Two new cases with the UBQLN2 gene mutation in Han Chinese.

Variations in the UBQLN2 gene are associated with a group of diseases with X-linked dominant inheritance and clinical phenotypes of amyotrophic lateral sclerosis (ALS) and/or frontal temporal lobe dementia (FTD). Cases with UBQLN2 variations have been rarely reported worldwide. The reported cases exhibit strong clinical heterogeneity. Here, we report two adult-onset cases with UBQLN2 variations in Han Chinese. Whole exome sequencing revealed the hemizygous P506S (c.1516C > T) and the heterozygous P509S variation (c.1525C > T), both of which were located within the hotspot mutation region. The patient with the P506S variation was a 24-year-old male. The clinical feature was spastic paraplegia without lower motor neuron damage. The patient's mother was an asymptomatic heterozygote carrier with skewed X-chromosome inactivation. The patient with the P509S variation was a 63-year-old female. Clinical features included ALS and parkinsonism. 18F-fluorodopa PET-CT revealed presynaptic dopaminergic deficits in bilateral posterior putamen. These cases further highlight the clinical heterogeneity of UBQLN2 cases.

The severity of corneal nerve loss differentiates motor subtypes in patients with Parkinson's disease.

Background: Parkinson's disease (PD) is a heterogeneous movement disorder with patients manifesting with either tremor-dominant (TD) or postural instability and gait disturbance (PIGD) motor subtypes. Small nerve fiber damage occurs in patients with PD and may predict motor progression, but it is not known whether it differs between patients with different motor subtypes. Objective: The aim of this study was to explore whether there was an association between the extent of corneal nerve loss and different motor subtypes. Methods: Patients with PD classified as TD, PIGD, or mixed subtype underwent detailed clinical and neurological evaluation and corneal confocal microscopy (CCM). Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) were compared between groups, and the association between corneal nerve fiber loss and motor subtypes was investigated. Results: Of the 73 patients studied, 29 (40%) had TD, 34 (46%) had PIGD, and 10 (14%) had a mixed subtype. CNFD (no./mm2, 24.09 ± 4.58 versus 28.66 ± 4.27; p < 0.001), CNBD (no./mm2, 28.22 ± 11.11 versus 37.37 ± 12.76; p = 0.015), and CNFL (mm/mm2, 13.11 ± 2.79 versus 16.17 ± 2.37; p < 0.001) were significantly lower in the PIGD group compared with the TD group. Multivariate logistic regression showed that higher CNFD (OR = 1.265, p = 0.019) and CNFL (OR = 1.7060, p = 0.003) were significantly associated with the TD motor subtype. The receiver operating characteristic (ROC) analysis demonstrated that combined corneal nerve metrics showed excellent discrimination between TD and PIGD, with an area under the curve (AUC) of 0.832. Conclusion: Greater corneal nerve loss occurs in patients with PIGD compared with TD, and patients with a higher CNFD or CNFL were more likely to have the TD subtype. CCM may have clinical utility in differentiating different motor subtypes in PD.

Corneal confocal microscopy differentiates patients with Parkinson's disease with and without autonomic involvement.

Autonomic dysregulation in Parkinson's disease (PD) can precede motor deficits and is associated with reduced quality of life, disease progression, and increased mortality. Objective markers of autonomic involvement in PD are limited. Corneal confocal microscopy (CCM) is a rapid ophthalmic technique that can quantify small nerve damage in a range of peripheral and autonomic neuropathies. Here we investigated whether CCM can be used to assess autonomic symptoms in PD. Based on the scale for outcomes in Parkinson's disease for autonomic symptoms (SCOPA-AUT), patients with PD were classified into those without autonomic symptoms (AutD-N), with single (AutD-S), and multiple (AutD-M) domain autonomic dysfunction. Corneal nerve fiber pathology was quantified using CCM, and the relationship with autonomic symptoms was explored. The study enrolled 71 PD patients and 30 control subjects. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and CNBD/CNFD ratio were lower in PD patients with autonomic symptoms compared to those without autonomic symptoms. Autonomic symptoms correlated positively with CNFD (r = -0.350, p = 0.004), and were not related to Levodopa equivalent daily dose (r = 0.042, p = 0.733) after adjusting for age, disease severity, disease duration or cognitive function. CCM parameters had high sensitivity and specificity in distinguishing patients with PD with and without autonomic symptoms. PD patients with autonomic symptoms have corneal nerve loss, and CCM could serve as an objective ophthalmic imaging technique to identify patients with PD and autonomic symptoms.

Correlation of matrix metalloproteinase 3 and matrix metalloproteinase 9 levels with non-motor symptoms in patients with Parkinson's disease.

Objective: Matrix metalloproteinases (MMPs) are essential for tissue formation, neuronal network remodeling, and blood-brain barrier integrity. MMPs have been widely studied in acute brain diseases. However, the relationship with Parkinson's disease (PD) remains unclear. The purpose of this study was to evaluate the serum MMP3 and MMP9 levels of PD patients and analyze their correlation with non-motor symptoms. Methods: In this cross-sectional study, we recruited 73 patients with idiopathic PD and 64 healthy volunteers. Serum MMP3 and MMP9 levels were measured by enzyme-linked immunosorbent assay (ELISA). Patients with PD were assessed for non-motor symptoms using the Non-motor Symptoms Scale (NMSS) and Parkinson's disease sleep scale (PDSS) and Mini Mental State Examination (MMSE). Results: Serum MMP3 levels were significantly decreased in PD patients, predominantly those with early-stage PD, compared with controls [12.56 (9.30, 17.44) vs. 15.37 (11.33, 24.41) ng/ml; P = 0.004], and the serum MMP9 levels of PD patients were significantly higher than those of healthy controls [522 (419, 729) vs. 329 (229, 473) ng/ml; P < 0.001]. MMP3 levels were positively correlated with the NMSS total score (r = 0.271, P = 0.020) and the single-item scores for item six, assessing the gastrointestinal tract (r = 0.333, P = 0.004), and there was an inverse correlation between serum MMP3 levels and PDSS score (r = -0.246, P = 0.036); meanwhile, MMP9 levels were positively correlated with the NMSS total score (r = 0.234, P = 0.047), and higher serum MMP9 levels were detected in the cognitive dysfunction subgroup than in the cognitively intact subgroup [658 (504, 877) vs. 502 (397, 608) ng/ml, P = 0.008]. Conclusion: The serum MMP3 level of PD patients (especially early-stage patients) was significantly lower than that of the healthy control group, and the MMP9 level was significantly higher than that of the healthy control group. MMP3 and MMP9 levels correlate with sleep disturbance and cognitive function in PD patients, respectively.

Autoimmune-mediated secondary-parkinsonism presented with micrographia and cognitive impairment.

Parkinson's disease is a neurodegenerative disorder while secondary-parkinsonism can be caused by infectious, inflammatory, traumatic, vascular, hereditary, paraneoplastic, or even induced by drug/metal poisoning. Here we report an uncommon subacute parkinsonism who presented with micrographia and mild cognitive impairment. The CSF examination showed inflammatory profile and positive anti-NMDAR antibody. The patient showed no improvement with levodopa/benserazide administration but satisfactory response to immunotherapy with methylprednisolone. This case indicated that autoimmune etiology should also be considered in parkinsonism to exclude a treatable condition.

Corneal nerve fiber loss relates to cognitive impairment in patients with Parkinson's disease.

Cognitive impairment in Parkinson's disease (PD) adversely influences quality of life. There is currently no available biomarker to predict cognitive decline in PD. Corneal confocal microscopy (CCM) has been used as a non-invasive tool for quantifying small nerve damage in PD. The present study investigated whether corneal nerve measures were associated with cognitive function in PD. Patients with PD were classified into those with normal cognitive function (PD-CN), mild cognitive impairment (PD-MCI), and dementia (PDD). Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) were quantified with CCM and compared with a control group. Sixty-five PD patients and thirty controls were studied. CNFD was decreased and CNBD was increased in PD patients compared to controls (P < 0.05). CNBD and CNBD/CNFD ratio was higher in PD-CN compared to controls. CNFD was positively correlated with the Montreal cognitive assessment (MoCA) score (r = 0.683, P < 0.001), but negatively associated with unified Parkinson disease rating scale (UPDRS)-part III (r = -0.481, P < 0.001) and total UPDRS scores (r = -0.401, P = 0.001) in PD patients. There was no correlation between CNFD and Levodopa equivalent daily dose (LEDD) (r = 0.176, P = 0.161). CNFD, CNBD, CNFL, and CNBD/CNFD ratio was lower with increasing Hoehn and Yahr stage. PD patients show evidence of corneal nerve loss compared with controls and corneal nerve parameters are associated with the severity of cognitive and motor dysfunction in PD. CCM could serve as an objective in vivo ophthalmic imaging technique to assess neurodegeneration in PD.

Long non-coding RNA CIR inhibits chondrogenic differentiation of mesenchymal stem cells by epigenetically suppressing ATOH8 via methyltransferase EZH2.

BACKGROUND: Osteoarthritis (OA) is the most common articular disorder, leading to joint malfunction and disability. Although the incidence of OA is increasing globally, the treatment of OA is very limited. LncRNA CIR has been implicated in OA through unclear mechanisms. Here, we investigated the role of lncRNA CIR in chondrogenic differentiation. METHODS: Human umbilical-cord-derived mesenchymal stem cells (hUC-MSCs) were obtained from human umbilical cords. Flow cytometry was used to analyze the surface markers of hUC-MSCs. Various culture conditions and corresponding staining assays were employed to assess the differentiation abilities of hUC-MSC. qRT-PCR, western blot, and immunostaining were used to measure expression levels of related genes and proteins such as lncRNA CIR, ATOH8, EZH2, and H3K27me3. RNA immunoprecipitation assay, biotin pull-down, and chromatin immunoprecipitaion assay were performed to analyze the interactions of lncRNA CIR, EZH2, H3K27me3 and ATOH8 promoter. RESULTS: hUC-MSCs exhibited MSCs features and could differentiate into chondrocytes under specific conditions. LncRNA CIR was downregulated while ATOH8 was upregulated during the chondrogenic differentiation of hUC-MSCs. Knockdown lncRNA CIR or overexpression of ATOH8 promoted chondrogenic differentiation. Further, lncRNA CIR bound to EZH2 and repressed ATOH8 expression via EZH2-mediated H3K27me3, which promotes the methylation of ATOH8. Inhibition of ATOH8 reversed the effects of knockdown lncRNA CIR on chondrogenic differentiation. CONCLUSION: LncRNA CIR suppresses chondrogenic differentiation of hUC-MSCs. Mechanistically, lncRNA CIR could inhibit ATOH8 expression that functions to promote chondrogenic differentiation through EZH2-mediated epigenetic modifications.

Potential use of corneal confocal microscopy in the diagnosis of Parkinson's disease associated neuropathy.

Parkinson's disease (PD) is a chronic, progressive neurodegenerative disease affecting about 2-3% of population above the age of 65. In recent years, Parkinson's research has mainly focused on motor and non-motor symptoms while there are limited studies on neurodegeneration which is associated with balance problems and increased incidence of falls. Corneal confocal microscopy (CCM) is a real-time, non-invasive, in vivo ophthalmic imaging technique for quantifying nerve damage in peripheral neuropathies and central neurodegenerative disorders. CCM has shown significantly lower corneal nerve fiber density (CNFD) in patients with PD compared to healthy controls. Reduced CNFD is associated with decreased intraepidermal nerve fiber density in PD. This review provides an overview of the ability of CCM to detect nerve damage associated with PD.

[Research on regional distribution and industrial status analysis of genuine medicinal resources of flowers in Henan province].

Flower medicinal materials usually refer to Chinese medicinal materials with a complete flower,inflorescence,or part of a flower as the different medicinal parts,they have an important share in the Chinese herbal medicine market and appeared frequently in Chinese medicine prescriptions. Firstly,the species and regional distribution of the flower medicinal materials resources in China were briefly summarized. Secondly,the characteristics,yield,producing area and origin distribution of the main flower medicinal materials in Henan province were discussed. Finally,the present situation and the main problems of the flower medicinal materials industry in Henan province were comprehensively analyzed,and the corresponding industrial development countermeasures were put forward.This research was intended to provide decision-making demonstration and scientific basis for the rational exploitation and utilization of resources,breeding of new varieties,planting division,production layout and the healthy and sustainable development of the flower medicinal materials industry in Henan province.

A mitovirus isolated from the phytopathogenic fungus Alternaria brassicicola.

Alternaria brassicicola is one of the causal agents of alternaria blackspot in rapeseed. In this study, a dsRNA segment was isolated and sequenced from the fungus. The complete nucleotide sequence of the dsRNA was 2506 bp in length and, using the fungal mitochondrial genetic code, was predicted to contain a single large open reading frame (ORF) in the positive strand. This ORF was predicted to encode a protein with 719 amino acids that contains characteristic conserved motifs of the RNA-dependent RNA polymerase (RdRp). BLAST analysis revealed that this protein had significant sequence similarity to the RdRp from viruses of the genus Mitovirus. These results indicated that the dsRNA segment represents the replicative form of a mitovirus, which is tentatively designated "Alternaria brassicicola mitovirus 1" (AbMV1) and is a new member of the genus Mitovirus in the family Narnaviridae.

Clinical Profiles and Short-Term Outcomes of Acute Disseminated Encephalomyelitis in Adult Chinese Patients.

BACKGROUND AND PURPOSE: Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder that predominantly affects children. Previous studies have mostly involved children in Western developed countries. METHODS: This study retrospectively reviewed the clinical profiles of ADEM in adult Chinese patients. RESULTS: ADEM occurred during summer and autumn in about two-thirds of the 42 included patients. Prior infection was found in five patients and no preimmunization was recorded. The most frequent clinical presentations were alterations in consciousness (79%) and behavior changes (69%), followed by motor deficits (64%) and fever (50%). About one-quarter (26%) of the patients showed positive results for oligoclonal bands, and about half of them exhibited increases in the IgG index and 24-hour IgG synthesis rate. Magnetic resonance imaging showed white- and gray-matter lesions in 83% and 23% of the patients, respectively. Steroids were the main treatment, and full recovery occurred in 62% of the patients, with residual focal neurological deficits recorded in a few patients. After a mean follow-up period of 3.4 years, two patients exhibited recurrence and one patient exhibited a multiphasic course. One patient was diagnosed with multiple sclerosis (MS). CONCLUSIONS: With the exception of the seasonal distribution pattern and prior vaccine rate, the clinical profiles of ADEM in adult Chinese patients are similar to those in pediatric populations. No specific markers are available for distinguishing ADEM from MS at the initial presentation. Careful clinical evaluations, cerebrospinal fluid measurements, and neuroradiological examinations with long-term follow-up will aid the correct diagnosis of ADEM.

The effect of amifostine on differentiation of the human megakaryoblastic Dami cell line.

Amifostine is a cytoprotective drug that was initially used to control and treat nuclear radiation injury and is currently used to provide organ protection in cancer patients receiving chemotherapy. Clinical studies have also found that amifostine has some efficacy in the treatment of cytopenia caused by conditions such as myelodysplastic syndrome and immune thrombocytopenia, both of which involve megakaryocyte maturation defects. We hypothesized that amifostine induced the differentiation of megakaryocytes and investigated this by exposing the human Dami megakaryocyte leukemia cell line to amifostine (1 mmol/L). After 12 days of amifostine exposure, optical microscopy showed that the proportion of Dami cells with diameters >20 µm had increased to 24.63%. Transmission electron microscopy identified the development of a platelet demarcation membrane system, while flow cytometry detected increased CD41a expression and decreased CD33 expression on the Dami cell surface. Ploidy analysis found that the number of polyploid cells with >4N DNA content increased to 27.96%. We did not detect any elevation in the mRNA or protein levels of megakaryocytic differentiation-associated transcription factors GATA-binding factor 1 (GATA-1) and nuclear factor, erythroid 2 (NF-E2), but nuclear import assay revealed an increased nuclear translocation of these proteins. These findings indicate that amifostine induced the differentiation of Dami cells into mature megakaryocytes via a mechanism involving increased nuclear translocation of the transcription factors, NF-E2 and GATA-1.

Mailuoning for acute ischaemic stroke.

BACKGROUND: Mailuoning is widely used in the treatment of acute ischaemic stroke in China. Animal experimental studies and clinical pharmacological research indicate that mailuoning might improve blood circulation, prevent ischaemic injury, and protect heart and brain tissue. This review was last published in 2009. As new data have become available, it is necessary to reassess the evidence from randomised controlled trials. OBJECTIVES: To determine the effects and safety of mailuoning agents (injection or oral liquid) in the treatment of people with acute ischaemic stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (May 2014), the Cochrane Central Register of Controlled Trials (CENTRAL;2014, Issue 4), MEDLINE (1966 to May 2014), Embase (1980 to May 2014), AMED (1985 to May 2014), the Chinese Stroke Trials Register (June 2014), the China Biological Medicine Database (CBM-disc; 1979 to June 2014), China Science and Technology Journal database (CSTJ; 1979 to June 2014), Wanfang Data Chinese databases (1979 to June 2014), and the China National Knowledge Infrastructure (1979 to June 2014). We searched clinical trials and research registers, handsearched 10 Chinese journals including relevant conference proceedings, scanned reference lists, and contacted the pharmaceutical company that manufactures mailuoning. We also attempted to contact trial authors to obtain further data. SELECTION CRITERIA: Randomised controlled trials comparing mailuoning with placebo or mailuoning plus other treatment compared with that other treatment in people with acute ischaemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trial quality, and extracted data. MAIN RESULTS: We included 21 trials, involving 1746 participants, in this update; six trials were new. The included trials did not report the numbers of dead and dependent participants at the end of at least three months' follow-up. Of the 12 trials that reported adverse events, five events occurred in two trials. There was no significant difference between the treatment group and the control group. We assessed 20 trials to be of a poor quality: When analysing these trials together, mailuoning was associated with a significant increase in the number of participants with an improved neurological deficit (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.23 to 0.42) and showed a significant improvement of neurological deficit with the European Stroke Scale (ESS) (mean difference (MD) (fixed) 8.29, 95% CI 3.44 to 13.15). One placebo-controlled trial, assessed to be of a better methodological quality, failed to show a significant improvement of neurological deficit at the end of three months' follow-up (MD (fixed) 2.49, 95% CI -1.45 to 6.43) or in quality of life. One trial, which reported cognitive function using the Montreal Cognitive Assessment as a continuous scale, showed a significant improvement of cognitive function (MD (fixed) 2.68, 95% CI 1.82 to 3.54). Two trials assessed activities of daily life: One trial showed a significant improvement, but the other did not. AUTHORS' CONCLUSIONS: This review did not provide sufficient evidence to support the routine use of mailuoning for the treatment of people with acute ischaemic stroke. High-quality large-scale randomised controlled trials are needed to confirm the efficacy of mailuoning.

The clinical absolute and relative scoring system-a quantitative scale measuring myasthenia gravis severity and outcome used in the traditional Chinese medicine.

Myasthenia gravis (MG) is a chronic autoimmune disease caused by autoantigen against the nicotine acetylcholine receptor at the neuromuscular junction. With modern treatment facilities, the treatment effect and outcome for MG has been greatly improved with MG and non-MG patients enjoying the same life expectancy. Many classifications of disease distribution and severity have been set up and tested all over the world, mainly in the western world. However, the absolute and relative scoring system for evaluating the severity and treatment effect of MG in China where traditional Chinese medicine (TCM) has been practiced for thousands of years has not been introduced worldwide. The TCM has achieved a great success in the treatment of MG in the country with a huge population. This article serves to introduce this scoring system to the world.

An adult case of multiphasic disseminated encephalomyelitis manifesting with optic neuritis.

A 25-year-old woman presented with a fever, headache, vomiting and somnolence. Cranial magnetic resonance imaging (MRI) showed multiple lesions in the cerebellum, brainstem, cerebral cortex and subcortex. Oligoclonal bands were positive in the cerebral spinal fluid (CSF). She experienced a good recovery after steroid treatment. Four months later, she developed right vision loss. Repeated MRI showed multiple cranial lesions different from those involved in the first attack in both size and distribution. An abnormal high signal was also observed in the front and intraorbital regions of the right optic nerve. The patient's vision progressively improved, and she obtained a full recovery following the administration of steroids. A diagnosis of multiphasic disseminated encephalomyelitis manifesting with optic neuritis was made.

Traditional Chinese medicine: a promising candidate for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder, characterized clinically by insidious onset of memory and cognition impairment, emergence of psychiatric symptoms and behavioral disorder, and impairment of activities of daily living (ADL). Traditional Chinese medicine (TCM) is practiced in the Chinese health care system for more than 2,000 years. In recent years, scientists have isolated many novel compounds from herbs, some of which improve dementia with fewer side effects than conventional drugs and are regarded as potential anti-AD drugs. In this review, we summarize the latest research progress on TCM showing their possible role of treatment of AD and other demented diseases and possible pharmacological actions.

[Anti-motion sickness efficacy of the extracted mixture of Chinese medical herbs and its influence on the blood level of hormones].

OBJECTIVE: To investigate the anti-motion sickness efficacy and influence on the blood level of some hormones of a Chinese prescription composed of 10 herbs such as spina date seed. METHODS: According to the report by Cramptom and Lucot, SD rats and Beagle dogs were rotated around a horizontal axis, and the rat behavior of pica for Kaolin and the latency to vomit in dog were observed. In addition, guinea pigs were rotated around a vertical axis, and the nystagmus was recorded. Blood levels of corticosterone, adrenocorticotrophic hormone (ACTH), corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) in rats were measured with radioimmunoassay. The influences of the extracted mixture of herbs on these variables were simultaneously investigated. RESULTS: Compared with control group, oral administration of the extracted mixture of herbs: (1) significantly inhibited the rat behavior of pica for Kaolin and prolonged the latency to vomit in dog dose-dependently; (2) decreased the frequency of nystagmus and mean slow phase speed in rat; (3) reduced the elevation of corticosterone, ACTH, CRH and AVP in rat blood induced by rotatory stimulation; and (4) these effects of the extracted mixture of herbs were almost identical to dimenhydrinate. CONCLUSION: (1) The extracted mixture of Chinese Medicinal Herbs we used could inhibit motion sickness effectively. (2) This drug could reduce the blood levels of hormones of hypothalamic-pituitary-adrenocortical axis and AVP elevated by provocative rotatory stimulation.

Neuroprotective effects of new protein kinase C activator TPPB against Aß25₋35 induced neurotoxicity in PC12 cells.

Alzheimer's disease (AD) is pathologically characterized by presence of senile plaques in the hippocampus, which are composed mainly of extracellular deposition of a polypeptide known as the beta amyloid, the Aß. It has been demonstrated on numerous occasions that it was the deposition and aggregation of this Aß peptide that cause neuronal dysfunction and even finally, the dementia. Lowering the deposition of Aß or decreasing its neurotoxicity has long been one of the purposes of AD therapy. In previous study, we reported that protein kinase C (PKC) activator TPPB could regulate APP processing by increasing α-secretase activity. In this study we further investigated the potential neuroprotective effect of TPPB against Aß(25-35)-induced neurotoxicity in PC12 cells. The results indicated that TPPB at concentration of 1 µM could antagonize Aß(25-35) induced cell damage as evidenced by MTT assays, LDH release and by morphological changes. Furthermore, the neuroprotection in cell viability can be blocked by inhibitors of PKC, Akt and MAPK. The experiment also indicated that TPPB could increase the phosphorylation of Akt, PKC, MARCKS and MAPK, which were inhibited by Aß(25-35) treatment. Finally, TPPB inhibited the activation of caspase-3 induced by Aß(25-35). Taken together, the experiment here implies that TPPB has a role against Aß(25-35)-induced neurotoxicity in PC12 cells and may suggest its therapeutic potential in AD.

[Effects of donepezil treatment on platelets α and ß secretase activities in Alzheimer's disease patients].

OBJECTIVE: To explore the effects of donepezil on the activities of platelet α and ß secretases in Alzheimer's disease (AD) patients. METHODS: During the period of 2007 - 2010, a total of 76 AD patients received either regular treatment alone or in combination with donepezil (5 mg/d) for a 12-week period. And their effects on ADAS-Cog (Alzheimer's disease assessment scale-cognitive subscale) total and ADL (activity of daily living) scores were measured. The effects of donepezil on α and ß secretase activities and sAPPα (soluble amyloid precursor protein α) secretion in AD patients and non-demented patients were detected by fluorescence and Western blot respectively. RESULTS: After the donepezil treatment, the ADAS-Cog scores of the treatment group decreased versus the control [(5.3 ± 4.4) vs (1.7 ± 1.6)]. And the differences were statistically significant (P < 0.01). And the ADL scores of the treatment group decreased versus the control [(41 ± 7) vs. (48 ± 6)]. And the differences were statistically significant (P < 0.05). As compared with that of pre-treatment (50 ± 6), the differences were statistically significant (P < 0.05). The activity of α secretase increased markedly while that of ß secretase decreased markedly versus the controls [(91% ± 9%) vs (64% ± 8%), P < 0.01; (119% ± 11%) vs (178% ± 17%), P < 0.01]. Both had significant statistical differences with those of pre-treatment (both P < 0.01). As compared with the non-demented group (100% ± 12%, P < 0.001), the sAPPα contents of treatment and control groups were (64% ± 14%, P < 0.01) and (26% ± 8%, P < 0.001) respectively. CONCLUSION: The administration of donepezil in AD patients improves cognitive functions and daily activities as indicated by the decreased ADAS-Cog total scores and ADL scores through the increased activity of α secretase and the decreased activity of ß secretase. The clinical efficacy of donepezil may be attributed to its pharmacological effects on the regulation of platelet secretase activities.

Blockade of the translocation and activation of c-Jun N-terminal kinase 3 (JNK3) attenuates dopaminergic neuronal damage in mouse model of Parkinson's disease.

Increasing evidence suggests that c-Jun N-terminal kinase (JNK) is an important kinase mediating neuronal death in Parkinson's disease (PD) model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). JNK3, the only neural-specific isoform, may play an important role in mediating the neurotoxic effects of MPTP in dopaminergic neuronal injury. To analyze the variation in JNK3 activation, the levels of phospho-JNK3 were measured at the various time points of occurrence of MPTP-induced lesions. In our study, we observed that during MPTP intoxication, two peaks of JNK3 activation appeared at 8 and 24h. To further define the mechanism of JNK3 activation and translocation, the antioxidant N-acetylcysteine (NAC), the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, and the alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist 6,7-dinitroquinoxaline-2,3(1H,4H)-dione (DNQX) were administered to the mice 30 min after each of the four MPTP injections. The results revealed that NAC clearly inhibited JNK3 activation during the early intoxication, whereas ketamine preferably attenuated JNK3 activation during the latter intoxication. DNQX had no significant effects on JNK3 activation during intoxication. Consequently, reactive oxygen species (ROS) and the NMDA receptor were closely associated with JNK3 activation following MPTP intoxication. NAC and ketamine exerted a preventive effect against MPTP-induced loss of tyrosine hydroxylase-positive neurons and suppressed the nuclear translocation of JNK3, suggesting that NAC and ketamine can prevent MPTP-induced dopaminergic neuronal death by suppressing JNK3 activation.