Bridging integrator 1 fragment accelerates tau aggregation and propagation by enhancing clathrin-mediated endocytosis in mice.

The bridging integrator 1 (BIN1) gene is an important risk locus for late-onset Alzheimer's disease (AD). BIN1 protein has been reported to mediate tau pathology, but the underlying molecular mechanisms remain elusive. Here, we show that neuronal BIN1 is cleaved by the cysteine protease legumain at residues N277 and N288. The legumain-generated BIN1 (1-277) fragment is detected in brain tissues from AD patients and tau P301S transgenic mice. This fragment interacts with tau and accelerates its aggregation. Furthermore, the BIN1 (1-277) fragment promotes the propagation of tau aggregates by enhancing clathrin-mediated endocytosis (CME). Overexpression of the BIN1 (1-277) fragment in tau P301S mice facilitates the propagation of tau pathology, inducing cognitive deficits, while overexpression of mutant BIN1 that blocks its cleavage by legumain halts tau propagation. Furthermore, blocking the cleavage of endogenous BIN1 using the CRISPR/Cas9 gene-editing tool ameliorates tau pathology and behavioral deficits. Our results demonstrate that the legumain-mediated cleavage of BIN1 plays a key role in the progression of tau pathology. Inhibition of legumain-mediated BIN1 cleavage may be a promising therapeutic strategy for treating AD.

Cholestanol accelerates α-synuclein aggregation and spreading by activating asparagine endopeptidase.

Cerebrotendinous xanthomatosis (CTX), an autosomal recessive disorder characterized by high levels of cholestanol in the blood and accumulation of cholestanol in multiple tissues, especially the brain, often presents in parkinsonism. However, it remains unknown whether cholestanol plays a role in the pathogenesis of sporadic Parkinson's disease (PD). Here, we show that the levels of serum cholestanol in patients with sporadic PD are higher than those in control participants. Cholestanol activates the protease asparagine endopeptidase (AEP) and induces the fragmentation of α-synuclein (α-syn) and facilitates its aggregation. Furthermore, cholestanol promotes the spreading of α-syn pathology in a mouse model induced by intrastriatal injection of α-syn fibrils. KO of AEP or administration of an AEP inhibitor ameliorates α-syn pathology, degeneration of the nigrostriatal dopaminergic pathway, and PD-like motor symptoms. These results not only indicate that cholestanol contributes to the aggregation and spreading of α-syn by activating AEP but also reveal an opportunity for treating PD with AEP inhibitors.

A predictive model for social participation of middle-aged and older adult stroke survivors: the China Health and Retirement Longitudinal Study.

Objective: This study aims to develop and validate a prediction model for evaluating the social participation in the community middle-aged and older adult stroke survivors. Methods: The predictive model is based on data from the China Health and Retirement Longitudinal Study (CHARLS), which focused on individuals aged 45 years or older. The study utilized subjects from the CHARLS 2015 and 2018 wave, eighteen factors including socio-demographic variables, behavioral and health status, mental health parameters, were analyzed in this study. To ensure the reliability of the model, the study cohort was randomly split into a training set (70%) and a validation set (30%). The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was used to identify the most effective predictors of the model through a 10-fold cross-validation. The logistic regression model was employed to investigate the factors associated with social participation in stroke patients. A nomogram was constructed to develop a prediction model. Calibration curves were used to assess the accuracy of the nomogram model. The model's performance was evaluated using the area under the curve (AUC) and decision curve analysis (DCA). Result: A total of 1,239 subjects with stroke from the CHARLS database collected in 2013 and 2015 wave were eligible in the final analysis. Out of these, 539 (43.5%) subjects had social participation. The model considered nineteen factors, the LASSO regression selected eleven factors, including age, gender, residence type, education level, pension, insurance, financial dependence, physical function (PF), self-reported healthy,cognition and satisfaction in the prediction model. These factors were used to construct the nomogram model, which showed a certain extent good concordance and accuracy. The AUC values of training and internal validation sets were 0.669 (95%CI 0.631-0.707) and 0.635 (95% CI 0.573-0.698), respectively. Hosmer-Lemeshow test values were p = 0.588 and p = 0.563. Calibration curves showed agreement between the nomogram model and actual observations. ROC and DCA indicated that the nomogram had predictive performance. Conclusion: The nomogram constructed in this study can be used to evaluate the probability of social participation in middle-aged individuals and identify those who may have low social participation after experiencing a stroke.

Research on depression in Parkinson disease: A bibliometric and visual analysis of studies published during 2012-2021.

BACKGROUND: The diagnosis and treatment rate of Parkinson disease (PD) with depression has a low diagnostic rate, and there is no consensus on the choice of treatment mode. This study evaluates the global research trends of scientific outputs related to depression in PD from multiple perspectives, using a bibliometric analysis and visualization tool to scientifically analyze the knowledge from the literature. METHODS: Literature related to depression in PD published from 2012 to 2021 was included and selected from the Web of Science Core Collection database in October 2021. CiteSpace software was used to visualize and analyze co-occurrence analyses for countries, institutions, authors, and keywords. RESULTS: A total of 4533 articles from the Web of Science database were included. The United States made the largest contribution with the majority of publications (1215; 29.40%). Toronto University was the most productive institution. PD, depression, quality of life, dementia, nonmotor symptom, prevalence, anxiety, Alzheimer disease, symptom, and disorder would be significantly correlated with depression in PD. The current hot spots in this field focus on the following: risk factors for depression in PD, assessment scale of depression in PD, and rehabilitation of depression in PD. CONCLUSIONS: This analysis not only reveals the current research trends and hotspots but also provides some instructive suggestions on the development of depression in PD.

Serum Iron Level as a Potential Predictor of Coronavirus Disease 2019 Severity and Mortality: A Retrospective Study.

BACKGROUND: Various types of pulmonary diseases are associated with iron deficiency. However, information on iron status in coronavirus disease 2019 (COVID-19) is scarce. METHODS: This study included 50 hospitalized patients with confirmed COVID-19. The role of serum iron in predicting severity and mortality of COVID-19 was evaluated. RESULTS: The most common symptoms of COVID-19 patients in this study were cough (82%), fever (64%), and chest distress (42%). Of the 50 patients, 45 (90%) patients had abnormally low serum iron levels (<7.8 µmol/L). The severity of COVID-19 was negatively correlated with serum iron levels before and after treatment and was positively correlated with C-reactive protein, serum amyloid A, D-dimer, lactate dehydrogenase, urea nitrogen, and myoglobin levels. Decreased serum iron level could predict the transition of COVID-19 from mild to severe and critical illness. Seven (53.8%) patients with a lower serum iron level after treatment in the critical group had died. There was a significant difference in posttreatment serum iron levels between COVID-19 survivors and nonsurvivors. CONCLUSIONS: Serum iron deficiency was detected in the patients with COVID-19. The severity and mortality of the disease was closely correlated with serum iron levels. Low serum iron concentration was an independent risk factor for death in COVID-19 patients.

Longitudinal Change of Severe Acute Respiratory Syndrome Coronavirus 2 Antibodies in Patients with Coronavirus Disease 2019.

BACKGROUND: A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently emerged and caused the rapid spread of coronavirus disease 2019 (COVID-19) worldwide. METHODS: We did a retrospective study and included COVID-19 patients admitted to Renmin Hospital of Wuhan University between 1 February and 29 February 2020. Antibody assay was conducted to detect COVID-19 envelope protein E and nucleocapsid protein N antigen. RESULTS: One hundred twelve patients were recruited with symptoms of fever, cough, fatigue, myalgia, and diarrhea. All patients underwent antibody tests. Fifty-eight (51.79%) were positive for both immunoglobulin M (IgM) and immunoglobulin G (IgG), 7 (6.25%) were negative for both antibodies, 1 (0.89%) was positive for only IgM, and 46 (41.07%) were positive for only IgG. IgM antibody appeared within a week post-disease onset, lasted for 1 month, and gradually decreased, whereas IgG antibody was produced 10 days after infection and lasted for a longer time. However, no significant difference in levels of IgM and IgG antibodies between positive and negative patients of nucleic acid test after treatment was found. CONCLUSIONS: Our results indicate that serological tests could be a powerful approach for the early diagnosis of COVID-19.

Coronavirus Disease 2019-related dyspnea cases difficult to interpret using chest computed tomography.

Patients with Coronavirus Disease 2019 (COVID-19) often have clinical characteristics, such as chest tightness and dyspnea. Continuous, unresolved dyspnea often indicates the progression of lung lesions. The mechanism that underlies the chest distress and dyspnea in patients with COVID-19 is still unclear. Chest CT has a higher sensitivity and can play an essential role in the diagnosis and treatment of the disease. However, our clinical observations showed that although some patients had significant chest distress and dyspnea, the lesions that were observed in the lungs during computed tomography were milder and not completely consistent with clinical symptoms. We analyzed the clinical characteristics, laboratory test results, and imaging findings of these patients. We found that extensive inflammation of the bilateral and respiratory bronchioles in patients with COVID-19 due to excessive activation of proinflammatory cytokines and chemotactic aggregation of T-lymphocytes at the site of inflammation are possible mechanisms underlying chest distress and dyspnea in patients with COVID-19. Short-time and lose-dose use of corticosteroid may be helpful to treat chest tightness and dyspnea in mild COVID-19 patients. Through this study, we aimed to improve our understanding of the pathogenesis of COVID-19.

LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP.

Glutamate overactivity in basal ganglia critically contributes to the exacerbation of dopaminergic neuron degeneration in Parkinson's disease (PD). Activation of group II metabotropic glutamate receptors (mGlu2/3 receptors), which can decrease excitatory glutamate neurotransmission, provides an opportunity to slow down the degeneration of the dopaminergic system. However, the roles of mGlu2/3 receptors in relation to PD pathology were partially recognized. By using mGlu2/3 receptors agonist (LY354740) and mGlu2/3 receptors antagonist (LY341495) in mice challenged with different cumulative doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we demonstrated that systemic injection of LY354740 reduced the level of extracellular glutamate and the extent of nigro-striatal degeneration in both acute and sub-acute MPTP mice, while LY341495 amplified the lesions in sub-acute MPTP mice only. LY354740 treatment improved behavioral dysfunctions mainly in acute MPTP mice and LY341495 treatment seemed to aggravate motor deficits in sub-acute MPTP mice. In addition, ligands of mGlu2/3 receptors also influenced the total amount of glutamate and dopamine in brain tissue. Interestingly, compared with normal mice, MPTP-treated mice abnormally up-regulated the expression of polo-like kinase 2 (PLK2)/pS129 α-synuclein and phosphorylation of Fyn/N-methyl-D-aspartate receptor subunit 2A/2B (GluN2A/2B). Both acute and sub-acute MPTP mice treated with LY354740 dose-dependently reduced all the above abnormal expression. Compared with MPTP mice treated with vehicle, mice pretreated with LY341495 exhibited much higher expression of p-Fyn Tyr416/p-GluN2B Tyr1472 and PLK2/pS129 α-synuclein in sub-acute MPTP mice models. Thus, our current data indicated that mGlu2/3 receptors ligands could influence MPTP-induced toxicity, which supported a role for mGlu2/3 receptors in PD pathogenesis.

Distinct anti-dyskinetic effects of amantadine and group II metabotropic glutamate receptor agonist LY354740 in a rodent model: An electrophysiological perspective.

L-DOPA-induced dyskinesia (LID) is a major complication of long-term dopamine replacement therapy in Parkinson's disease. Characteristic neural oscillation and abnormal activity of striatal projection neurons (SPNs) are typical pathological events of LID, which would be reliable biomarkers for assessment of novel anti-dyskinetic approach if fully profiled. Glutamate dysregulation plays a critical role in the development of LID, and the group II metabotropic glutamate receptors (mGluR2/3) is believed to regulate the release of glutamate on the presynaptic terminals and inhibits postsynaptic excitation. However, the anti-dyskinetic effect of modulating mGluR2/3 is still unclear. In this study, rats with unilateral dopaminergic lesion were injected with L-DOPA (12 mg/kg, i.p.) for seven days, while motor behavior was correlated with in vivo electrophysiology analyzing LFP and single-cell activity in both primary motor cortex and dorsolateral striatum. Our study showed that as LID established, high γ oscillation (hγ) predominated during LID, the number of unstable responses of SPN to dopamine increased, and the coherence between these patterns of oscillation and spiking activity also increased. We found that pretreatment of NMDA receptor antagonist, amantadine 60 mg/kg, i.p. (AMAN) significantly reduced abnormal involuntary movements (AIMs), in parallel with the reduction of hγ oscillation, and more markedly with a decrease in unstable responses of SPNs. In contrast, a mGluR2/3 agonist, LY354740 12 mg/kg, i.p. (LY) significantly shortened the duration of LID but merely exhibited a weak effect in diminishing the intensity of LID or reversing SPN responses. Together results indicate that AIMs in the rat model of PD are associated with abnormal corticostriatal signaling, which could be reversed by NMDAR antagonism more efficiently than mGluR2/3 agonism.

Upregulation of ATG7 attenuates motor neuron dysfunction associated with depletion of TARDBP/TDP-43.

A shared neuropathological hallmark in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is nuclear clearance and cytoplasmic aggregation of TARDBP/TDP-43 (TAR DNA binding protein). We previously showed that the ability of TARDBP to repress nonconserved cryptic exons was impaired in brains of patients with ALS and FTD, suggesting that its nuclear depletion contributes to neurodegeneration. However, the critical pathways impacted by the failure to repress cryptic exons that may contribute to neurodegeneration remain undefined. Here, we report that transcriptome analysis of TARDBP-deficient neurons revealed downregulation of ATG7, a critical gene required for macroautophagy/autophagy. Mouse and Drosophila models lacking TARDBP/TBPH in motor neurons exhibiting age-dependent neurodegeneration and motor deficits showed reduction of ATG7 and accumulation of SQSTM1/p62 inclusions. Importantly, genetic upregulation of the autophagy pathway improved motor function and survival in TBPH-deficient flies. Together with our observation that ATG7 is reduced in ALS-FTD brain tissues, these findings identify the autophagy pathway as one key effector of nuclear depletion of TARDBP that contributes to neurodegeneration. We thus suggest that the autophagy pathway is a therapeutic target for ALS-FTD and other disorders exhibiting TARDBP pathology.Abbreviations: ALS: amyotrophic lateral sclerosis; ANOVA: analysis of variance; ChAT: choline acetyltransferase; CTSD: cathepsin D; FTD: frontotemporal dementia; LAMP1: lysosomal associated membrane protein 1; NMJ: neuromuscular junction; RBFOX3/NeuN: RNA binding fox-1 homolog 3; SQSTM1: sequestosome 1; TARDBP/TDP-43: TAR DNA binding protein 43.

Involvement of p38 mitogen-activated protein kinase in altered expressions of AQP1 and AQP4 after carbon monoxide poisoning in rat astrocytes.

Cerebral oedema is a major pathological change of acute carbon monoxide (CO) poisoning, the pathogenesis of which is still unclear. In the aquaporin (AQP) water channel family, AQP1 and AQP4 play critical roles in the progress of cerebral oedema of various neuropathological events. However, their functions in CO poisoning have not been demonstrated. In this study, we investigated the expressions of AQPs and associated mechanisms of brain injury in an acute CO poisoning rat model. Compared with the control injected intraperitoneally with equal volume of air, the dry weight/wet weight (DW/WW) ratio of brain water content, levels of AQP1, AQP4, phosph-p38 mitogen-activated protein kinase (p-p38 MAPK) and astrocyte marker, glial fibrillary acidic protein (GFAP) in the frontal cortex and hippocampal CA1 of acute CO poisoning group significantly increased at 6, 12, 24 hours after CO injection. Intracerebroventricular injection with a p38 MAPK inhibitor, SB203580 (200 µmol/L/kg/d), before CO injection reduced water content in the brain tissues and significantly decreased levels of AQP1, AQP4, p-p38 MAPK and GFAP. Therefore, our study showed that the overexpressions of AQP1 and AQP4 were involved in the development of CO poisoning-induced cerebral oedema, which could be attenuated by inhibition of p-p38 MAPK signalling. Manipulation of AQPs and p38 MAPK may be a new therapeutic strategy for acute CO poisoning.

7,8-Dihydroxyflavone Protects Nigrostriatal Dopaminergic Neurons from Rotenone-Induced Neurotoxicity in Rodents.

7,8-Dihydroxyflavone (7,8-DHF) is thought to be a promising therapeutic agent for various neurodegenerative diseases. The major purpose of this study was to investigate the neuroprotective effects of 7,8-DHF on the rotenone-induced motor deficit of Parkinson's disease. Nine-month-old rats were treated with rotenone (2 mg/kg/day, i.h.) for 5 weeks to establish the animal model of Parkinson's disease (PD), and 7,8-DHF (5 mg/kg, i.p.) was administrated daily throughout the whole period of rotenone injection. Five weeks later, an open field test was used to assess the motor ability of the animals. TH immunostaining was performed to evaluate rotenone-induced neurotoxicity on substantia nigra (SN) dopaminergic neurons and the DA terminals in the striatum. Western blot analyses were used to examine the expressions of TH, BDNF/TrkB signaling cascades, phospho-α-synuclein (Ser129), α-synuclein, and phospho-tau (Ser396) in SN. The results revealed that treatment with 7,8-DHF improved PD model's behavioral performance and reduced dopaminergic neuron loss in the SN and striatum, associated with the activation of TrkB receptors and its signaling cascades, and reduced p-MAPK, p-α-synuclein, and p-tau. Collectively, these results indicated that 7,8-DHF displayed prominent neuroprotective properties, providing a promising therapeutic strategy for PD treatment.

2',3'-Dideoxycytidine, a DNA Polymerase-ß Inhibitor, Reverses Memory Deficits in a Mouse Model of Alzheimer's Disease.

The etiology and pathogenesis of Alzheimer's disease (AD) are not fully understood. Thus, there are no drugs available that can provide a cure for it. We and others found that DNA polymerase-ß (DNA pol-ß) is required for neuronal death in several neurodegenerative models. In the present study, we tested the effect of a DNA pol-ß inhibitor 2',3'- Dideoxycytidine (DDC) in AD models both in vitro and in vivo. DDC protected primary neurons from amyloid-ß (Aß)-induced toxicity by inhibiting aberrant DNA replication mediated by DNA pol- ß. Chronic oral administration of DDC alleviated Aß deposition and memory deficits in the Tg2576 mouse model of AD. Moreover, DDC reversed synaptic loss in Tg2576 mice. These results suggest that DDC represents a novel therapeutic agent for the treatment of AD.

TRH Analog, Taltirelin Improves Motor Function of Hemi-PD Rats Without Inducing Dyskinesia via Sustained Dopamine Stimulating Effect.

Thyrotropin-releasing hormone (TRH) and its analogs are able to stimulate the release of the endogenic dopamine (DA) in the central nervous system. However, this effect has not been tested in the Parkinson's disease (PD), which is characterized by the DA deficiency due to the dopaminergic neurons loss in the substantia nigra. Here, we investigated the therapeutic effect of Taltirelin, a long-acting TRH analog on 6-hydroxydopamine-lesioned hemi-Parkinsonian rat model. 1-10 mg/kg Taltirelin i.p. administration significantly improved the locomotor function and halted the electrophysiological abnormities of PD animals without inducing dyskinesia even with high-dose for 7 days treatment. Microdialysis showed that Taltirelin gently and persistently promoted DA release in the cortex and striatum, while L-DOPA induced a sharp rise of DA especially in the cortex. The DA-releasing effect of Taltirelin was alleviated by reserpine, vanoxerine (GBR12909) or AMPT, indicating a mechanism involving vesicular monoamine transporter-2 (VMAT-2), dopamine transporter (DAT) and tyrosine hydroxylase (TH). The in vivo and in vitro experiments further supported that Taltirelin affected the regulation of TH expression in striatal neurons, which was mediated by p-ERK1/2. Together, this study demonstrated that Taltirelin improved motor function of hemi-PD rats without inducing dyskinesia, thus supporting a further exploration of Taltirelin for PD treatment.

LRRK2 G2019S Mutation Inhibits Degradation of α-Synuclein in an In Vitro Model of Parkinson's Disease.

The G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of Parkinson's disease (PD). However, the molecular mechanisms of LRRK2 mutation contributing to the onset and progression of PD have not been fully illustrated. We generated HEK293 cells stably transfected with α-synuclein and investigated the effect of LRRK2 G2019S mutation on the degradation of α-synuclein. The lysosomal activity was assessed by the protein degradation of glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A. It was found that α-synuclein was mainly degraded in lysosomes. LRRK2 G2019S inhibited the degradation of α-synuclein, and promoted its aggregation. LRRK2 G2019S also decreased the activities of lysosomal enzymes including cathepsin B and cathepsin L. Furthermore, the inhibitory effect of LRRK2 G2019S on lysosomal functions did not depend on its kinase activity. These findings indicated that the inhibitory effect of LRRK2 G2019S on α-synuclein degradation could underlie the pathogenesis of aberrant α-synuclein aggregation in PD with LRRK2 mutation.

Bilateral Implantation of Shear Stress Modifier in ApoE Knockout Mouse Induces Cognitive Impairment and Tau Abnormalities.

Vascular cognitive impairment (VCI) encompasses all causes of cerebrovascular disease that lead to cognitive decline, or overt dementia, atherosclerotic disease being the most common contributor. However, few rodent models that mimic the pathology of VCI replicated the clinical cerebrovascular atherosclerosis. Here we aimed to investigate the mechanism underlying VCI in an Apolipoprotein E knockout (ApoE-KO) mouse model fed with western style food with implantation of bilateral shear stress modifiers. We established a cognitive decline in spatial learning and memory developed in the bilateral modifier treated mice. Brain imaging and pathological examinations demonstrated reduced glucose intake and neuronal loss in hippocampus. Although no amyloid plaques or neurofibrillary tangles (NFTs) were observed, tau pathology including hyperphosphorylation, paired helical filament formation and pathologic truncation were found at considerable higher extent in the bilateral modifier group 8 weeks post the procedure. In addition, gliosis and microglia activation were confirmed in corpus callosum (CC) and ventral striatum. Thus, this ApoE-KO mouse model faithfully replicates the stenosis of common carotid artery (CCA) and cognitive impairment following atherosclerotic deposition and global cerebral hypoperfusion. The close correlation of cognitive decline and tau pathology indicates the toxic tau species could be at least partially responsible for the neurodegenerative changes induced by the chronic hypoxia/ischemia.

Targeting prion-like protein spreading in neurodegenerative diseases.

The infectious template-mediated protein conversion is a unique mechanism for the onset of rare and fatal neurodegenerative disorders known as transmissible spongiform encephalopathies, or prion diseases, which affect humans and other animal species. However, emerging studies are now demonstrating prion-like mechanisms of self-propagation of protein misfolding in a number of common, non-infectious neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. It has been proposed that distinct and unrelated proteins (beta-amyloid, tau, α-synuclein, TAR DNA-binding protein 43 and huntingtin, etc.) associated with common neurodegenerative disorders can seed conversion and spread via cell-to-cell transfer, sustaining the transmission of neurotoxic agents along a stereotypic route, sharing features at the heart of the intrinsic nature of prions. Here we review the most recent development on both the molecular mechanisms underlying the pathogenesis of prion-like neurodegenerative diseases as well as innovative methods and strategies for potential therapeutic applications.

TRH Analog, Taltirelin Protects Dopaminergic Neurons From Neurotoxicity of MPTP and Rotenone.

Dopaminergic neurons loss is one of the main pathological characters of Parkinson's disease (PD), while no suitable neuroprotective agents have been in clinical use. Thyrotropin-releasing hormone (TRH) and its analogs protect neurons from ischemia and various cytotoxins, but whether the effect also applies in PD models remain unclear. Here, we showed that Taltirelin, a long-acting TRH analog, exhibited the neuroprotective effect in both cellular and animal models of PD. The in vitro study demonstrated that Taltirelin (5 µM) reduced the generation of reactive oxygen species (ROS) induced by MPP+ or rotenone, alleviated apoptosis and rescued the viability of SH-SY5Y cells and rat primary midbrain neurons. Interestingly, SH-SY5Y cells treated with Taltirelin also displayed lower level of p-tau (S396) and asparagine endopeptidase (AEP) cleavage products, tau N368 and α-synuclein N103 fragments, accompanied by a lower intracellular monoamine oxidase-B (MAO-B) activity. In the subacute MPTP-induced and chronic rotenone-induced PD mice models, we found Taltirelin (1 mg/kg) significantly improved the locomotor function and preserved dopaminergic neurons in the substantia nigra (SN). In accordance with the in vitro study, Taltirelin down-regulated the levels of p-tau (S396), p-α-synuclein (S129) tau N368 and α-synuclein N103 fragments in SN and striatum. Together, this study demonstrates that Taltirelin may exert neuroprotective effect via inhibiting MAO-B and reducing the oxidative stress and apoptosis, preventing AEP activation and its subsequent pathological cleavage of tau and α-synuclein, thus provides evidence for Taltirelin in protective treatment of PD.

2',3'-Dideoxycytidine Protects Dopaminergic Neurons in a Mouse Model of Parkinson's Disease.

DNA polymerase-ß (DNA pol-ß) plays a crucial role in the pathogenesis of Parkinson's disease (PD). The aim of this study was to investigate the neuroprotective effects of a DNA polymerase-ß inhibitor 2',3'-dideoxycytidine (DDC) in PD models. In the in vitro studies, primary cultured neurons were challenged with 1-methyl-4-phenylpyridinium ion (MPP+). The expression of DNA pol-ß was assessed using western blot. The neuroprotective effect of DNA pol-ß knockdown and DNA pol-ß inhibitor DDC was determined using cell viability assay and caspase-3 activity assay. We found that MPP+ induced neuronal death and the activation of caspase-3 in a dose-dependent manner. The expression of DNA pol-ß increased after the neurons were exposed to MPP+. DNA pol-ß siRNA or DNA pol-ß inhibitor DDC attenuated neuronal death induced by MPP+. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, MPTP treatment triggered behavioral deficits and nigrostriatal lesions. Pretreatment with DDC attenuated MPTP-induced behavioral deficits, dopaminergic neuronal death and striatal dopamine depletion in the MPTP mouse model. These results indicate that DNA pol-ß inhibitors may present a novel promising therapeutic option for the neuroprotective treatment of PD.

Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats.

L-DOPA-induced dyskinesia (LID) represents one of the major problems of the long-term therapy of patients with Parkinson's disease (PD). Although, the pathophysiologic mechanisms underlying LID are not completely understood, activation of the extracellular signal regulated kinase (ERK) is recognized to play a key role. ERK is phosphorylated by mitogen-activated protein kinase kinase (MEK), and thus MEK inhibitor can prevent ERK activation. Here the effect of the MEK inhibitor PD98059 on LID and the associated molecular changes were examined. Rats with unilateral 6-OHDA lesions of the nigrostriatal pathway received daily L-DOPA treatment for 3 weeks, and abnormal involuntary movements (AIMs) were assessed every other day. PD98059 was injected in the lateral ventricle daily for 12 days starting from day 10 of L-DOPA treatment. Striatal molecular markers of LID were analyzed together with gene regulation using microarray. The administration of PD98059 significantly reduced AIMs. In addition, ERK activation and other associated molecular changes including ΔFosB were reversed in rats treated with the MEK inhibitor. PD98059 induced significant up-regulation of 418 transcripts and down-regulation of 378 transcripts in the striatum. Tyrosine hydroxylase (Th) and aryl hydrocarbon receptor nuclear translocator (Arnt) genes were down-regulated in lesioned animals and up-regulated in L-DOPA-treated animals. Analysis of protein levels showed that PD98059 reduced the striatal TH. These results support the association of p-ERK1/2, ΔFosB, p-H3 to the regulation of TH and ARNT in the mechanisms of LID, and pinpoint other gene regulatory changes, thus providing clues for identifying new targets for LID therapy.