153 results found
Ward RJ, Dexter DT, Crichton RR, 2022, Iron, Neuroinflammation and Neurodegeneration, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 23
Coetzee T, Ball MP, Boutin M, et al., 2021, Correction: Data Sharing Goals for Nonprofit Funders of Clinical Trials., J Particip Med, Vol: 13
[This corrects the article DOI: 10.2196/23011.].
Ward RJ, Dexter DT, Martin-Bastida A, et al., 2021, Is Chelation Therapy a Potential Treatment for Parkinson's Disease?, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 22
Coetzee T, Ball MP, Boutin M, et al., 2021, Data Sharing Goals for Nonprofit Funders of Clinical Trials., J Particip Med, Vol: 13
Sharing clinical trial data can provide value to research participants and communities by accelerating the development of new knowledge and therapies as investigators merge data sets to conduct new analyses, reproduce published findings to raise standards for original research, and learn from the work of others to generate new research questions. Nonprofit funders, including disease advocacy and patient-focused organizations, play a pivotal role in the promotion and implementation of data sharing policies. Funders are uniquely positioned to promote and support a culture of data sharing by serving as trusted liaisons between potential research participants and investigators who wish to access these participants' networks for clinical trial recruitment. In short, nonprofit funders can drive policies and influence research culture. The purpose of this paper is to detail a set of aspirational goals and forward thinking, collaborative data sharing solutions for nonprofit funders to fold into existing funding policies. The goals of this paper convey the complexity of the opportunities and challenges facing nonprofit funders and the appropriate prioritization of data sharing within their organizations and may serve as a starting point for a data sharing toolkit for nonprofit funders of clinical trials to provide the clarity of mission and mechanisms to enforce the data sharing practices their communities already expect are happening.
Martin-Bastida A, Tilley BS, Bansal S, et al., 2020, Iron and inflammation: in vivo and post-mortem studies in Parkinson’s disease, Journal of Neural Transmission, ISSN: 0300-9564
Sharma PK, Wells L, Rizzo G, et al., 2020, DREADD activation of pedunculopontine cholinergic neurons reverses motor deficits and restores striatal dopamine signaling in parkinsonian rats., Neurotherapeutics, Vol: 17, Pages: 1120-1141, ISSN: 1878-7479
The brainstem-based pedunculopontine nucleus (PPN) traditionally associates with motor function, but undergoes extensive degeneration during Parkinson's disease (PD), which correlates with axial motor deficits. PPN-deep brain stimulation (DBS) can alleviate certain symptoms, but its mechanism(s) of action remains unknown. We previously characterized rats hemi-intranigrally injected with the proteasomal inhibitor lactacystin, as an accurate preclinical model of PD. Here we used a combination of chemogenetics with positron emission tomography imaging for in vivo interrogation of discrete neural networks in this rat model of PD. Stimulation of excitatory designer receptors exclusively activated by designer drugs expressed within PPN cholinergic neurons activated residual nigrostriatal dopaminergic neurons to produce profound motor recovery, which correlated with striatal dopamine efflux as well as restored dopamine receptor 1- and dopamine receptor 2-based medium spiny neuron activity, as was ascertained with c-Fos-based immunohistochemistry and stereological cell counts. By revealing that the improved axial-related motor functions seen in PD patients receiving PPN-DBS may be due to stimulation of remaining PPN cholinergic neurons interacting with dopaminergic ones in both the substantia nigra pars compacta and the striatum, our data strongly favor the PPN cholinergic-midbrain dopaminergic connectome as mechanism for PPN-DBS's therapeutic effects. These findings have implications for refining PPN-DBS as a promising treatment modality available to PD patients.
Lewis FW, Fairooz S, Elson JL, et al., 2020, Novel 1-hydroxypyridin-2-one metal chelators prevent and rescue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson's disease, ARCHIVES OF TOXICOLOGY, Vol: 94, Pages: 813-831, ISSN: 0340-5761
Gonzalez Carter D, Goode A, Kiryushko D, et al., 2019, Quantification of blood-brain barrier transport and neuronal toxicity of unlabelled multiwalled carbon nanotubes as a function of surface charge, Nanoscale, Vol: 11, Pages: 22054-22069, ISSN: 2040-3364
Nanoparticles capable of penetrating the blood-brain barrier (BBB) will greatly advance the delivery of therapies against brain disorders. Carbon nanotubes hold great potential as delivery vehicles due to their high aspect-ratio and cell-penetrating ability. Studies have shown multiwalled carbon nanotubes (MWCNT) cross the BBB, however they have largely relied on labelling methods to track and quantify transport, or on individual electron microscopy images to qualitatively assess transcytosis. Therefore, new direct and quantitative methods, using well-defined and unlabelled MWCNT, are needed to compare BBB translocation of different MWCNT types. Using highly controlled anionic (-), cationic (+) and non-ionic (0) functionalized MWCNT (fMWCNT), we correlate UV-visible spectroscopy with quantitative transmission electron microscopy, quantified from c. 270 endothelial cells, to examine cellular uptake, BBB transport and neurotoxicity of unlabelled fMWCNT. Our results demonstrate that: i) a large fraction of cationic and non-ionic, but not anionic fMWCNT become trapped at the luminal brain endothelial cell membrane; ii) despite high cell association, fMWCNT uptake by brain endothelial cells is low (< 1.5% ID) and does not correlate with BBB translocation, iii) anionic fMWCNT have highest transport levels across an in vitro model of the human BBB compared to non-ionic or cationic nanotubes; and iv) fMWCNT are not toxic to hippocampal neurons at relevant abluminal concentrations; however, fMWCNT charge has an effect on carbon nanotube neurotoxicity at higher fMWCNT concentrations. This quantitative combination of microscopy and spectroscopy, with cellular assays, provides a crucial strategy to predict brain penetration efficiency and neurotoxicity of unlabelled MWCNT and other nanoparticle technologies relevant to human health.
Martin-Bastida A, Tilley B, Alireza T, et al., 2019, The interaction between iron metabolism and inflammation in Parkinson's disease: an in vivo and post mortem study, International Congress of Parkinson's Disease and Movement Disorders, Publisher: WILEY, Pages: S730-S730, ISSN: 0885-3185
Leo BF, Fearn S, Gonzalez-Carter D, et al., 2019, Label-free TOF-SIMS imaging of sulfur producing enzymes inside microglia cells following exposure to silver nanowires, Analytical Chemistry, Vol: 91, Pages: 11098-11107, ISSN: 0003-2700
There are no methods sensitive enough to detect enzymes within cells, without the use of analyte labelling. Here we show that it is possible to detect protein ion signals of three different H2S-synthesizing enzymes inside microglia after pre-treatment with silver nanowires (AgNW) using time of flight-secondary ion mass spectrometry (TOF-SIMS). Protein fragment ions, including the fragment of amino acid (C4H8N+ - 70 amu), fragments of the sulfur producing cystathionine-containing enzymes and the Ag+ ion signal could be detected without the use of any labels; the cells were mapped using the C4H8N+ amino acid fragment. Scanning electron microscopy imaging and energy dispersive x-ray chemical analysis showed that the AgNWs were inside the same cells imaged by TOF-SIMS and transformed chemically into crystalline Ag2S within cells in which the sulfur producing proteins were detected. The presence of these sulfur producing cystathionine-containing enzymes within the cells was confirmed by Western Blots and confocal microscopy images of fluorescently labelled antibodies against the sulfur producing enzymes. Label-free ToF-SIMS is very promising for the label-free identification of H2S-contributing enzymes and their cellular localization in biological systems. The technique could in future be used to identify which of these enzymes are most contributory.
Harrison IF, Powell NM, Dexter DT, 2019, The histone deacetylase inhibitor nicotinamide exacerbates neurodegeneration in the lactacystin rat model of Parkinson's disease, JOURNAL OF NEUROCHEMISTRY, Vol: 148, Pages: 136-156, ISSN: 0022-3042
Gonzalez-Carter DA, Ong ZY, McGilvery CM, et al., 2019, L-DOPA functionalized, multi-branched gold nanoparticles as brain-targeted nano-vehicles, Nanomedicine: Nanotechnology, Biology and Medicine, Vol: 15, Pages: 1-11, ISSN: 1549-9634
The blood-brain barrier (BBB) is a protective endothelial barrier lining the brain microvasculature which prevents brain delivery of therapies against brain diseases. Hence, there is an urgent need to develop vehicles which efficiently penetrate the BBB to deliver therapies into the brain. The drug L-DOPA efficiently and specifically crosses the BBB via the large neutral amino acid transporter (LAT)-1 protein to enter the brain. Thus, we synthesized L-DOPA-functionalized multi-branched nanoflower-like gold nanoparticles (L-DOPA-AuNFs) using a seed-mediated method involving catechols as a direct reducing-cum-capping agent, and examined their ability to cross the BBB to act as brain-penetrating nanovehicles. We show that L-DOPA-AuNFs efficiently penetrate the BBB compared to similarly sized and shaped AuNFs functionalized with a non-targeting ligand. Furthermore, we show that L-DOPA-AuNFs are efficiently internalized by brain macrophages without inducing inflammation. These results demonstrate the application of L-DOPA-AuNFs as a non-inflammatory BBB-penetrating nanovehicle to efficiently deliver therapies into the brain.
Kiryushko D, Pankratova S, Klingelhofer J, et al., 2018, The S100A4 protein signals through the ErbB4 receptor to promote neuronal survival., Theranostics, Vol: 8, Pages: 3977-3990, ISSN: 1838-7640
Understanding the mechanisms of neurodegeneration is crucial for development of therapies to treat neurological disorders. S100 proteins are extensively expressed in the injured brain but S100's roleand signalling in neural cells remain elusive. We recently demonstrated that the S100A4 protein protects neurons in brain injury and designed S100A4-derived peptides mimicking its beneficial effects. Here we show that neuroprotection by S100A4 involves the growth factor family receptorErbB4 and its ligand Neuregulin 1 (NRG), key regulators of neuronal plasticity and implicated in multiple brain pathologies. The neuroprotective effect of S100A4 depends on ErbB4 expression andthe ErbB4 signalling partners ErbB2/Akt, and is reduced by functional blockade of NRG/ErbB4 in cell models of neurodegeneration. We also detect binding of S100A4 with ErbB1 (EGFR) and ErbB3. S100A4-derived peptides interact with, and signal through ErbB, are neuroprotective inprimary and immortalized dopaminergic neurons, and do not affect cell proliferation/motility - features which make them promising as potential neuroprotectants. Our data suggest that the S100- ErbB axis may be an important mechanism regulating neuronal survival and plasticity
Moreau C, Duce JA, Rascol O, et al., 2018, Iron as a therapeutic target for Parkinson's disease, MOVEMENT DISORDERS, Vol: 33, Pages: 568-574, ISSN: 0885-3185
Harrison IF, Smith AD, Dexter DT, 2018, Pathological histone acetylation in Parkinson's disease: Neuroprotection and inhibition of microglial activation through SIRT 2 inhibition, NEUROSCIENCE LETTERS, Vol: 666, Pages: 48-57, ISSN: 0304-3940
Ong ZY, Chen S, Nabavi E, et al., 2017, Multibranched Gold Nanoparticles with Intrinsic LAT-1 Targeting Capabilities for Selective Photothermal Therapy of Breast Cancer., ACS Applied Materials and Interfaces, Vol: 9, Pages: 39259-39270, ISSN: 1944-8244
Because of the critical role of the large neutral amino acid transporter-1 (LAT-1) in promoting tumor growth and proliferation, it is fast emerging as a highly attractive biomarker for the imaging and treatment of human malignancies, including breast cancer. While multibranched gold nanoparticles (AuNPs) have emerged as a promising modality in the photothermal therapy (PTT) of cancers, some of the key challenges limiting their clinical translation lie in the need to develop reproducible and cost-effective synthetic methods as well as the selective accumulation of sufficient AuNPs at tumor sites. In this study, we report a simple and direct seed-mediated synthesis of monodispersed multibranched AuNPs using the catechol-containing LAT-1 ligands, L- and D-dopa, to confer active cancer targeting. This route obviates the need for additional conjugation with targeting moieties such as peptides or antibodies. Nanoflower-like AuNPs (AuNF) with diameters of approximately 46, 70, and 90 nm were obtained and were found to possess excellent colloidal stability and biocompatibility. A significantly higher intracellular accumulation of the L- and D-dopa functionalized AuNFs was observed in a panel of breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-468, and MDA-MB-453) when compared to the nontargeting control AuNFs synthesized with dopamine and 4-ethylcatechol. Importantly, no significant difference in uptake between the targeting and nontargeting AuNFs was observed in a non-tumorigenic MCF-10A breast epithelial cell line, hence demonstrating tumor selectivity. For PTT of breast cancer, Ag(+) was introduced during synthesis to obtain L-dopa functionalized nanourchin-like AuNPs (AuNUs) with strong near-infrared (NIR) absorbance. The L-dopa functionalized AuNUs mediated selective photothermal ablation of the triple negative MDA-MB-231 breast cancer cell line and sensitized the cells to the anticancer drugs cisplatin and docetaxel. This work brings forward an effective strategy
Hanak C, Benoit J, Fabry L, et al., 2017, Changes in Pro-Inflammatory Markers in Detoxifying Chronic Alcohol Abusers, Divided by Lesch Typology, Reflect Cognitive Dysfunction, ALCOHOL AND ALCOHOLISM, Vol: 52, Pages: 529-534, ISSN: 0735-0414
Witoelar A, Jansen IE, Wang Y, et al., 2017, Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases., JAMA Neurol, Vol: 74, Pages: 780-792
Importance: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. Objectives: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. Design, Setting, and Participants: Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. Main Outcomes and Measures: The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases. Results: Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in met
Martin-Bastida A, Ward RJ, Newbould R, et al., 2017, Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson's disease, Scientific Reports, Vol: 7, ISSN: 2045-2322
Parkinson’s disease (PD) is associated with increased iron levels in the substantia nigra (SNc). This study evaluated whether the iron chelator, deferiprone, is well tolerated, able to chelate iron from various brain regions and improve PD symptomology. In a randomised double-blind, placebo controlled trial, 22 early onset PD patients, were administered deferiprone, 10 or 15 mg/kg BID or placebo, for 6 months. Patients were evaluated for PD severity, cognitive function, depression rating and quality of life. Iron concentrations were assessed in the substantia nigra (SNc), dentate and caudate nucleus, red nucleus, putamen and globus pallidus by T2* MRI at baseline and after 3 and 6 months of treatment. Deferiprone therapy was well tolerated and was associated with a reduced dentate and caudate nucleus iron content compared to placebo. Reductions in iron content of the SNc occurred in only 3 patients, with no changes being detected in the putamen or globus pallidus. Although 30 mg/kg deferiprone treated patients showed a trend for improvement in motor-UPDRS scores and quality of life, this did not reach significance. Cognitive function and mood were not adversely affected by deferiprone therapy. Such data supports more extensive clinical trials into the potential benefits of iron chelation in PD.
Petrova D, Hurley M, Prokopenko I, et al., 2017, Clinico-neuropathological classification of Parkinson's disease subtypes, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0028-3878
Sharma P, Wells L, Coello C, et al., 2017, Chemogenetic modulation of the pedunculopontine nucleus coupled with C-11-PHNO uptake reveals striatal dopamine release accompanies profound motor recovery in a rodent model of Parkinson's disease, 28th International Symposium on Cerebral Blood Flow, Metabolism and Function / 13th International Conference on Quantification of Brain Function with PET, Publisher: SAGE PUBLICATIONS INC, Pages: 88-89, ISSN: 0271-678X
Gonzalez Carter DA, Leo BF, Ruenraroengsak P, et al., 2017, Silver nanoparticles reduce brain inflammation and related neurotoxicity through induction of H2S-synthesizing enzymes, Scientific Reports, Vol: 7, ISSN: 2045-2322
Silver nanoparticles (AgNP) are known to penetrate into the brain and cause neuronal death. However, there is a paucity in studies examining the effect of AgNP on the resident immune cells of the brain, microglia. Given microglia are implicated in neurodegenerative disorders such as Parkinson’s disease (PD), it is important to examine how AgNPs affect microglial inflammation to fully assess AgNP neurotoxicity. In addition, understanding AgNP processing by microglia will allow better prediction of their long term bioreactivity. In the present study, the in vitro uptake and intracellular transformation of citrate-capped AgNPs by microglia, as well as their effects on microglial inflammation and related neurotoxicity were examined. Analytical microscopy demonstrated internalization and dissolution of AgNPs within microglia and formation of non-reactive silver sulphide (Ag2S) on the surface of AgNPs. Furthermore, AgNP-treatment up-regulated microglial expression of the hydrogen sulphide (H2S)-synthesizing enzyme cystathionine-γ-lyase (CSE). In addition, AgNPs showed significant anti-inflammatory effects, reducing lipopolysaccharide (LPS)-stimulated ROS, nitric oxide and TNFα production, which translated into reduced microglial toxicity towards dopaminergic neurons. Hence, the present results indicate that intracellular Ag2S formation, resulting from CSE-mediated H2S production in microglia, sequesters Ag+ ions released from AgNPs, significantly limiting their toxicity, concomitantly reducing microglial inflammation and related neurotoxicity.
Jansen IE, Ye H, Heetveld S, et al., 2017, Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing, GENOME BIOLOGY, Vol: 18, ISSN: 1474-760X
Sundriyal S, Moniot S, Mahmud Z, et al., 2017, Thienopyrimidinone Based Sirtuin-2 (SIRT2)-Selective Inhibitors Bind in the Ligand Induced Selectivity Pocket, JOURNAL OF MEDICINAL CHEMISTRY, Vol: 60, Pages: 1928-1945, ISSN: 0022-2623
Sirtuins (SIRTs) are NAD-dependent deacylases, known to be involved in a variety of pathophysiological processes and thus remain promising therapeutic targets for further validation. Previously, we reported a novel thienopyrimidinone SIRT2 inhibitor with good potency and excellent selectivity for SIRT2. Herein, we report an extensive SAR study of this chemical series and identify the key pharmacophoric elements and physiochemical properties that underpin the excellent activity observed. New analogues have been identified with submicromolar SIRT2 inhibtory activity and good to excellent SIRT2 subtype-selectivity. Importantly, we report a cocrystal structure of one of our compounds (29c) bound to SIRT2. This reveals our series to induce the formation of a previously reported selectivity pocket but to bind in an inverted fashion to what might be intuitively expected. We believe these findings will contribute significantly to an understanding of the mechanism of action of SIRT2 inhibitors and to the identification of refined, second generation inhibitors.
Ward RJ, Dexter DT, Crichton RR, 2017, Treatment of Neurodegenerative Diseases by Chelators, RSC Metallobiology, Pages: 153-182
Changes in metal ion homeostasis occur with aging which may precipitate the development of neurodegenerative diseases in susceptible individuals. Slight increases in iron content of specific brain regions, sometimes as little as two-fold, may have a devastating effect on brain function. In this current review we shall initially discuss changes that occur in brain iron homeostasis during healthy aging and longevity, and how alterations of its concentration and distribution may expedite various neurodegenerative diseases. Changes in metal ion homeostasis of other metal ions, namely copper and zinc, also occur in neurodegenerative diseases and will be discussed. Over the past five years the use of iron chelators to slow the progression of the disease and even improve clinical symptoms in some neurodegenerative diseases has been reported; clinical trials have confirmed their efficacy in specific neurodegenerative diseases, namely Friederich's ataxia and Parkinson's disease. The development of new chelators which are able to target specific regions of the brain, combined with drugs which are able to modulate the inflammatory processes, will further advance hope for the eradication of these debilitating neurodegenerative diseases.
Gonzalez-Carter D, Goode A, Fiammengo R, et al., 2016, Inhibition of leptin-ObR interaction does not prevent leptin translocation across a human blood-brain barrier model, Journal of Neuroendocrinology, Vol: 28, ISSN: 1365-2826
The adipocyte-derived hormone leptin regulates appetite and energy homeostasis through activation of leptin receptors (ObR) on hypothalamic neurons, hence leptin must be transported through the blood-brain barrier (BBB) to reach its CNS target sites. During obesity however, leptin BBB transport is decreased, in part precluding leptin as a viable clinical therapy against obesity. Though the short isoform of the ObR (ObRa) has been implicated in the transport of leptin across the BBB due to its elevated expression in cerebral microvessels, accumulating evidence indicates leptin BBB transport is independent of ObRa. Here, we employed an ObR-neutralizing antibody (9F8) to directly examine the involvement of endothelial ObR in leptin transport across an in vitro human BBB model composed of the human endothelial cell line hCMEC/D3. Our results indicate that, while leptin transport across the endothelial monolayer was non-paracellular, and energy- and endocytosis-dependent, it was not inhibited by pre-treatment with 9F8, despite the latter’s ability to recognize hCMEC/D3-expressed ObR, prevent leptin-ObR binding and inhibit leptin-induced STAT-3 phosphorylation in hCMEC/D3 cells. Furthermore, hCMEC/D3 cells expressed the transporter protein LRP-2, capable of binding and endocytosing leptin. In conclusion, our results demonstrate leptin binding to and signalling through ObR is not required for efficient transport across human endothelial monolayers, indicating ObR is not the primary leptin transporter at the human BBB, a role which may fall upon LRP-2. A deeper understanding of leptin BBB transport will help elucidate the exact causes for leptin resistance seen in obesity and aid in the development of more efficient BBB-penetrating leptin analogues.
Srai SK, Kallo V, Ward R, et al., 2016, THE EFFECT OF NEUROINFLAMMATION ON IRON REGULATION IN CELLS OF THE CENTRAL NERVOUS SYSTEM, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 91, Pages: E165-E165, ISSN: 0361-8609
Bastida A, Ward R, Piccini P, et al., 2016, SYSTEMIC INFLAMMATION INFLUENCES THE ABILITY OF DEFERIPRONE TO CHELATE IRON FROM SPECIFIC BRAIN REGIONS IN PARKINSON'S DISEASE PATIENTS, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 91, Pages: E232-E232, ISSN: 0361-8609
Harrison IF, Anis HK, Dexter DT, 2016, Associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal lactacystin model of parkinsonism and their neuroprotection by valproate., Neuroscience Letters, Vol: 614, Pages: 16-23, ISSN: 1872-7972
Parkinson's disease (PD) manifests clinically as bradykinesia, rigidity, and development of a resting tremor, primarily due to degeneration of dopaminergic nigrostriatal pathways in the brain. Intranigral administration of the irreversible ubiquitin proteasome system inhibitor, lactacystin, has been used extensively to model nigrostriatal degeneration in rats, and study the effects of candidate neuroprotective agents on the integrity of the dopaminergic nigrostriatal system. Recently however, adjacent extra-nigral brain regions such as the ventral tegmental area (VTA) have been noted to also become affected in this model, yet their integrity in studies of candidate neuroprotective agents in the model have largely been overlooked. Here we quantify the extent and distribution of dopaminergic degeneration in the VTA of rats intranigrally lesioned with lactacystin, and quantify the extent of VTA dopaminergic neuroprotection after systemic treatment with an epigenetic therapeutic agent, valproate, shown previously to protect dopaminergic SNpc neurons in this model. We found that unilateral intranigral administration of lactacystin resulted in a 53.81% and 31.72% interhemispheric loss of dopaminergic SNpc and VTA neurons, respectively. Daily systemic treatment of lactacystin lesioned rats with valproate however resulted in dose-dependant neuroprotection of VTA neurons. Our findings demonstrate that not only is the VTA also affected in the intranigral lactacystin rat model of PD, but that this extra-nigral brain region is substrate for neuroprotection by valproate, an agent shown previously to induce neuroprotection and neurorestoration of SNpc dopaminergic neurons in this model. Our results therefore suggest that valproate is a candidate for extra-nigral as well as intra-nigral neuroprotection.
Ruffmann C, Calboli FC, Bravi I, et al., 2015, Cortical Lewy bodies and Aβ burden are associated with prevalence and timing of dementia in Lewy body diseases., Neuropathology and Applied Neurobiology, Vol: 42, Pages: 436-450, ISSN: 1365-2990
AIMS: Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. METHODS: 121 cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Aβ plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. RESULTS: The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, p<0.001). The total cortical Aβ plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (p=0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE ϵ4 allele was associated with a higher cortical LB burden (p=0.02), particularly in the neocortical frontal, parietal, and temporal regions. CONCLUSIONS: High CLB burden is a key neuropathological substrate of dementia in LBD. Elevated cortical LB pathology and Aβ plaque deposition are both correlated with a faster progression to dementia. The higher CLB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be mediated by the APOE ϵ4 allele. This article is protected by copyright. All rights reserved.
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