Ying Zhao,
Zhentao Zhang,
Xian Qiao,
Yuan Feng,
Harrish Reesaul,
Yongxue Zhang,
Shenggang Sun,
Zhicheng Lin,
Tao Wang
[show abstract]
[hide abstract]
ABSTRACT: 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), an effective free radical scavenger, provides neuroprotection in stroke models and patients. In this study, we investigated its neuroprotective effects in a chronic rotenone rat model for Parkinson's disease. Here we showed that a five-week treatment with edaravone abolished rotenone's activity to induce catalepsy, damage mitochondria and degenerate dopamine neurons in the midbrain of rotenone-treated rats. This abolishment was attributable at least partly to edaravone's inhibition of rotenone-induced reactive oxygen species production or apoptotic promoter Bax expression and its up-regulation of the vesicular monoamine transporter 2 (VMAT2) expression. Collectively, edaravone may provide novel clinical therapeutics for PD.
PLoS ONE 01/2011; 6(6):e20677. · 4.09 Impact Factor
-
Nian Xiong,
Xuebing Cao,
Zhentao Zhang, Jinsha Huang,
Chunnuan Chen,
Zhaowen Zhang,
Min Jia,
Jing Xiong,
Zhihou Liang,
Shenggang Sun,
Zhicheng Lin,
Tao Wang
[show abstract]
[hide abstract]
ABSTRACT: Several studies have shown functional improvements, neuroprotective, and neuroregenerative effects after mesenchymal stem cells transplantation to parkinsonian animal models. However, questions remain about the safety, feasibility, and long-term efficacy of this approach. In this study, we investigated migration, therapeutic, tumorigenesis, and epileptogenic effects of human umbilical cord mesenchymal stromal cells (HUMSCs) 1 year after transplantation into rotenone-induced hemiparkinsonian rats. Our data indicated that DiI-labeled HUMSCs migrated in the lesioned hemisphere, from corpus striatum (CPu) to substantia nigra. By integrating with host cells and differentiating into NSE, GFAP, Nestin, and tyrosine hydroxylase-positive cells, HUMSCs prevented 48.4% dopamine neurons from degeneration and 56.9% dopamine terminals from loss, both correlating with improvement of apomorphine-induced rotations. The CD50 and CD97 value of pentylenetetrazol and semiquantitative immunohistochemical analysis of proliferating cell nuclear antigen (PCNA), β-catenin, C-myc, and NF-κB expression showed no significant difference between HUMSCs transplanted and untransplanted groups, whereas the expressions of Bcl-2 and P53 in the grafted CPu were upregulated by 281% and 200% compared to ungrafted CPu. The results of this long-term study suggest that HUMSCs transplantation, 1 of the most potential treatments for Parkinson's disease, is an effective and safe approach.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2010; 16(11):1519-29. · 3.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The biochemical pathways that mediate the degeneration of dopaminergic neurons in the substantia nigra of patients with Parkinson's disease are largely unknown. Recently, aberrant cell cycle events have been shown to be associated with neuronal death in several neurodegenerative diseases. In the present study, we investigated the role of DNA polymerases (DNA pols) in 1-methyl-4-phenylpyridinium (MPP(+))-induced neuronal apoptosis in cerebellar granule cells. After exposure to MPP(+), the neurons entered S phase of the cell cycle. Neuronal cell cycle re-entry and apoptosis were attenuated by flavopiridol, which is a broad inhibitor of cyclin-dependent kinases (CDKs). MPP(+) exposure significantly increased the expression of DNA pol-beta and primase but did not affect the expression of the canonical replicative DNA pols, including DNA pol-delta and pol-epsilon. Dideoxycytidine, which is a pharmacological inhibitor of DNA pol-beta, attenuated the neuronal apoptosis mediated by MPP(+). In a similar manner, the expression of a dominant negative form of DNA pol-beta was also neuroprotective. These results suggest that DNA pol-beta may have a causal role in MPP(+)-induced neuronal apoptosis.
Apoptosis 11/2009; 15(1):105-15. · 4.07 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The hallmarks of Parkinson's disease (PD) are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of intracellular inclusion bodies in surviving neurons. Although the specific etiology and pathogenesis of sporadic PD remains unknown, neuronal death was proven to be associated with mitochondrial dysfunction and protein misfolding. However, molecular links between mitochondrial dysfunction and protein misfolding remains obscure. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a classical glycolytic enzyme, is responsible for carbohydrate metabolism under normal circumstances. When translocated to the nucleus, GAPDH promotes neuron apoptosis in several neurodegenerative disorders. But it seems that GAPDH translocation is not the sole mechanism responsible for neuronal apoptosis. We found that rotenone, a common mitochondrial complex I inhibitor used to produce experimental parkinsonism, cannot only induce GAPDH translocation but also trigger intermolecular disulfide bonding and result in the formation of intracytoplasmic aggregates of GAPDH. This suggests a link between mitochondrial dysfunction and protein misfolding, and sheds light on the pathophysiology of Lewy body formation in Parkinson's disease.
Brain research 06/2009; 1279:1-8. · 2.46 Impact Factor
-
Nian Xiong, Jinsha Huang,
Zhentao Zhang,
Zhaowen Zhang,
Jing Xiong,
Xingyuan Liu,
Min Jia,
Fang Wang,
Chunnuan Chen,
Xuebing Cao,
Zhihou Liang,
Shenggang Sun,
Zhicheng Lin,
Tao Wang
[show abstract]
[hide abstract]
ABSTRACT: A clinically-related animal model of Parkinson's disease (PD) may enable the elucidation of the etiology of the disease and assist the development of medications. However, none of the current neurotoxin-based models recapitulates the main clinical features of the disease or the pathological hallmarks, such as dopamine (DA) neuron specificity of degeneration and Lewy body formation, which limits the use of these models in PD research. To overcome these limitations, we developed a rat model by stereotaxically (ST) infusing small doses of the mitochondrial complex-I inhibitor, rotenone, into two brain sites: the right ventral tegmental area and the substantia nigra. Four weeks after ST rotenone administration, tyrosine hydroxylase (TH) immunoreactivity in the infusion side decreased by 43.7%, in contrast to a 75.8% decrease observed in rats treated systemically with rotenone (SYS). The rotenone infusion also reduced the DA content, the glutathione and superoxide dismutase activities, and induced alpha-synuclein expression, when compared to the contralateral side. This ST model displays neither peripheral toxicity or mortality and has a high success rate. This rotenone-based ST model thus recapitulates the slow and specific loss of DA neurons and better mimics the clinical features of idiopathic PD, representing a reliable and more clinically-related model for PD research.
PLoS ONE 01/2009; 4(11):e7878. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To investigate the feasibility of radiolabelled annexin V imaging for early diagnosis of Parkinson's disease.
99mTc-HYNIC-annexin V was prepared and its binding to apoptotic cell models of Parkinson's disease was studied in vitro. Cellular models of Parkinson's disease were produced by administering different concentrations of 1-methyl-4-phenylpyridinium to PC12 and SH-SY5Y cell lines. Cell apoptosis rates were analysed by flow cytometry. Annexin V was labelled with 99mTc by hydrazinonicotinamide (HYNIC). Cell binding studies were carried out using cellular models of Parkinson's disease. Cell uptake studies were also performed after different levels of MPP treatment, and the correlation between the degree of apoptosis and Tc-HYNIC-annexin V uptake was analysed.
The specific activity of 99mTc-HYNIC-annexin V was 3.7-74 x 10 Bq.mg protein. In-vitro binding of 99mTc-HYNIC-annexin V to model cells was specific, saturable and time dependent. Scatchard analysis gave a Kd of 7.16+/-1.78 nmol.l, Bmax values of 179+/-33 fmol per 10(6) cells (PC12) and 220+/-26 fmol per 10(6) cells (SHSY5Y). MPP at different concentrations can induce cell apoptosis in a dose-dependent manner; cellular uptake of 99mTc-HYNIC-annexin V as indicated by membrane-bound radiolabelled annexin V activity was linearly correlated with total fluorescence, as observed by FITC-annexin V flow cytometry (PC12: r=0.924; SH-SY5Y: r=0.937, P<0.01).
99mTc-HYNIC-annexin V retains its receptor-binding activity and has a high affinity to cellular models of Parkinson's disease. The uptake of radioactivity correlated well with cell apoptosis rates; thus, 99mTc-annexin V is a potential imaging agent with which to detect early neuron damage in Parkinson's disease.
Nuclear Medicine Communications 12/2007; 28(12):895-901. · 1.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The clinical manifestations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS syndrome) are nonspecific and can easily be misdiagnosed. Magnetic resonance spectroscopy (MRS)-based detection of lactate in the brain has been found to be of diagnostic help in MELAS syndrome, however, the issue of whether MRS features vary by stage remains unresolved. We assessed the causative mutation and radiological features of a family of MELAS. Four of the family members harbored the A3243G mutation, probably of maternal inheritance. However, the clinical phenotypic expression was different in these patients. MRS showed a lactate peak, decreased N-acetylaspartate, choline, and creatine, which became more pronounced with progression of the disease, demonstrating that brain-MRS-based detection of lactate may be a suitable way to monitor the progression and treatment of MELAS.
Neurology India 60(1):86-9. · 0.96 Impact Factor
