Reciprocal Induction Between ��-Synuclein and ��-Amyloid in Adult Rat Neurons

In spite of definite roles for ??-amyloid (A??) in familial Alzheimer??s disease (AD), the cause of sporadic AD remains unknown. Amyloid senile plaques and Lewy body pathology frequently coexist in neocortical and hippocampal regions of AD and Parkinson??s diseases. However, the relationship between A?? and ??-synuclein (??-Syn), the principle components in the pathological structures, in neuronal toxicity and the mechanisms of their interaction are not well studied. As A?? and ??-Syn accumulate in aging patients, the biological functions and toxicity of these polypeptides in the aging brain may be different from those in young brain. We examined the neurotoxicity influences of A??1-42 or ??-Syn on mature neurons and the effects of A??1-42 or ??-Syn on the production of endogenous ??-Syn or A??1-40 reciprocally using a model of culture enriched with primary neurons from the hippocampus of adult rats. Treatment of neurons with high concentrations of A??1-42 or ??-Syn caused significant apoptosis of neurons. Following A??1-42 treatment at sub apoptotic concentrations, both intra- and extra-cellular ??-Syn levels were significantly increased. Reciprocally, the non-toxic levels of ??-Syn treatment also increased intra- and extra-cellular A??1-40 levels. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, suppressed ??-Syn-induced A??1-40 elevation, as well as A??1-42-induced ??-Syn elevation. Thus, high concentrations of A??1-42 and ??-Syn exert toxic effects on mature neurons; however, non-toxic concentration treatment of these polypeptides induced the production of each other reciprocally with possible involvement of PI3K pathway.     

Relation between TGF-β 1 levels in cerebrospinal fluid and ETV outcome in premature newborns with posthemorrhagic hydrocephalus

Object  

Therapy of posthaemorrhagic hydrocephalus (PHH) by using ventriculo-peritoneal drainage bears considerable rate of complications and remains a challenge in premature newborns. The role of endoscopic third ventriculostomy (ETV) in these patients is unclear, through obstruction is proven in some patients with PHH. Transforming growth factor beta 1 (TGF-β1) release into the cerebrospinal fluid (CSF) in time of primary bleeding is suggested as one of the possible pathophysiologic reasons of PHH formation. Relation between TGF-β1 levels and ETV success rate has not been reported yet. The aim of our study is to detect group of patients, according to the levels of TGF-β1, who have magnetic resonance imaging (MRI)-proven obstruction hydrocephalus without participation of hyporesorption—so that we can expect success of ETV.     

The Novel Cholinesterase–Monoamine Oxidase Inhibitor and Antioxidant,Ladostigil, Confers Neuroprotection in Neuroblastoma Cells and Aged Rats

The current therapeutic advance in which future drugs are designed to possess varied pharmacological properties and act on multiple targets has stimulated the development of the multimodal drug, ladostigil (TV3326; (N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate). Ladostigil combines neuroprotective effects with monoamine oxidase (MAO)-A and MAO-B and cholinesterase (ChE) inhibitory activities in a single molecule, as a potential treatment for Alzheimer’s disease (AD) and Lewy body disease. In the present study, we demonstrate that ladostigil (10⁻⁶–10 μM) dose-dependently increased cell viability, associated with increased activity of catalase and glutathione reductase and decrease of intracellular reactive oxygen species production in a cytotoxic model of human SH-SY5Y neuroblastoma cells exposed to hydrogen peroxide (H₂O₂). In addition, ladostigil significantly upregulated mRNA levels of several antioxidant enzymes (catalase, NAD(P)H quinone oxidoreductase 1 and peroxiredoxin 1) in both H₂O₂-treated SH-SY5Y cells, as well as in the high-density human SK-N-SH neuroblastoma cultured apoptotic models. In vivo chronic treatment with ladostigil (1 mg/kg per os per day for 30 days) markedly upregulated mRNA expression levels of various enzymes involved in metabolism and oxidation processes in aged rat hippocampus. In addition to its unique combination of ChE and MAO enzyme inhibition, these results indicate that ladostigil displays neuroprotective activity against oxidative stress-induced cell apoptosis, which might be valuable for aging and age-associated neurodegenerative diseases. Orit Bar-Am, Orly Weinreb, and Tamar Amit share equal recognition.     

Wogonin Induced Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Human Malignant Neuroblastoma Cells Via IRE1α-Dependent Pathway

Journal of Molecular Neuroscience - Wogonin, a flavonoid isolated from Scutellaria baicalensis Georgi, has been reported to exhibit a variety of biological effects including anti-cancer effects. It...     

Autophagy Activation Alleviates Amyloid-β-Induced Oxidative Stress,Apoptosis and Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells

Autophagy is an evolutionary conserved catabolic process that ensures continuous removal of damaged cell organelles and long-lived protein aggregates to maintain cellular homeostasis. Although autophagy has been implicated in amyloid-β (Aβ) production and deposition, its role in pathogenesis of Alzheimer’s disease remains elusive. Thus, the present study was undertaken to assess the cytoprotective and neuroprotective potential of autophagy on Aβ-induced oxidative stress, apoptosis and neurotoxicity in human neuroblastoma SH-SY5Y cells. The treatment of Aβ1-42 impaired the cell growth and redox balance, and induced apoptosis and neurotoxicity in SH-SY5Y cells. Next, the treatment of rapamycin (RAP) significantly elevated the expression of autophagy markers such as microtubule-associated protein-1 light chain-3 (LC3), sequestosome-1/p62, Beclin-1, and unc-51-like kinase-1 (ULK1) in SH-SY5Y cells. RAP-induced activation of autophagy notably alleviated the Aβ1-42-induced impairment of redox balance by decreasing the levels of pro-oxidants such as reactive oxygen species, lipid peroxidation and Ca²⁺ influx, and concurrently increasing the levels of antioxidant enzymes such as superoxide dismutase and catalase. The RAP-induced autophagy also ameliorated Aβ1-42-induced loss of mitochondrial membrane potential and apoptosis. Additionally, the activated autophagy provided significant neuroprotection against Aβ1-42-induced neurotoxicity by elevating the expression of neuronal markers such as synapsin-I, PSD95, NCAM, and CREB. However, 3-methyladenine treatment significantly exacerbated the neurotoxic effects of Aβ1-42. Taken together, our study demonstrated that the activation of autophagy provided possible neuroprotection against Aβ-induced cytotoxicity, oxidative stress, apoptosis, and neurotoxicity in SH-SY5Y neuronal cells.     

Human urinary kallidinogenase suppresses cerebral inflammation in experimental stroke and downregulates nuclear factor-��B

The purpose of this study is to investigate the possible mechanism and the neuroprotective effect of human urinary kallidinogenase (HUK) in cerebral ischemia. The mouse middle cerebral artery occlusion (MCAO) model was used. Mice were treated with HUK (20 PNAU/g per day, intravenous) or saline as control, from the beginning of reperfusion to 72 h. Neurological deficits, infarct size, and BWC were measured at 6, 24, 48, and 72 h after MCAO, respectively. Pathological changes of brain were observed by TUNEL assay. Inflammatory factors were measured by real-time PCR and western blotting. Activation of MAPKs, Akt, and nuclear factor-κB (NF-κB) was detected by western blotting. Our results indicated that HUK significantly improved neurofunction, decreased infarct size, and suppressed edema, as well as inflammatory mediators as compared with the vehicle group. Furthermore, HUK inhibited the NF-κB pathway and activated the MAPK/ERK pathway in this neuroprotection.     

The Prospective Links Between Hyperactive/Impulsive,Inattentive, and Oppositional-Defiant Behaviors in Childhood and Antisocial Behavior in Adolescence: The Moderating Influence of Gender and the Parent–Child Relationship Quality

We prospectively investigated the effect of child hyperactive/impulsive, inattentive, and oppositional/defiant behaviors on the development of youth antisocial behaviors, and the moderating influence of gender and the parent–child relationship quality in a normative sample. Participants (N = 673, 50 % girls) were assessed at 10 years of age (parent reports) and at age 15 (parent and adolescent reports). Using latent change models, we found that initial levels of, as well as increases in, hyperactivity/impulsivity and oppositional behaviors and initial levels of inattention behaviors predicted youth antisocial behaviors. The increase in oppositional behaviors was predictive of youth antisocial behaviors in girls only. Child hyperactive/impulsive behaviors predicted youth antisocial behaviors only in children for whom the quality of the parent–child relationship deteriorated from childhood to adolescence. Thus, both initial levels of and increases in disruptive behaviors as well as gender are important for understanding the development of antisocial behaviors in adolescence. We received partial support for the hypothesized, moderating role of a high-quality parent–child relationship.     

∆<Superscript>9</Superscript>-Tetrahydrocannabinol Decreases NOP Receptor Density and mRNA Levels in Human SH-SY5Y Cells

Several studies demonstrated a cross-talk between the opioid and cannabinoid system. The NOP receptor and its endogenous ligand nociceptin/orphanin FQ represent an opioid-related functional entity that mediates some non-classical opioid effects. The relationship between cannabinoid and nociceptin/NOP system is yet poorly explored. In this study, we used the neuroblastoma SH-SY5Y cell line to investigate the effect of delta-9-tetrahydrocannabinol (∆⁹-THC) on nociceptin/NOP system. Results revealed that the exposure to ∆⁹-THC (100, 150, and 200 nM) for 24 h produces a dose-dependent NOP receptor B _max down-regulation. Moreover, ∆⁹-THC caused a dose-dependent decrease in NOP mRNA levels. The selective cannabinoid receptor CB1 antagonist AM251 (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide) reduces both effects, suggesting that ∆⁹-THC activation of CB1 receptor is involved in the observed effects. These data show evidence of a cross-talk between NOP and CB1 receptors, thus suggesting a possible interplay between cannabinoid and nociceptin/NOP system.     

The Emerging Relationship Between Interstitial Fluid–Cerebrospinal Fluid Exchange,Amyloid-β, and Sleep

Amyloid-β (Aβ) plaques are a key histopathological hallmark of Alzheimer’s disease (AD), and soluble Aβ species are believed to play an important role in the clinical development of this disease. Emerging biomarker data demonstrate that Aβ plaque deposition begins decades before the onset of clinical symptoms, suggesting that understanding the biological determinants of the earliest steps in the development of AD pathology may provide key opportunities for AD treatment and prevention. Although a clinical association between sleep disruption and AD has long been appreciated, emerging clinical studies and insights from the basic neurosciences have shed important new light on how sleep and Aβ homeostasis may be connected in the setting of AD. Aβ, like many interstitial solutes, is cleared in part through the exchange of brain interstitial fluid and cerebrospinal fluid along a brain-wide network of perivascular pathways recently termed the glymphatic system. Glymphatic function is primarily a feature of the sleeping brain, rather than the waking brain, and is slowed in the aging and posttraumatic brain. These changes may underlie the diurnal fluctuations in interstitial and cerebrospinal fluid Aβ levels observed in both the rodent and the human. These and other emerging studies suggest that age-related sleep disruption may be one key factor that renders the aging brain vulnerable to Aβ deposition and the development of AD. If this is true, sleep may represent a key modifiable risk factor or therapeutic target in the preclinical phases of AD.     

Spontaneous pain, pain threshold, and pain tolerance in Parkinson��s disease

The mechanisms underlying pain in Parkinson's disease (PD) are unclear. Although a few studies have reported that PD patients may have low pain threshold and tolerance, none could accurately assess whether there was a correlation between sensory thresholds and demographic/clinical features of PD patients. Thus, tactile threshold, pain threshold, and pain tolerance to electrical stimuli in the hands and feet were assessed in 106 parkinsonian patients (of whom 66 reported chronic pain) and 51 age- and sex-matched healthy subjects. Linear regression models determined relationships between psychophysical parameters and demographic/clinical features. Female gender, severity of disease, medical disease associated with painful symptoms, and dyskinesia were more frequently observed in PD patients experiencing pain, even though dyskinesia did not reach significance. Pain threshold and pain tolerance were significantly lower in PD patients than in control subjects, whereas the tactile threshold yielded comparable values in both groups. Multivariable linear regression analyses yielded significant inverse correlations of pain threshold and pain tolerance with motor symptom severity and Beck depression inventory. Pain threshold and pain tolerance did not differ between PD patients with and without pain. In the former group, there was no relationship between pain threshold and the intensity/type of pain, and number of painful body parts. These findings suggest that pain threshold and pain tolerance tend to decrease as PD progresses, which can predispose to pain development. Female gender, dyskinesia, medical conditions associated with painful symptoms, and postural abnormalities secondary to rigidity/bradikinesia may contribute to the appearance of spontaneous pain in predisposed subjects.     

Psychosis Genetics: Modeling the Relationship Between Schizophrenia, Bipolar Disorder, and Mixed (or ��Schizoaffective��) Psychoses

As a result of improving technologies and greatly increased sample sizes, the last 2 years has seen unprecedented advances in identification of specific genetic risk factors for psychiatric phenotypes. Strong genetic associations have been reported at common polymorphisms within ANK3 and CACNA1C in bipolar disorder and ZNF804A in schizophrenia and a relatively specific association between common variation in GABA_A receptor genes and cases with features of both bipolar disorder and schizophrenia. Further, the occurrence of rare copy number variants (CNVs) has been shown to be increased in schizophrenia compared with controls. These emerging data provide a powerful resource for exploring the relationship between psychiatric phenotypes and can, and should, be used to inform conceptualization, classification, and diagnosis in psychiatry. It is already clear that, in general, genetic associations are not specific to one of the traditional diagnostic categories. For example, variation at ZNF804A is associated with risk of both bipolar disorder and schizophrenia, and some rare CNVs are associated with risk of autism and epilepsy as well as schizophrenia. These data are not consistent with a simple dichotomous model of functional psychosis and indicate the urgent need for moves toward approaches that (a) better represent the range of phenotypic variation seen in the clinical population and (b) reflect the underlying biological variation that gives rise to the phenotypes. We consider the implications for models of psychosis and the importance of recognizing and studying illness that has prominent affective and psychotic features. We conclude that if psychiatry is to translate the opportunities offered by new research methodologies, we must finally abandon a 19th-century dichotomy and move to a classificatory approach that is worthy of the 21st century.     

The Importance of Mindfulness in Explaining the Relationship Between Adolescents’ Anxiety and Dropout Intentions

Failure to complete high school is associated with a myriad of negative outcomes. Some research has suggested a link between student anxiety and risk of dropout. Recently, there has been increasing evidence that mindfulness may diminish anxiety in adolescents; however, the relationship between anxiety, mindfulness and dropout has yet to be investigated. Thus, the current study examined the role of mindfulness and anxiety in adolescents’ intentions for dropping out of school. The sample consisted of 471 Grade 9 students (53.1 % female; M _age = 14.45 years, SD = .527). All participants completed the Beck Anxiety Inventory for Youth, the Child and Adolescent Mindfulness Measure and an English translation of Le questionnaire de dépistage des élèves à risque de décrochage scolaire (questionnaire for screening of students at risk of school dropout) in groups. Results showed that anxiety demonstrated a moderate significant negative association with mindfulness, and a low significant positive association with reports of dropout intention. A significant low negative correlation was also found for mindfulness and dropout intention. Interestingly, mindfulness was found to partially mediate the relationship between anxiety and dropout intention, with a medium effect. Implications for future research and practice regarding mindfulness as a protective factor for dropout intention are discussed.     

The Relationships Between Obsessive–Compulsive Symptom Dimensions and Cognitions in Obsessive–Compulsive Disorder

Several studies have linked obsessive–compulsive symptoms to specific obsessive–compulsive cognitions, however methodologies have varied, and no study has determined obsessive–compulsive symptoms using the most widely used clinician rating scale, the Yale–Brown Obsessive–Compulsive Scale (Y-BOCS). Considering that almost all studies that used factor analysis to ascertain OCD symptom dimensions were based on the Y-BOCS and that self-report instruments assessing obsessive–compulsive symptoms correlate poorly with the Y-BOCS, there is a need to use the Y-BOCS to examine the relationship between obsessive–compulsive cognitions and obsessive–compulsive symptom dimensions. This study examined the relationship between five Y-BOCS-derived obsessive–compulsive symptom dimensions and the three obsessive–compulsive cognitive domains identified by the obsessive-beliefs questionnaire (OBQ). The symmetry/ordering symptom dimension was associated with increased perfectionism/intolerance of uncertainty, the unacceptable/taboo thoughts symptom dimension was associated with increased importance/control of thoughts and the doubt/checking symptom dimension was associated with increased responsibility/threat estimation. There was no statistical evidence of an association between any OBQ belief sub-scale and the hoarding symptom dimension nor the contamination/cleaning symptom dimension. The findings encourage symptom-based approaches to cognitive-behavioural therapy for some OCD symptoms and call for further research on cognitions associated with contamination/cleaning symptoms and hoarding.