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ABSTRACT: The secreted glycoprotein Dickkopf-1(Dkk1), an antagonist of the Wnt/β-catenin pathway, has been implicated in many neurodegenerative diseases. However, it is unknown whether Dkk1 is involved in the pathogenesis of Parkinson's disease (PD). In this study, we discovered that Dkk1 was induced in MPP(+)-treated PC12 cells and the increase of Dkk1 preceded PC12 cell loss. RhDkk1 aggravated the neurotoxicity of MPP(+) in PC12 cells. Furthermore, the level of Dkk1 was correlated with the number of apoptotic PC12 cells. The apoptosis could be decreased by Dkk1-siRNA in MPP(+)-induced PC12 cells and Dkk1-siRNA regulated the expression of β-catenin and p-Ser9-GSK-3β in MPP(+)-induced PC12 cells. LiCl (an inhibitor of GSK-3β) also rescued the loss of PC12 cell viability and the apoptosis induced by MPP(+). These data suggest that the induction of Dkk1 contributes to the MPP(+)-induced neurotoxicity in PC12 cells via inhibition of the canonical Wnt pathway and Dkk1 antagonists which could rescue the Wnt pathway might be neuroprotective in PD.
Neuropharmacology 11/2012; · 4.81 Impact Factor
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ABSTRACT: Dickkopf-1 (Dkk1), an antagonist of the Wnt/β-catenin pathway, has been implicated in many neurodegenerative diseases. However, it's unknown whether Dkk1 is involved in the pathogenesis of Parkinson's disease. In this study, we discovered that Dkk1 was increased in 6-hydroxydopamin(6-OHDA)-lesioned rats. In the meanwhile, inhibition of the canonical Wnt signaling pathway, including the activation of glycogen synthase kinase-3β (GSK-3β) and decrease of β-catenin, was also found in 6-OHDA-lesioned rats. Treatment with rhDkk1 aggravated the dopaminergic neuron damage of the substantia nigra and the inhibition of the canonical Wnt signaling pathway in 6-OHDA-lesioned rats, while the above effects in these rats were abolished by pretreatment with LiCl, an inhibitor of GSK-3β, for consecutive 7 d. These data suggest that Dkk1 plays an important role in the etiology of PD models and it contributes to the neurodegeneration in 6-OHDA-lesioned rats via inhibition of the canonical Wnt pathway.
Neuroscience Letters 08/2012; 525(2):83-8. · 2.11 Impact Factor
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ABSTRACT: Tetramine is an illegal rat poison that has resulted in a number of accidental mass poisonings in China.
To investigate the long term outcome of tetramine poisoning.
A survey of epileptic attacks in 370 patients in the Hubei province of P. R. China who had survived tetramine poisoning in the last decade was undertaken by means of telephone calls, letters, and interviews. Data describing the initial acute episode was gathered from medical and public health records.
Among the 370 patients surveyed (188 males, 182 females, age range 10 to 71 y), 352 experienced seizures during the initial poisoning. One hundred fifty-eight individuals are currently seizure-free, after an average medication period of 2.93 years. The other patients have recurrent epilepsy, including 156 with tonic-clonic seizures and 39 with partial seizures. Six patients have other neurological problems.
Tetramine, a rat poison sometimes ingested by mistake, blocks GABA receptors and causes seizures. These seizures can persist for years after the initial poisoning, even when no seizures are present initially. Sodium valproate, which has the ability to increase the amount of GABA in the CNS, would be a reasonable choice for the treatment of epilepsy caused by tetramine poisoning.
Clinical Toxicology 03/2012; 50(3):172-5. · 2.22 Impact Factor
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ABSTRACT: Previous studies have suggested that glutathione-S-transferase π (GST-π) over-expression in the brain tissue is associated with refractory epilepsy. However, whether the change in GST-π level in the peripheral blood is in line with that in brain tissue remains unknown. This study examined the correlation between GST-π in brain tissue and that in peripheral blood in rat models of pilocarpine-induced refractory epilepsy. The animals were divided into drug-resistant group and drug-responsive group according to the response to anti-epileptic drugs. GST-π expression in brain tissue was immunohistochemically determined, while the expression of GST-π in peripheral blood was analyzed by Western blotting. In the hippocampus and cortex, GST-π was mainly found in the cytoplasm and membrane of neurons, and the GST-π expression level was higher in drug-resistant group than in the drug-responsive group and saline control group (P<0.05). Moreover, there was no significant difference between responders and saline control animals (P>0.05). The change in expression of GST-π in peripheral blood showed the same pattern as that in brain tissues, suggesting GST-π might contribute to drug resistance in epilepsy. Importantly, the GST-π over-expression in peripheral blood could be used as a marker for resistance to anti-epileptic agents.
Journal of Huazhong University of Science and Technology 10/2011; 31(5):701-4. · 0.38 Impact Factor
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ABSTRACT: Although the etiology of Alzheimer's disease (AD) is not fully understood, multiple lines of evidence suggests the importance of amyloid-beta (Abeta) in the initiation/progression of the disease. In this study, we investigated protective effects of erythropoietin (EPO) on Abeta(25-35)-induced cell death in cultured rat pheochromocytoma cells (PC12 cells). EPO (2U/ml) in combination with Abeta(25-35) increased the cell viability and reduced the number of apoptotic cells by MTT assay, Trypan blue dye exclusion method, TUNEL staining and Hoechst 33342 staining. In mechanistic study, EPO induced time-dependent phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. Treatment of PC12 cells with PI3K inhibitors LY294002 abolished the protective effects of EPO. EPO also induced the phosphorylation of glycogen synthase kinase-3beta (GSK-3beta), a downstream target of PI3K/Akt, and GSK-3beta inhibitors lithium chloride blocked Abeta(25-35)-induced cell apoptosis in a manner similar to EPO, suggesting that GSK-3beta inhibition is involved in EPO-mediated cytoprotection. Moreover, the expression of anti-apoptotic protein Bcl-2 was increased by EPO involving PI3K/Akt pathway. These studies demonstrate that EPO is an effective neuroprotective agent and is a viable candidate for treating AD.
Neuropharmacology 04/2009; 56(6-7):1027-34. · 4.81 Impact Factor
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ABSTRACT: Erythropoietin (EPO), a haematopoietic growth factor has been reported to display neuroprotective properties in different animal models. In the present study, we investigated the neuroprotective effects of EPO on Abeta(25-35)-induced neuronal toxicity and its potential mechanisms in PC12 cells. Abeta(25-35) significantly reduced cell viability and increased the number of apoptotic-like cells. In addition, increased ROS production and decreased mitochondrial membrane potential were also found after Abeta(25-35) exposure. All of these phenotypes induced by Abeta(25-35) were markedly reversed by EPO. Pretreatment with EPO prior to Abeta(25-35) exposure significantly elevated cell viability, reduced Abeta(25-35)-induced apoptosis, decreased ROS production, and stabilized mitochondrial membrane potential. Furthermore, EPO also attenuated the downstream cascade following ROS, including Bcl-2/Bax, and caspase-3 activation. Our results suggest that EPO holds potential for neuroprotection and therefore, may be promising for the treatment of Alzheimer's disease.
Neuroscience Letters 09/2008; 442(2):143-7. · 2.11 Impact Factor
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ABSTRACT: The present study shows that JAK2-STAT3 inflammatory signaling mediates thrombin-stimulated microglia activation. In rat primary microglia, thrombin rapidly activated JAK2 and induced phosphorylation of STAT3. In addition, thrombin increased transcription of the inflammation-associated genes tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), production of TNF-alpha, NO and induced neurodegeneration of dopaminergic neurons in mesencephalic cultures. AG490, a JAK inhibitor, markedly reduced activation of JAK2 and STAT3 in thrombin-treated microglia. AG490 also inhibited thrombin-induced transcription and expression of TNF-alpha, iNOS and/or NO release, moreover rescued dopaminergic neurons. These results suggest that JAK2-STAT3 signaling pathway plays a critical role in mediating thrombin-induced activation of microglia and degeneration of dopaminergic neurons.
Journal of Neuroimmunology 09/2008; 204(1-2):118-25. · 2.96 Impact Factor
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ABSTRACT: To evaluate the role of thrombin-activated microglia in the neurodegeneration of nigral dopaminergic neurons in the rat substantia nigra (SN) in vivo.
After stereotaxic thrombin injection into unilateral SN of rats, immunostaining, reverse transcription polymerase chain reaction (RT-PCR) and biochemical methods were used to observe tyrosine hydroxylase (TH) immunoreactive positive cells, microglia activation, nitric oxide (NO) amount and inducible nitric-oxide synthase (iNOS) expression.
(1) Selective damage to dopaminergic neurons was produced after thrombin injection, which was evidenced by loss of TH immunostaining in time-dependent manner; (2) Strong microglial activation was observed in the SN; (3) RT-PCR demonstrated the early and transient expression of neurotoxic factors iNOS mRNA in the SN. Immunofluorescence results found that thrombin induced expression of iNOS in microglia. The NO production in the thrombin-injected rats was significantly higher than that of controls (P < 0.05).
Thrombin intranigral injection can injure the dopaminergic neurons in the SN. Thrombin-induced microglia activation precedes dopaminergic neuron degeneration, which suggest that activation of microglia and release of NO may play important roles in dopaminergic neuronal death in the SN.
Neuroscience Bulletin 04/2008; 24(2):66-72. · 1.31 Impact Factor
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ABSTRACT: To explore whether the upregulation of inducible nitric oxide synthase (iNOS) is involved in lipopolysaccharide (LPS)-induced neurodegeneration.
108 SD rats were randomly divided into 2 groups: experimental group and normal control group, and each group was sub-divided into 5 subgroups of 18 rats to undergo examination at different time points (6 h, 12 h, 1 d, 3 d, and 7 d). LPS was stereotaxically infused into the substantia nigra (SN) of left side of the experimental rats and PBS was used instead for the control rats. At different time points different numbers of rats from each subgroup were killed to take out the SN. Biochemical method was used to test the activity of NO and iNOS in 6 rats from each subgroup, iNOS mRNA expression was tested by RT-PCR in 3 rats from each subgroup, and iNOS protein expression was tested by Western blotting in 4 rats from each subgroup. Immunohistochemistry was used to detect the iNOS positive cells.
iNOS positive cells were found since 6h after the intranigral injection of LPS, peaked 1d after, began to decrease 3d after, and basically disappeared 7d after; and were not found in the control group and the SN at the opposite side of the experimental rats. The percentage of iNOS-positive neurons 1d after the injection was 45.30 +/- 4.63, significantly higher than that of the control group (0.11 +/- 0.04, P < 0.01). RT-PCR and Western blotting showed that expression of iNOS mRNA and expression of iNOS protein at all time points were all higher than those of the normal controls and PBS controls (all P < 0.01). iNOS activity and NO amount in the LPS-injected SN began to increase 6 h after the injection, significantly higher then that of the control group (P < 0.05), peaked 1d after, (P < 0.01), began to decrease 3d after, and basically returned to normal level.
Up-regulation of iNOS may be one of the crucial mechanisms in LPS-induced degeneration of DA neurons.
Zhonghua yi xue za zhi 12/2006; 86(45):3177-81.
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ABSTRACT: To study the protective effects of triptolide (Tri) on the lipopolysaccharide (LPS)-mediated degeneration of dopaminergic neurons in substantia nigra.
Forty SD rats were randomly divided into four groups: the sham group, the LPS model group, the Tri group and the normal saline group, 10 in each group. Fourteen days later, the apomorphine-induced rotational behavior, the content of dopamine (DA) and its metabolites in the striatum of the injured side, the number of tyrosine-hydroxylase (TH) positive neurons and activation of microglia in rats were observed.
Injection of LPS in substantia nigra could induce cerebral simulated immunoinflammatory reaction, leading to degeneration of dopaminergic neuron and induce ipsilateral directed rotational behavior of rats, which could be improved by Tri. Moreover, Tri could raise the lowered content of DA and its metabolites as well as the TH positive neurons in striatum, and suppress the activation of microglia significantly (P<0.01).
Tri could protect the dopaminergic neurons from degeneration due to the inflammation mediated by LPS through inhibiting the activation of microglia.
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine / Zhongguo Zhong xi yi jie he xue hui, Zhongguo Zhong yi yan jiu yuan zhu ban 08/2006; 26(8):715-8.
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ABSTRACT: In order to investigate the neurotoxicity of lipopolysaccharide (LPS) on the dopaminergic neurons of substantia nigra and the pathogenesis of Parkinson disease, LPS was stereotaxically infused into substantia nigra (SN). At different dosages and different time points with 5 microg LPS, the damage of the dopaminergic neurons in SN was observed by using tyrosine-hydroxylase (TH) immunohistochemical staining. The results showed that 14 days after injection of 0.1 microg to 10 microg LPS into the rat SN, TH-positive (TH+) neurons in the SN were decreased by 5%, 15%, 20%, 45 %, 96% and 99% respectively. After injection of 5 microg LPS, as compared with the control groups, TH+ neurons began to decrease at 3rd day and obviously decrease at 14th day, only 5% of total cells, and almost disappeared 30 days later. The results suggested that LPS could induce the degeneration of dopaminergic neurons in the SN in a dose- and time-dependent manner.
Journal of Huazhong University of Science and Technology 02/2004; 24(1):83-6. · 0.38 Impact Factor
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ABSTRACT: Although the etiology of Alzheimer's disease (AD) is not fully understood, multiple lines of evidence suggests the importance of amyloid-β (Aβ) in the initiation/progression of the disease. In this study, we investigated protective effects of erythropoietin (EPO) on Aβ25–35-induced cell death in cultured rat pheochromocytoma cells (PC12 cells). EPO (2 U/ml) in combination with Aβ25–35 increased the cell viability and reduced the number of apoptotic cells by MTT assay, Trypan blue dye exclusion method, TUNEL staining and Hoechst 33342 staining. In mechanistic study, EPO induced time-dependent phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. Treatment of PC12 cells with PI3K inhibitors LY294002 abolished the protective effects of EPO. EPO also induced the phosphorylation of glycogen synthase kinase-3β (GSK-3β), a downstream target of PI3K/Akt, and GSK-3β inhibitors lithium chloride blocked Aβ25–35-induced cell apoptosis in a manner similar to EPO, suggesting that GSK-3β inhibition is involved in EPO-mediated cytoprotection. Moreover, the expression of anti-apoptotic protein Bcl-2 was increased by EPO involving PI3K/Akt pathway. These studies demonstrate that EPO is an effective neuroprotective agent and is a viable candidate for treating AD.
Neuropharmacology.
