ABSTRACT
BACKGROUND: It is a challenge to characterize the consciousness level of patients with severe disturbance of consciousness and predict their prognosis effectively for Chinese doctors. We aimed to investigate the psychometric property and the diagnostic practicality of severe disturbance of consciousness by Chinese Nanjing persistent vegetative state scale (CNPVSS) which was first set up in 1996 and modified in 2001 and 2011. METHODS: The concurrent validity, inter-rater consistency and diagnostic accuracy of CNPVSS and Chinese version of coma recovery scale-revised (CRS-R) were investigated by assessment of 380 patients with severe disorders of consciousness. RESULTS: Total scores of the CNPVSS were correlated significantly with that of the CRS-R, indicating acceptable concurrent validity. Sub-scale analysis showed moderate to high inter-rater reliability and test-retest reliability. CNPVSS was superior to CRS-R on the diagnosis sensitivity. The CNPVSS was able to distinguish 65 patients in emergence from minimal consciousness state who were misclassified as in minimal consciousness state (MCS) by the CRS-R, and it could also distinguish two patients in MCS who were misclassified as in vegetative state by the CRS-R. CONCLUSION: The CNPVSS is an appropriate measurement and is sensitive to distinguish the MCS patients from the VS patients.
Subject(s)
Coma , Persistent Vegetative State , China , Humans , Persistent Vegetative State/diagnosis , Recovery of Function , Reproducibility of ResultsABSTRACT
Neural stem cell (NSC) transplantation has emerged as a promising approach for the treatment of neurological disorders such as cerebral ischemia. As the majority of newly generated cells from exogenous NSCs fail to integrate into the ischemic brain and establish functional synaptic networks, NSC transplantation for ischemic stroke experiences limited neurological function recovery. Augment of endogenous neurite growth in the process of NSC differentiation is an avenue to promote synaptic networks. Phosphatase and tensin homolog (PTEN), a tumor suppressor, has been established to regulate axon growth in the adult central nervous system. The aim of this study was to explore the role of PTEN on neurite growth during NSC differentiation. Our results revealed that the protein expression of PTEN was significantly increased during NSC differentiation, whereas the expression of phosphorylated S6 ribosomal (p-S6R) was markedly decreased. Small interfering RNA knockdown of PTEN in NSCs can accelerate neurite outgrowth during NSC differentiation. These results indicated a remarkable effect of PTEN inhibition on neuronal process after NSC differentiation, and identified a novel route to promote endogenous neurite growth in differentiated NSCs, which may facilitate the application of NSC transplantation in ischemic stroke.
Subject(s)
Cell Differentiation/physiology , Neural Stem Cells/metabolism , Neuronal Outgrowth/physiology , PTEN Phosphohydrolase/metabolism , Animals , Neurogenesis/physiology , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation of group I mGluRs (mGluR1 and mGluR5) in cultured hippocampal neurons by application of (S)-3,5-Dihydroxyphenylglycine (DHPG) causes the regulated internalization of N-methyl-D-aspartate receptors (NMDARs), which subsequently activates protein kinase D1 (PKD1). Through phosphorylating the C-terminals of the NMDAR GluN2 subunits, PKD1 down-regulates the activity of remaining (non-internalized) surface NMDARs. The knockdown of PKD1 does not affect the DHPG-induced inhibition of AMPA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs) but prevents the DHPG-induced inhibition of NMDAR-mediated mEPSCs in vitro. Thus, we investigated the in vivo effects of bilateral infusions of DHPG into the hippocampal CA1 area of rats in the Morris water maze (MWM) and the novel object discrimination (NOD) tests. METHODS: A total of 300 adult male Sprague Dawley rats (250-280 g) were used for behavioral tests. One hundred ninety four were used in MWM test and the other 106 rats in the NOD test. Following one week of habituation to the vivarium, rats were bilaterally implanted under deep anesthesia with cannulas aimed at the CA1 area of the hippocampus (CA1 coordinates in mm from Bregma: AP -3.14; lateral +/-2; DV -3.0). Through implanted cannulas artificial cerebrospinal fluid (ACSF), the group1 mGluR antagonist 6-Methyl-2-(phenylethynyl)pyridine (MPEP), the dynamin-dependent internalization inhibitor Dynasore, or the PKD1 inhibitor CID755673 were infused into the bilateral hippocampal CA1 areas (2 µL per side, over 5 min). The effects of these infusions and the effects of PKD1 knockdown were examined in MWM or NOD test. RESULTS: DHPG infusion increased the latency to reach the platform in the MWM test and reduced the preference for the novel object in the NOD task. We found that the DHPG effects were dose-dependent and could be maintained for up to 2 days. Notably, these effects could be prevented by pre-infusion of the group1 mGluR antagonist MPEP, the dynamin-dependent internalization inhibitor Dynasore, the PKD1 inhibitor CID755673, or by PKD1 knockdown in the hippocampal CA1 area. CONCLUSION: Altogether, these findings provide direct evidence that PKD1-mediated signaling may play a critical role in the induction of learning and memory impairments by DHPG infusion into the hippocampal CA1 area.
Subject(s)
Hippocampus/metabolism , Hippocampus/physiopathology , Learning , Memory , Protein Kinase C/genetics , Animals , CA1 Region, Hippocampal/metabolism , CA1 Region, Hippocampal/physiopathology , Disease Models, Animal , Dose-Response Relationship, Drug , Gene Knockout Techniques , Learning Disabilities/etiology , Learning Disabilities/physiopathology , Locomotion , Male , Maze Learning , Memory Disorders/etiology , Memory Disorders/physiopathology , Methoxyhydroxyphenylglycol/adverse effects , Methoxyhydroxyphenylglycol/analogs & derivatives , Protein Kinase C/metabolism , Rats , Spatial MemoryABSTRACT
Although the effects of emotion of different emotional intensity on memory have been investigated, it remain unclear whether the influence of emotional intensity on memory varies depending on the stimulus valence polarity (i.e., positive or negative). To address this, event-related potentials were recorded when subjects performed a continuous old/new discrimination task, for highly negative (HN), mildly negative (MN) and neutral pictures in the negative session; and for highly positive (HP), mildly positive (MP) and neutral pictures in the positive session. The results showed that relative to neutral stimuli, both HN and MN stimuli showed increased memory discrimination scores, and enhanced old/new effect in early FN400 (Frontal Negativity), but not late positive component (LPC) amplitudes. By contrast, relative to MP stimuli, HP and neutral stimuli showed increased memory discrimination scores and enhanced old/new effect in LPC but not FN400 amplitudes. Additionally, we observed a significant positive correlation between the memory discrimination score and the old/new effect in the amplitudes of the FN400 and LPC, respectively. These results indicate that both HN and MN stimuli were remembered better than neutral stimuli; whereas the recognition was worse for MP stimuli than Neutral and HP stimuli. In conclusion, in the present study, we observed that the effect of emotion intensity on memory depends on the stimulus valence polarity.
Subject(s)
Emotions/physiology , Evoked Potentials/physiology , Recognition, Psychology/physiology , Adult , Electroencephalography , Female , Humans , Male , Young AdultABSTRACT
OBJECTIVE: To analyze the clinical features and genetic cause for a family affected with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: Clinical manifestations, neuroimaging, and genetic analysis were performed. RESULTS: The main clinical features have included stroke, emotional disturbance and history of migraine without progressive memory impairment. A positive family history was confirmed. Cranial MRI has revealed multi-infarct lesions and white matter hyperintensity involving bilateral basal ganglia, subcortex and brain stem. All such features were in keeping with the diagnosis of CADASIL. A rare 2182C>T mutation in exon 14 of the NOTCH3 gene was identified in all available cases. CONCLUSION: Both clinical and molecular features suggested that the family has been affected with CADASIL.
Subject(s)
Migraine Disorders/genetics , Receptors, Notch/genetics , Adult , Aged , Female , Humans , Male , Middle Aged , Receptor, Notch3ABSTRACT
BACKGROUND: The functional improvement following bone marrow stromal cells (BMSCs) transplantation after stroke is directly related to the number of engrafted cells and neurogenesis in the injured brain. Here, we tried to evaluate whether 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), a free radical scavenger, might influence BMSCs migration to ischemic brain, which could promote neurogenesis and thereby enhance treatment effects after stroke. METHODS: Rat transient middle cerebral artery occlusion (MCAO) model was established. Two separate MCAO groups were administered with either MCI-186 or phosphate-buffered saline (PBS) solution to evaluate the expression of stromal cell-derived factor-1 (SDF-1) in ischemic brain, and compared to that in sham group (n = 5/ group/time point[at 1, 3, and 7 days after operation]). The content of chemokine receptor-4 (CXCR4, a main receptor of SDF-1) at 7 days after operation was also observed on cultured BMSCs. Another four MCAO groups were intravenously administered with either PBS, MCI-186, BMSCs (2 × 106), or a combination of MCI-186 and BMSCs (n = 10/group). 5-bromo-2-deoxyuridine (BrdU) and Nestin double-immunofluorescence staining was performed to identify the engrafted BMSCs and neuronal differentiation. Adhesive-removal test and foot-fault evaluation were used to test the neurological outcome. RESULTS: MCI-186 upregulated the expression of SDF-1 in ischemic brain and CXCR4 content in BMSCs was enhanced after hypoxic stimulation. When MCAO rats were treated with either MCI-186, BMSCs, or a combination of MCI-186 and BMSCs, the neurologic function was obviously recovered as compared to PBS control group (P < 0.01 or 0.05, respectively). Combination therapy represented a further restoration, increased the number of BMSCs and Nestin+ cells in ischemic brain as compared with BMSCs monotherapy (P < 0.01). The number of engrafted-BMSCs was correlated with the density of neuronal cells in ischemic brain (r = 0.72 , P < 0.01) and the improvement of foot-fault (r = 0.70, P < 0.01). CONCLUSION: MCI-186 might promote BMSCs migration to the ischemic brain, amplify the neurogenesis, and improve the effects of cell therapy.
Subject(s)
Antipyrine/analogs & derivatives , Brain Ischemia/drug therapy , Brain Ischemia/therapy , Mesenchymal Stem Cells/physiology , Stroke/drug therapy , Stroke/therapy , Animals , Antipyrine/therapeutic use , Bone Marrow Cells/cytology , Bone Marrow Cells/physiology , Brain Ischemia/metabolism , Chemokine CXCL12/metabolism , Disease Models, Animal , Edaravone , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/metabolism , Infarction, Middle Cerebral Artery/therapy , Male , Neurogenesis/physiology , Rats , Rats, Sprague-Dawley , Stroke/metabolismABSTRACT
BACKGROUND: Our recent event-related potential (ERP) study showed that adolescents are more emotionally sensitive to negative events compared to adults, regardless of the valence strength of the events. The current work aimed to confirm this age-related difference in response to emotional stimuli of diverse intensities by examining Electroencephalography (EEG) oscillatory power in time-frequency analysis. METHODS: Time-frequency analyses were performed on the EEG data recorded for highly negative (HN), moderately negative (MN) and Neutral pictures in 20 adolescents and 20 adults during a covert emotional task. The results showed a significant age by emotion interaction effect in the theta and beta oscillatory power during the 500-600 ms post stimulus. RESULTS: Adolescents showed significantly less pronounced theta synchronization (ERS, 5.5-7.5 Hz) for HN stimuli, and larger beta desynchronization (ERD; 18-20 Hz) for both HN and MN stimuli, in comparison with neutral stimuli. By contrast, adults exhibited no significant emotion effects in theta and beta frequency bands. In addition, the analysis of the alpha spectral power (10.5-12 Hz; 850-950 ms) showed a main effect of emotion, while the emotion by age interaction was not significant. Irrespective of adolescents or adults, HN and MN stimuli elicited enhanced alpha suppression compared to Neutral stimuli, while the alpha power was similar across HN and MN conditions. CONCLUSIONS: These results confirmed prior findings that adolescents are more sensitive to emotionally negative stimuli compared to adults, regardless of emotion intensity, possibly due to the developing prefrontal control system during adolescence.
ABSTRACT
BACKGROUND: Constitutive and regulated internalization of cell surface proteins has been extensively investigated. The regulated internalization has been characterized as a principal mechanism for removing cell-surface receptors from the plasma membrane, and signaling to downstream targets of receptors. However, so far it is still not known whether the functional properties of remaining (non-internalized) receptor/channels may be regulated by internalization of the same class of receptor/channels. The N-methyl-D-aspartate receptor (NMDAR) is a principal subtype of glutamate-gated ion channel and plays key roles in neuronal plasticity and memory functions. NMDARs are well-known to undergo two types of regulated internalization - homologous and heterologous, which can be induced by high NMDA/glycine and DHPG, respectively. In the present work, we investigated effects of regulated NMDAR internalization on the activity of residual cell-surface NMDARs and neuronal functions. RESULTS: In electrophysiological experiments we discovered that the regulated internalization of NMDARs not only reduced the number of cell surface NMDARs but also caused an inhibition of the activity of remaining (non-internalized) surface NMDARs. In biochemical experiments we identified that this functional inhibition of remaining surface NMDARs was mediated by increased serine phosphorylation of surface NMDARs, resulting from the activation of protein kinase D1 (PKD1). Knockdown of PKD1 did not affect NMDAR internalization but prevented the phosphorylation and inhibition of remaining surface NMDARs and NMDAR-mediated synaptic functions. CONCLUSION: These data demonstrate a novel concept that regulated internalization of cell surface NMDARs not only reduces the number of NMDARs on the cell surface but also causes an inhibition of the activity of remaining surface NMDARs through intracellular signaling pathway(s). Furthermore, modulating the activity of remaining surface receptors may be an effective approach for treating receptor internalization-induced changes in neuronal functions of the CNS.
Subject(s)
Cell Membrane/metabolism , Endocytosis , Protein Kinase C/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Down-Regulation/drug effects , Endocytosis/drug effects , Enzyme Activation/drug effects , Gene Knockdown Techniques , Glycine/pharmacology , HEK293 Cells , Humans , Methoxyhydroxyphenylglycol/analogs & derivatives , Methoxyhydroxyphenylglycol/pharmacology , Mice , Models, Biological , N-Methylaspartate/pharmacology , Phosphorylation/drug effects , Phosphoserine/metabolism , Rats, WistarABSTRACT
Diabetes-induced cognitive deficit (DICD) is a prevalent disease with substantial morbidity and mortality and as a global health problem with serious economic burdens. Astaxanthin (AST) has a good prospect in production of nutritional, medical, and particularly functional health drug. The present study was aimed to study the effect of AST on DICD in diabetes mellitus (DM) rat through suppression of oxidative stress, nitric oxide synthase (NOS) pathway, inflammatory reaction and upregulation of PI3K/Akt. In the study, Morris water maze teat was used to detect the cognitive function of DM rat. Afterwards, we measured the body weight and blood glucose levels of DM rats. Then, oxidative stress, the activities of eNOS and iNOS, and inflammatory factors were analyzed using a commercial kit in cerebral cortex and hippocampus. Finally, the caspase-3/9 and phosphoinositide 3-kinase (PI3K)/Akt expressions were also checkout with Real Time PCR and immunoblotting, respectively. In this experiment, AST could availably enhance the body weight and reduce blood glucose levels of DM rats. Moreover, AST could observably perfect cognitive function of DM rat. Next, the activities of oxidative stress, nitric oxide synthase and inflammation were distinctly diminution in DM rat, after the treatment of AST. Furthermore, our present results demonstrated that AST had the protective effect on the brain cell of DM rat, decreased the caspase-3/9 expression and promoted the expression of PI3K/Akt in cerebral cortex and hippocampus.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Brain/drug effects , Cognition Disorders/prevention & control , Cognition/drug effects , Diabetes Mellitus, Experimental/drug therapy , Inflammation Mediators/metabolism , Inflammation/prevention & control , Nitric Oxide Synthase/metabolism , Oxidative Stress/drug effects , Phosphatidylinositol 3-Kinase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , Body Weight/drug effects , Brain/enzymology , Brain/immunology , Caspase 3/metabolism , Caspase 9/metabolism , Cognition Disorders/enzymology , Cognition Disorders/etiology , Cognition Disorders/immunology , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/enzymology , Diabetes Mellitus, Experimental/immunology , Inflammation/enzymology , Inflammation/etiology , Inflammation/immunology , Inflammation/psychology , Male , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type III/metabolism , Rats, Wistar , Signal Transduction/drug effects , Time Factors , Xanthophylls/pharmacologyABSTRACT
Urocortin (UCN) has exhibited antiinflammatory and neuroprotective effects on intracerebral hemorrhage (ICH). However, the underlying mechanisms are still not clear. Therefore, this study was aimed to investigate effects of UCN1 on ICH in vitro and in vivo and further explore the possible mechanism. ICH was induced by an infusion of autologous blood into the unilateral striatum of anesthetized male Sprague-Dawley rats. The rats were randomly divided into three groups (8 rats per group): sham ICH control group, ICH saline group and ICH UCN1 group. UCN1 was infused into the lateral ventricle after 1h post-ICH. Neurological deficits were evaluated by modified neurological severity score (mNSS). Brain edema was assessed using the dry/wet method. The neurological cell metabolic activity of N2a and SH-SY5Y was detected by CCK-8. The level of VEGF, JNK and p38 were determined by enzyme-linked immunosorbent assay and western blot. Post-treatment with UCN1 could improve neurological deficits and reduce brain edema. Moreover, UCN1 could increase the metabolic activity of neuron cells dose-dependently and these effects could be abolished by corticotropin-releasing factor receptor 2 (CRFR2) antagonist anti-Svg-30. Furthermore, the level of VEGF, JNK and p38 were up-regulated by post-treatment with UCN1 via CRFR2. The protective effects of UCN1 against ICH are possibly mediated by activating the phosphorylation of JNK and p38 and further increasing the level of VEGF via CRFR2.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Cerebral Hemorrhage/prevention & control , Mitogen-Activated Protein Kinase 8/metabolism , Mitogen-Activated Protein Kinase 9/metabolism , Neuroprotective Agents/pharmacology , Receptors, Corticotropin-Releasing Hormone/metabolism , Urocortins/pharmacology , Vascular Endothelial Growth Factor A/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Anti-Inflammatory Agents/therapeutic use , Brain Edema/pathology , Cell Line, Tumor , Cerebral Hemorrhage/metabolism , Cerebral Hemorrhage/physiopathology , Enzyme Activation , Humans , Male , Mice , Neuroprotective Agents/therapeutic use , Phosphorylation , Random Allocation , Rats, Sprague-Dawley , Urocortins/therapeutic useABSTRACT
BACKGROUND AND OBJECTIVE: Previous genetic studies in Parkinson's disease (PD) have provided conclusive evidence for association of genes with strong biological rationale for PD. Recently several studies in different populations have found a strong association between idiopathic PD and the single-nucleotide polymorphism (SNP) rs2736990, located within an intron of the α-synuclein (SNCA) gene. In this study, we aimed to verify these findings and to explore the characteristic of the association in a subset of Chinese Han PD patients. MATERIALS AND METHODS: A total of 515 unrelated patients with sporadic PD and 450 healthy ethnically matched control subjects were recruited consecutively for the study. Patients and healthy controls were genotyped for SNCA rs2736990 variant by polymerase chain reaction - ligase detection reaction. RESULTS: Our data showed a significant association between the rs2736990 polymorphism and PD, the frequency of the allele C in PD patients was significantly higher than that in controls (P = 0.017, OR = 1.26, 95% confident intervals (CI) =1.04-1.51). The distribution of C > T genotypes was different between patients and controls (P = 0.027). Furthermore, allele C of SNP rs2736990 in early-onset PD was significantly more frequent than that in healthy controls (P = 0.007, odds ratio = 1.60, 95% CI = 1.13-2.26). CONCLUSIONS: Our study demonstrated that SNCA rs2736990 C > T polymorphism was associated with susceptibility to PD in Chinese Han population. Further studies are needed to replicate the association we found.
Subject(s)
Genetic Predisposition to Disease , Parkinson Disease/genetics , Polymorphism, Single Nucleotide/genetics , alpha-Synuclein/genetics , Adult , Aged , Asian People/ethnology , Asian People/genetics , Case-Control Studies , Female , Gene Frequency , Genetic Association Studies , Genotype , Humans , Male , Middle Aged , Parkinson Disease/ethnologyABSTRACT
Physical therapy can promote neurovascular plasticity and functional recovery after CNS disorders such as ischemic stroke. We have previously demonstrated that whisker stimulation promotes angiogenesis in the penumbra of the ischemic barrel cortex. The aim of this study was to examine whether atorvastatin and whisker stimulation can act synergistically in enhancing angiogenesis in the barrel cortex following ischemia. Rats were divided into sham-operation, control, atorvastatin-treatment, whisker stimulation and combination therapy groups. And they were trained continuously for 10 trials per half day until the rat fulfilled 80% correct choices for continuous thirty trials, which were considered to reach the criteria. The number was significantly less in the combination therapy group than that in the whisker stimulation group (P<0.01). Immunofluorescence was used to detect angiogenesis 14 d following focal ischemia. These data showed that the combination therapy was more effective in enhancing VEGF and BDNF expression than whisker stimulation (P<0.01). Our study indicated that atorvastatin can improve the discrimination ability of whisker stimulation in rats and amplify post-ischemic angiogenesis induced by whisker stimulation, potentially via enhanced expression of VEGF and BDNF in the peri-infarct region.
Subject(s)
Brain Ischemia/physiopathology , Heptanoic Acids/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Neovascularization, Physiologic/drug effects , Pyrroles/pharmacology , Somatosensory Cortex/drug effects , Vibrissae/physiology , Animals , Atorvastatin , Brain Ischemia/therapy , Brain-Derived Neurotrophic Factor/metabolism , Fluorescent Antibody Technique , Microvessels/drug effects , Microvessels/metabolism , Rats , Rats, Sprague-Dawley , Somatosensory Cortex/blood supply , Somatosensory Cortex/metabolism , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Bone marrow stem cells (BMSCs) have been one of the most important cell sources for cell replacement therapy (CRT) in cerebral infarction. However, long-lasting oxidative stress during stroke, which plays an important role in neuron damage, deteriorates the microenvironment for cell survival, differentiation and removal. Thus the outcome of CRT in ischemic diseases was poor. DL-3-n-Butylphthalide (NBP) has protective effects on ischemic brain tissue through multiple mechanisms and has been used for stroke treatment in China for several years. In this study, hydrogen peroxide (H(2)O(2)) was used to induce oxidative stress injury to rat bone marrow stem cells (rBMSCs), imitating the microenvironment surrounding transplanted cells in the ischemic brain in vitro. The protective effects of NBP on rBMSCs against apoptosis induced by oxidative stress were investigated. Our results indicated that NBP could protect rBMSCs against apoptosis due to antioxidative properties and modulation of PI3K/Akt pathway. NBP could be used in combination with BMSCs for the treatment of cerebral infarction by improving the oxidative stress microenvironments and cell survival, however, further studies remain warranted.
Subject(s)
Antioxidants/pharmacology , Apoptosis/drug effects , Benzofurans/pharmacology , Hematopoietic Stem Cells/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Animals , Bone Marrow Cells/drug effects , Bone Marrow Cells/metabolism , Enzyme Activation/drug effects , Hematopoietic Stem Cells/metabolism , Hydrogen Peroxide/toxicity , Oxidants/toxicity , Rats , Signal Transduction/drug effectsABSTRACT
BACKGROUND: Over the last decades, increasing knowledge about the genetic architecture of Parkinson's disease(PD) has provided novel insights into the pathogenesis of the disorder. Recently, several studies in different populations have found a strong association between idiopathic PD and the single-nucleotide polymorphism (SNP) rs356219, which is located in the 3'UTR of the SNCA gene. In this study, we aimed to verify these findings and to explore further the nature of the association in a subset of Chinese Han PD patients. METHODS: Four hundred and three unrelated patients with sporadic PD and 315 healthy ethnically matched control subjects were recruited consecutively for the study. Patients and normal controls were genotyped for SNCA rs356219 variant by ligase detection reaction (LDR). RESULTS: A statistically significant difference was found in the frequencies of the single alleles of rs356219 (χ(2) = 12.986,P = 0.002) between PD patients and normal subjects. The distribution of A > G genotypes was different between patients and controls (χ(2) = 13.243, P < 0.001). The OR for subjects with the variant genotypes (AG and GG) was 1.88 (95%CI = 1.27-2.78, P = 0.001). The frequencies of the homozygous genotype for this variant was 42.2% (170 patients), which was significantly higher than that in controls (32.4%, P < 0.001). CONCLUSION: The results suggested that SNCA rs356219 variant might have an increased risk of susceptibility to PD in a Chinese Han population. Further studies are needed to replicate the association that we found.
Subject(s)
Asian People/genetics , Genetic Predisposition to Disease/genetics , Parkinson Disease/genetics , Polymorphism, Single Nucleotide/genetics , alpha-Synuclein/genetics , Aged , Asian People/ethnology , Case-Control Studies , Chi-Square Distribution , DNA Mutational Analysis , Female , Gene Frequency , Genetic Association Studies , Genotype , Humans , Male , Middle Aged , Parkinson Disease/ethnology , Retrospective StudiesABSTRACT
BACKGROUND: Several classes of medications such as tricyclic antidepressants, anticonvulsants, narcotic analgesics, and α2-δ ligands, such as pregabalin, have been reported to be efficacious in the treatment of painful diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN) in whites. However, no large double-blind, placebo-controlled trials have been reported that evaluated the efficacy of pregabalin for the treatment of neuropathic pain in a Chinese population in China. OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of flexible-dose pregabalin in treatment of Chinese patients diagnosed with painful DPN or PHN. METHODS: This was a double-blind, parallel-group study in which patients were randomized in a 2:1 ratio and treated with either flexible-dose pregabalin, 150 to 600 mg/d, or corresponding flexible-dose placebo for 8 weeks. The primary efficacy end point was change in the mean pain score based on a daily pain rating scale (DPRS; ranging from 0 [no pain] to 10 [worst possible pain]). Secondary end points included Daily Sleep Interference scale, short form-McGill Pain Questionnaire (SF-MPQ) scale, and the Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) scales. Adverse events and physical and laboratory examination results were also collected. RESULTS: Pregabalin and placebo treatment groups were well-matched in terms of demographic and patient characteristics. On the primary outcome, end point change in mean DPRS score, treatment with pregabalin (N = 206) resulted in significant improvement compared with results with placebo (N = 102), with a least squares mean difference score of -0.6 (P = 0.005). With regard to responder rates, 64% and 52% of patients treated with pregabalin and placebo, respectively, reported ≥30% improvement in DPRS scores (P = 0.04). Treatment with pregabalin also resulted in significant efficacy compared with that of placebo on secondary measures, including SF-MPQ VAS score (P = 0.012), SF-MPQ present pain intensity index score (P = 0.003), sleep interference score (P = 0.023), and PGIC and CGIC scores (P = 0.004 and P = 0.001, respectively). Adverse events were observed in 50.0% of pregabalin patients and 40.2% of placebo patients (P = 0.105), with the most common adverse event being dizziness (11.2%). CONCLUSIONS: Study results suggest that relative to placebo, pregabalin in daily doses of 150 to 600 mg/d was effective and well tolerated in Chinese patients diagnosed with moderate-to-severe DPN or PHN, indicated through improved pain scores and PGIC scores.
Subject(s)
Analgesics/therapeutic use , Diabetic Neuropathies/drug therapy , Neuralgia, Postherpetic/drug therapy , gamma-Aminobutyric Acid/analogs & derivatives , Adolescent , Adult , Aged , Analgesics/administration & dosage , Analgesics/adverse effects , China , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Middle Aged , Pain Measurement , Pregabalin , Treatment Outcome , Young Adult , gamma-Aminobutyric Acid/administration & dosage , gamma-Aminobutyric Acid/adverse effects , gamma-Aminobutyric Acid/therapeutic useABSTRACT
BACKGROUND: Similar to the neural network, the vascular network is formed from central axial structures that send sprouts along predetermined trajectories to their distal destinations. Indeed, recent evidence indicates that neuronal guidance factors and their receptors function as angiogenic regulators. As neural guidance cues, netrin-1 is the most extensively studied gene in the field of angiogenesis. Despite achieving some advances in mesenchymal stem cell (MSC) therapy in angiogenesis, there are still a certain number of patients who fail to respond to cell therapy. Thus, a novel therapeutic strategy to enhance the angiogenic property of transplanted cells is desirable. This study examined the impact of combined netrin-1 protein and MSC implantation on therapeutic angiogenesis in a rat model of hind limb ischemia. METHODS: Hind limb ischemic rats (n = 24) were divided randomly into four groups (six rats per group): control group (0.05 mL saline); netrin-1 group (1 µg netrin-1 dissolved in 0.05 mL saline); MSC group (1 × 10(6) MSCs); and netrin-1/MSCs group (1 µg netrin-1 combined with MSCs). Netrin-1 and/or MSCs were injected directly into the muscle of the ischemic limb. Gross appearance of ischemic limb, collateral vessel formation, and vascular endothelial growth factor (VEGF) level were assessed 28 d after treatment. RESULTS: The results showed that pretreatment of MSCs with a recombinant netrin-1 protein markedly augmented the angiographic score and capillary density, improved function of the ischemic limb, and increased levels of VEGF in the plasma and damaged tissues. Further studies assaying the cell migration and network formation suggested that netrin-1 promoted MSC migration and enhanced its ability to participate in tube formation. CONCLUSIONS: These results demonstrated that transplantation of MSCs pretreated with netrin-1 protein significantly improved the therapeutic effect of MSCs and, therefore, may provide a novel therapeutic approach for ischemic disease.
Subject(s)
Hindlimb/blood supply , Ischemia/drug therapy , Mesenchymal Stem Cell Transplantation/methods , Neovascularization, Physiologic/drug effects , Nerve Growth Factors/pharmacology , Tumor Suppressor Proteins/pharmacology , Animals , Cell Movement/drug effects , Combined Modality Therapy , Diabetic Angiopathies/drug therapy , Disease Models, Animal , Netrin-1 , Rats , Rats, Wistar , Reperfusion/methods , Vascular Endothelial Growth Factor A/metabolismABSTRACT
OBJECTIVE: To investigate the relationship of Semaphorin 5A (SEMA5A) and risk of Parkinson's disease (PD). METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to check two single nucleotide polymorphisms (SNPs) within SEMA5A in 244 PD patients and 174 healthy control subjects of Chinese Han ancestry. And the results were verified by gene sequencing. RESULTS: The SEMA5A variant genotype (allele) of rs7702187 and rs3798097 had no correlation with the risk of PD in the samples (rs7702187: OR(genotype AT) 0.95, 95% CI 0.61-1.48, OR (genotype AA) = 1.84, 95% CI 0.85-3.99, OR(genotype AT + AA) = 1.21, 95% CI 0.82-1.77, P > 0.05; rs3798097: OR(genotype CT) = 1.06, 95% CI 0.62-1.79, OR(genotype TT) = 0.72, 95% CI 0.10-5.18, OR(genotype CT + T) = 1.01, 95% CI 0.62-1.67, P > 0.05). Comparing with the most common haplotype TC, neither AC haplotype nor TT haplotype showed any correlation with risk of PD (OR = 1.19, 95% CI 0.84-1.69 for AC haplotype P > 0.05; OR = 0.99, 95% CI 0.59-1.70 for TT haplotype, P > 0.05). CONCLUSION: SEMA5A is not implicated in PD risk in a Chinese Han population.
Subject(s)
Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Parkinson Disease/genetics , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , Alleles , China/epidemiology , Female , Gene Frequency , Genetic Predisposition to Disease/ethnology , Genotype , Haplotypes , Humans , Male , Middle Aged , Parkinson Disease/epidemiology , Parkinson Disease/ethnology , SemaphorinsABSTRACT
BACKGROUND: Vasoactive drug alprostadil improves microcirculation and can be effective in treating disorders of peripheral nerves. Vascular endothelial growth factor (VEGF) has been shown to have protective action in cerebral ischemia, disorders of spinal cord, and also peripheral nerves. However, the mechanism of action of VEGF in peripheral nerve injuries is uncertain. OBJECTIVES: To study the effect of application of alprostadil on the pathological and functional repair of crush nerve injuries and also the expression of VEGF. MATERIALS AND METHODS: Rat sciatic nerves were crushed by pincers to establish the model of crush injury. All of the 400 sprague dawley (SD) rats were randomly divided into: Control; saline; saline+VEGF-antibody; alprostadil; and alprostadil+VEGF antibody groups. The SPSS 11.5 software was used for statistical analysis. The expression of VEGF in dorsal root ganglia (DRGs), following crush injury to sciatic nerves, was studied by reverse transcribed-polymerase chain reaction (RT-PCR), immunohistochemistry, electromicroscope, and electrophysiology. The effects of alprostadil on expression of VEGF, repair of neural pathology, and recovery of neural function were also evaluated. RESULTS: We found that VEGF messenger ribonucleic acid (mRNA) was significantly increased in alprostadil and alprostadil+VEGF-antibody groups, compared to the saline and saline+VEGF antibody groups. The number of VEGF-positive neurons was significantly increased in the alprostadil group, compared to the saline, saline+VEGF antibody, and alprostadil+VEGF antibody groups. Besides, addition of this drug also caused less pathological changes in DRGs, better improvement of nerve conduction velocities of sciatic nerves, and more increase of toe spaces of right hind limbs of rats. CONCLUSIONS: The vasoactive agent alprostadil may reduce the pathological lesion of peripheral nerves and improve the rehabilitation of the neural function, which may relate to upregulation of the expression of VEGF, following crush injury to the peripheral nerves.
Subject(s)
Alprostadil/pharmacology , Alprostadil/therapeutic use , Fibrinolytic Agents/therapeutic use , Gene Expression Regulation/drug effects , Nerve Regeneration/drug effects , Sciatic Neuropathy/drug therapy , Vascular Endothelial Growth Factor A/metabolism , Analysis of Variance , Animals , Antibodies/therapeutic use , Disease Models, Animal , Female , Fibrinolytic Agents/pharmacology , Ganglia, Spinal/metabolism , Ganglia, Spinal/ultrastructure , Male , Microscopy, Immunoelectron/methods , Neural Conduction/drug effects , Psychomotor Performance/drug effects , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Sciatic Neuropathy/pathology , Sciatic Neuropathy/physiopathology , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/immunologyABSTRACT
BACKGROUND: The underlying mechanism of early neurobiological impairment after subarachnoid hemorrhage (SAH) is not well understood, but the system of reactive oxygen superoxide (ROS) might be involved. Edaravone (MCI-186), a potent free radical scavenger that prevents apoptosis of neurons, was thus used in this study to see its possible therapeutic effect in early brain injury due to SAH in a rat model. METHODS: One hundred and twenty male Sprague-Dawley rats were randomly assigned to four groups: group 1, control rats receiving sham operation only; group 2, rats with SAH treated by saline; group 3, rats with SAH treated with 1 mg/kg MCI-186 injected intraperitoneally; and group 4, rats with SAH treated with 3 mg/kg MCI-186. Treated with either saline or MCI-186 twice daily for two consecutive days after SAH, the rats were sacrificed for measurements of malondialdehyde (MDA) and activity of superoxide dismutase (SOD) and histological analysis of caspase-3 protein by Western blotting and immunohistochemical staining. In addition, mortality and neurological scores were statistically analyzed by the chi-square test and Dunn's procedure respectively for each group. One-way analysis of variance followed by the Tukey's procedure was also used in data analysis. RESULTS: The rats in group 2 that received saline only showed neurological impairment as well as elevated mortality, and were found to have significantly increased levels of MDA and caspase-3, but reduced SOD activities in brain tissues (P < 0.05). When treated with MCI-186 at two different dosages, the rats in groups 3 and 4 had markedly decreased levels of MDA and caspase-3 but increased SOD activities in the brain tissue (P < 0.05), along with improved scores of neurological evaluation (P < 0.05). CONCLUSIONS: This study sheds some lights on the therapy of SAH-induced early brain injury by providing the promising data indicating that MCI-186, a radical scavenger, can efficiently diminish apoptosis of neurons and thus prevent the function loss of the brain in rats with SAH.