rudyvdbrink/CitationDatabase huggingface dataset:
The molecular mechanism of rotenone-induced α-synuclein aggregation: emphasizing the role of the calcium/GSK3β pathway.
Toxicology letters, 2015

Environmental toxin exposure is associated with the development of Parkinson's disease (PD), and environmental factors can influence the onset of the majority of sporadic PD cases via genetically mediated pathways. Rotenone, a widespread pesticide, induces Parkinsonism and the formation of Lewy bodies in animals; however, the molecular mechanism that underlies α-synuclein aggregation remains unclear. Here, we assessed the aggregation of α-synuclein in PC12 cells with or without cross-linking following rotenone exposure via a variety of methods, including western blotting, immunofluorescence and electron microscopy. We demonstrated that rotenone increased the intracellular calcium levels and induced the aggregation and phosphorylation of α-synuclein in a calcium-dependent manner. Aggregated α-synuclein is typically degraded by autophagy, and rotenone impaired this process. The attenuation of autophagy and α-synuclein alterations were reversed by scavenging calcium. Calcium regulates the activity of AKT-glycogen synthase kinase 3 (GSK3)β. We demonstrated that rotenone attenuated the phosphorylation of AKT and GSK3β, and the elimination of calcium reversed these phenomena. As a GSK3β inhibitor, lithium promoted autophagy and decreased the aggregation and phosphorylation of α-synuclein. GSK3β activation through overexpression depressed autophagy and increased the total protein level and phosphorylation of α-synuclein. These results suggest that rotenone-induced α-synuclein aggregation is mediated by the calcium/GSK3β signaling pathway.
Functions of chondroitin sulfate and heparan sulfate in the developing brain.
Neurochemical research, 2011

Chondroitin sulfate and heparan sulfate proteoglycans are major components of the cell surface and extracellular matrix in the brain. Both chondroitin sulfate and heparan sulfate are unbranched highly sulfated polysaccharides composed of repeating disaccharide units of glucuronic acid and N-acetylgalactosamine, and glucuronic acid and N-acetylglucosamine, respectively. During their biosynthesis in the Golgi apparatus, these glycosaminoglycans are highly modified by sulfation and C5 epimerization of glucuronic acid, leading to diverse heterogeneity in structure. Their structures are strictly regulated in a cell type-specific manner during development partly by the expression control of various glycosaminoglycan-modifying enzymes. It has been considered that specific combinations of glycosaminoglycan-modifying enzymes generate specific functional microdomains in the glycosaminoglycan chains, which bind selectively with various growth factors, morphogens, axon guidance molecules and extracellular matrix proteins. Recent studies have begun to reveal that the molecular interactions mediated by such glycosaminoglycan microdomains play critical roles in the various signaling pathways essential for the development of the brain.
Concurrent blockade of free radical and microsomal prostaglandin E synthase-1-mediated PGE2 production improves safety and efficacy in a mouse model of amyotrophic lateral sclerosis.
Journal of neurochemistry, 2012

While free radicals and inflammation constitute major routes of neuronal injury occurring in amyotrophic lateral sclerosis (ALS), neither antioxidants nor non-steroidal anti-inflammatory drugs have shown significant efficacy in human clinical trials. We examined the possibility that concurrent blockade of free radicals and prostaglandin E(2) (PGE(2))-mediated inflammation might constitute a safe and effective therapeutic approach to ALS. We have developed 2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] (AAD-2004) as a derivative of aspirin. AAD-2004 completely removed free radicals at 50 nM as a potent spin-trapping molecule and inhibited microsomal PGE(2) synthase-1 (mPGES-1) activity in response to both lipopolysaccharide-treated BV2 cell with IC(50) of 230 nM and recombinant human mPGES-1 protein with IC(50) of 249 nM in vitro. In superoxide dismutase 1(G93A) transgenic mouse model of ALS, AAD-2004 blocked free radical production, PGE(2) formation, and microglial activation in the spinal cords. As a consequence, AAD-2004 reduced autophagosome formation, axonopathy, and motor neuron degeneration, improving motor function and increasing life span. In these assays, AAD-2004 was superior to riluzole or ibuprofen. Gastric bleeding was not induced by AAD-2004 even at a dose 400-fold higher than that required to obtain maximal therapeutic efficacy in superoxide dismutase 1(G93A). Targeting both mPGES-1-mediated PGE(2) and free radicals may be a promising approach to reduce neurodegeneration in ALS and possibly other neurodegenerative diseases.
A genome-wide association study of mitochondrial DNA copy number in two population-based cohorts.
Human genomics, 2019

Mitochondrial DNA copy number (mtDNA CN) exhibits interindividual and intercellular variation, but few genome-wide association studies (GWAS) of directly assayed mtDNA CN exist. We undertook a GWAS of qPCR-assayed mtDNA CN in the Avon Longitudinal Study of Parents and Children (ALSPAC) and the UK Blood Service (UKBS) cohort. After validating and harmonising data, 5461 ALSPAC mothers (16-43 years at mtDNA CN assay) and 1338 UKBS females (17-69 years) were included in a meta-analysis. Sensitivity analyses restricted to females with white cell-extracted DNA and adjusted for estimated or assayed cell proportions. Associations were also explored in ALSPAC children and UKBS males.
Total and phosphorylated tau protein as biological markers of Alzheimer's disease.
Experimental gerontology, 2010

Advances in our understanding of tau-mediated neurodegeneration in Alzheimer's disease (AD) are moving this disease pathway to center stage for the development of biomarkers and disease modifying drug discovery efforts. Immunoassays were developed detecting total (t-tau) and tau phosphorylated at specific epitopes (p-tauX) in cerebrospinal fluid (CSF), methods to analyse tau in blood are at the experimental beginning. Clinical research consistently demonstrated CSF t- and p-tau increased in AD compared to controls. Measuring these tau species proved informative for classifying AD from relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau231) differentiated between AD and frontotemporal dementia, tau phosphorylated at serine 181 (p-tau181) enhanced classification between AD and dementia with Lewy bodies. T- and p-tau are considered "core" AD biomarkers that have been successfully validated by controlled large-scale multi-center studies. Tau biomarkers are implemented in clinical trials to reflect biological activity, mechanisms of action of compounds, support enrichment of target populations, provide endpoints for proof-of-concept and confirmatory trials on disease modification. World-wide quality control initiatives are underway to set required methodological and protocol standards. Discussions with regulatory authorities gain momentum defining the role of tau biomarkers for trial designs and how they may be further qualified for surrogate marker status.
RANK deletion in neuropeptide Y neurones attenuates oestrogen deficiency-related bone loss.
Journal of neuroendocrinology, 2019

The RANKL pathway is known to be an important aspect of the pathogenesis of oestrogen deficiency-induced bone loss. RANK deletion specifically in neuropeptide Y (NPY) neurones has been shown to enhance the ability of the skeleton to match increases in body weight caused by high-fat diet feeding, likely via the modulation of NPY levels. In the present study, we used ovariectomy in female mice to show that RANK deletion in NPY neurones attenuates bone loss caused by long-term oestrogen deficiency, particularly in the vertebral compartment. Ovariectomy led to a reduction in NPY expression levels in the arcuate nucleus of NPY
An optimized protocol for the acute isolation of human microglia from autopsy brain samples.
Glia, 2012

Microglia are increasingly recognized to be crucially involved in the maintenance of tissue homeostasis of the brain and spinal cord. Not surprisingly is therefore the growing scientific interest in the microglia phenotypes associated with various physiological and pathological processes of the central nervous system. Until recently the investigation of these phenotypes was hindered by the lack of an isolation protocol that (without an extended culturing period) would offer a microglia population of high purity and yield. Thus, our objective was to establish a rapid and efficient method for the isolation of human microglia from postmortem brain samples. We tested multiple elements of already existing protocols (e.g., density separation, immunomagnetic bead separation) and combined them to minimize preparation time and maximize yield and purity. The procedure presented in this article enables acute isolation of human microglia from autopsy (and biopsy) samples with a purity and yield that is suitable for downstream applications, such as protein and gene expression analysis and functional assays. Moreover, the present protocol is appropriate for the isolation of microglia from autopsy samples irrespective of the neurological state of the brain or specific brain regions and (with minor modification) could be even used for the isolation of microglia from human glioma tissue.
Microglia amplify inflammatory activation of astrocytes in manganese neurotoxicity.
Journal of neuroinflammation, 2017

As the primary immune response cell in the central nervous system, microglia constantly monitor the microenvironment and respond rapidly to stress, infection, and injury, making them important modulators of neuroinflammatory responses. In diseases such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, and human immunodeficiency virus-induced dementia, activation of microglia precedes astrogliosis and overt neuronal loss. Although microgliosis is implicated in manganese (Mn) neurotoxicity, the role of microglia and glial crosstalk in Mn-induced neurodegeneration is poorly understood.
Neuronal brain injury after cerebral ischemic stroke is ameliorated after subsequent administration of (R)-ketamine, but not (S)-ketamine.
Pharmacology, biochemistry, and behavior, 2020

Although stroke is the most common acute cerebrovascular disease, there are no currently effective therapeutic drugs for ischemic stroke. (R,S)-ketamine has been shown to protect against brain injury in rodents after middle cerebral artery occlusion (MCAO). Interestingly, we reported that (R)-ketamine has greater beneficial effects than (S)-ketamine in animal models of depression and Parkinson's disease. This study was undertaken whether two enantiomers of ketamine show neuroprotective effects in MCAO model. MCAO-induced brain injury and behavioral abnormalities in mice was attenuated by subsequent administration of (R)-ketamine (10 mg/kg, twice, 1 and 24 h after MCAO), but not (S)-ketamine (10 mg/kg, twice, 1 and 24 h after MCAO). Furthermore, the treatment with (R)-ketamine (10 mg/kg, twice, 30 min before and 24 h after MCAO) significantly protected against brain injury and behavioral abnormalities in mice after MCAO. These findings suggest that (R)-ketamine can protect against neuronal injury and behavioral abnormalities in mice after MCAO. Therefore, it is likely that (R)-ketamine could represent a therapeutic drug for ischemic stroke.
Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury.
Brain : a journal of neurology, 2018

Chondroitinase ABC is a promising preclinical therapy that promotes functional neuroplasticity after CNS injury by degrading extracellular matrix inhibitors. Efficient delivery of chondroitinase ABC to the injured mammalian spinal cord can be achieved by viral vector transgene delivery. This approach dramatically modulates injury pathology and restores sensorimotor functions. However, clinical development of this therapy is limited by a lack of ability to exert control over chondroitinase gene expression. Prior experimental gene regulation platforms are likely to be incompatible with the non-resolving adaptive immune response known to occur following spinal cord injury. Therefore, here we apply a novel immune-evasive dual vector system, in which the chondroitinase gene is under a doxycycline inducible regulatory switch, utilizing a chimeric transactivator designed to evade T cell recognition. Using this novel vector system, we demonstrate tight temporal control of chondroitinase ABC gene expression, effectively removing treatment upon removal of doxycycline. This enables a comparison of short and long-term gene therapy paradigms in the treatment of clinically-relevant cervical level contusion injuries in adult rats. We reveal that transient treatment (2.5 weeks) is sufficient to promote improvement in sensory axon conduction and ladder walking performance. However, in tasks requiring skilled reaching and grasping, only long term treatment (8 weeks) leads to significantly improved function, with rats able to accurately grasp and retrieve sugar pellets. The late emergence of skilled hand function indicates enhanced neuroplasticity and connectivity and correlates with increased density of vGlut1+ innervation in spinal cord grey matter, particularly in lamina III-IV above and below the injury. Thus, our novel gene therapy system provides an experimental tool to study temporal effects of extracellular matrix digestion as well as an encouraging step towards generating a safer chondroitinase gene therapy strategy, longer term administration of which increases neuroplasticity and recovery of descending motor control. This preclinical study could have a significant impact for tetraplegic individuals, for whom recovery of hand function is an important determinant of independence, and supports the ongoing development of chondroitinase gene therapy towards clinical application for the treatment of spinal cord injury.
Electrocorticographic dissociation of alpha and beta rhythmic activity in the human sensorimotor system.
eLife, 2019

This study uses electrocorticography in humans to assess how alpha- and beta-band rhythms modulate excitability of the sensorimotor cortex during psychophysically-controlled movement imagery. Both rhythms displayed effector-specific modulations, tracked spectral markers of action potentials in the local neuronal population, and showed spatially systematic phase relationships (traveling waves). Yet, alpha- and beta-band rhythms differed in their anatomical and functional properties, were weakly correlated, and traveled along opposite directions across the sensorimotor cortex. Increased alpha-band power in the somatosensory cortex ipsilateral to the selected arm was associated with spatially-unspecific inhibition. Decreased beta-band power over contralateral motor cortex was associated with a focal shift from relative inhibition to excitation. These observations indicate the relevance of both inhibition and disinhibition mechanisms for precise spatiotemporal coordination of movement-related neuronal populations, and illustrate how those mechanisms are implemented through the substantially different neurophysiological properties of sensorimotor alpha- and beta-band rhythms.
Diurnal Corticosterone Presence and Phase Modulate Clock Gene Expression in the Male Rat Prefrontal Cortex.
Endocrinology, 2016

Mood disorders are associated with dysregulation of prefrontal cortex (PFC) function, circadian rhythms, and diurnal glucocorticoid (corticosterone [CORT]) circulation. Entrainment of clock gene expression in some peripheral tissues depends on CORT. In this study, we characterized over the course of the day the mRNA expression pattern of the core clock genes Per1, Per2, and Bmal1 in the male rat PFC and suprachiasmatic nucleus (SCN) under different diurnal CORT conditions. In experiment 1, rats were left adrenal-intact (sham) or were adrenalectomized (ADX) followed by 10 daily antiphasic (opposite time of day of the endogenous CORT peak) ip injections of either vehicle or 2.5 mg/kg CORT. In experiment 2, all rats received ADX surgery followed by 13 daily injections of vehicle or CORT either antiphasic or in-phase with the endogenous CORT peak. In sham rats clock gene mRNA levels displayed a diurnal pattern of expression in the PFC and the SCN, but the phase differed between the 2 structures. ADX substantially altered clock gene expression patterns in the PFC. This alteration was normalized by in-phase CORT treatment, whereas antiphasic CORT treatment appears to have eliminated a diurnal pattern (Per1 and Bmal1) or dampened/inverted its phase (Per2). There was very little effect of CORT condition on clock gene expression in the SCN. These experiments suggest that an important component of glucocorticoid circadian physiology entails CORT regulation of the molecular clock in the PFC. Consequently, they also point to a possible mechanism that contributes to PFC disrupted function in disorders associated with abnormal CORT circulation.
mGluR2 positive allosteric modulators: a patent review (2009 - present).
Expert opinion on therapeutic patents, 2013

The mGlu2 receptor, which belongs to the group II subfamily of metabotropic glutamate receptors (mGlu) along with the mGlu3 receptor, has proven to be of particular importance in neuropharmacology. Preferentially expressed on presynaptic nerve terminals, the mGlu2 receptor negatively modulates glutamate and GABA release and is widely distributed in the brain. High levels of mGlu2 receptors are seen in brain areas such as prefrontal cortex, hippocampus and amygdala where glutamate hyperfunction may be implicated in disorders and diseases such as anxiety and schizophrenia. Given the promise offered by mGlu2/3 receptor activation, there is increased interest in identifying small molecules which activate the receptor. A preferred approach is via positive allosteric modulators (PAMs) which bind at an alternative site to agonists.
Feedback contribution to surface motion perception in the human early visual cortex.
eLife, 2020

Human visual surface perception has neural correlates in early visual cortex, but the role of feedback during surface segmentation in human early visual cortex remains unknown. Feedback projections preferentially enter superficial and deep anatomical layers, which provides a hypothesis for the cortical depth distribution of fMRI activity related to feedback. Using ultra-high field fMRI, we report a depth distribution of activation in line with feedback during the (illusory) perception of surface motion. Our results fit with a signal re-entering in superficial depths of V1, followed by a feedforward sweep of the re-entered information through V2 and V3. The magnitude and sign of the BOLD response strongly depended on the presence of texture in the background, and was additionally modulated by the presence of illusory motion perception compatible with feedback. In summary, the present study demonstrates the potential of depth-resolved fMRI in tackling biomechanical questions on perception.
Recovery dynamics of multifocal pupillographic objective perimetry from tropicamide dilation.
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 2020

To study the pupillary system by combining mydriasis and multifocal pupillographic objective perimetry (mfPOP). In particular, we explored how the dynamics of recovery differ for concurrently measured direct and consensual sensitivity, response delay, and signal-to-noise ratios (SNRs) for binocular mydriasis.
New imaging markers for preconceptional and first-trimester utero-placental vascularization.
Placenta, 2018

The availability of imaging makers of early placental circulation development is limited. This study aims to develop a feasible and reliable method to assess preconceptional and early first-trimester utero-placental vascular volumes using three-dimensional power Doppler (3D PD) ultrasound on two different Virtual Reality (VR) systems.
Intravenous thrombolysis in stroke patients under 55 years of age: is there a different effect according to etiology and severity?
Journal of thrombosis and thrombolysis, 2014

The effect of intravenous thrombolysis (IVT) according to etiology and stroke severity in young patients with ischemic stroke (IS) has not been described previously. To analyze the effect of IVT in young patients with IS according to etiological subtype and stroke severity. Observational study with inclusion of IS patients under 55 years of age (2007-2012). Two groups were compared according to IVT treatment. Favorable outcomes were defined as 3 months modified Rankin Scale ≤2. Multivariate analyses were performed to determine those factors independently associated with favorable outcomes, and subgroup analyses were conducted to assess the effect of IVT according to etiological stroke subtype and severity on admission, adjusted for other prognostic variables. We evaluated 262 patients. 63 (24%) received IVT. The mean age and the sex distribution were similar in the IVT treated and the non-treated groups. Multivariate analyses showed that IVT was associated with a higher probability of favorable outcome (OR, 95% CI: 4.652, 1.294-16.722) whereas artery dissection (OR, 95% CI: 0.191, 0.056-0.654) and NIHSS (OR, 95% CI: 0.727, 0.664-0.797) were associated with a lower probability of a favorable outcome. The subgroup analysis showed that the beneficial effect of IVT on outcomes was significant in moderate-severe strokes (NIHSS ≥8) (OR, 95% CI: 3.782, 1.095-13.069) and in cardioembolism (OR, 95% CI: 41.887, 1.001-1751.596). In IS patients under 55 years of age, those with moderate-severe strokes benefit more from IVT than those with mild strokes. Cardioembolic infarctions may benefit more from IV tPA than other etiologies.
Association of TOR1A and GCH1 Polymorphisms with Isolated Dystonia in India.
Journal of molecular neuroscience : MN, 2021

Isolated dystonia is a common movement disorder often caused by genetic mutations, although it is predominantly sporadic in nature. Common variants of dystonia-related genes were reported to be risk factors for idiopathic isolated dystonia. In this study, we aimed to analyse the roles of previously reported GTP cyclohydrolase (GCH1) and Torsin family 1 member A (TOR1A) polymorphisms in an Indian isolated dystonia case-control group. A total of 292 sporadic isolated dystonia patients and 316 control individuals were genotyped for single-nucleotide polymorphisms (SNPs) of GCH1 (rs3759664:G > A, rs12147422:A > G and rs10483639:C > G) and TOR1A (rs13300897:G > A, rs1801968:G > C, rs1182:G > T and rs3842225:G > Δ) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and confirmed by direct Sanger sequencing. The statistical significance of allelic, genotypic and haplotypic associations of all of the SNPs were evaluated using the two-tailed Fisher exact test. The minor allele (A) of rs3759664 is significantly associated with isolated limb dystonia as a risk factor (p = 0.005). The minor allele (C) of rs1801968 is strongly associated with isolated dystonia (p < 0.0001) and most of its subtypes. The major allele of rs3842225 (G) may act as a significant risk factor for Writer's cramp (p = 0.03). Four different haplogroups comprising of either rs1182 or rs3842225 or in combination with rs1801968 and rs13300897 were found to be significantly associated with isolated dystonia. No other allelic, genotypic or haplotypic association was found to be significant with isolated dystonia cohort or its endophenotype stratified groups. Our study suggests that TOR1A common variants have a significant role in isolated dystonia pathogenesis in the Indian population, whereas SNPs in the GCH1 gene may have a limited role.