Spelling suggestions: "subject:"neurodegenerative disorders"" "subject:"neurodegenerative isorders""
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Factors important in the survival and functional capacity of intracerebral adrenal and embryonic nigral graftsBarker, Roger Alistair January 1994 (has links)
No description available.
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Molecular genetic study of autosomal dominant cerebellar ataxia in pedigrees from Cuba and ThailandTwells, Rebecca Christina Joan January 1995 (has links)
No description available.
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Studies on novel immunophilins and the effects of immunosuppressant drugs on neuronsMcCann, Fiona Elizabeth January 2001 (has links)
No description available.
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Regulation of cell death in sympathetic neuronsEdwards, Susan N. January 1992 (has links)
No description available.
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Modelling Machado-Joseph disease by YAC transgenesisCemal, Cemal Kubilay January 2001 (has links)
No description available.
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Novel adamantane derivatives as multifunctional neuroprotective agentsKadernani, Yakub Esmail Y.E. January 2013 (has links)
>Magister Scientiae - MSc / The pathology of neurodegenerative disorders involves multiple steps, and it is probably for
this reason that targeting one particular step in a multi-step process has only yielded limited
results. Nitric oxide (NO) is synthesised from L-Arginine by an enzyme known as nitric
oxide synthase (NOS). Three isoforms of NOS exist, including endothelial NOS (eNOS),
neuronal NOS (nNOS), and inducible NOS (iNOS). In the central nervous system (CNS),
nNOS is involved in the synthesis of NO, which is involved in various neurological
functions. NO is a free radical and this probably explains why an excess amount of it has
been implicated in the development of neurodegenerative disorders. In the CNS, the Nmethyl-
D-aspartate (NMDA) receptor in its active state allows the influx of calcium ions
which activate nNOS thus increasing the amount of NO and other detrimental reactive
nitrogen species within neuronal cells. Calcium entry through voltage-gated calcium channels
(VGCC) may also contribute to this. Although calcium ions are important for physiological
functioning, an excess is responsible for excitotoxicity, which can ultimately lead to
neurodegeneration.
Our aim was to synthesise a series of adamantane-derived compounds that act at multiple
target sites in the neurodegenerative pathway. By conjugating benzyl and phenylethyl
moieties with different functional groups (-H, -NO2, -NH2, -NHC(NH)NH2, -OCH3) to the
amantadine structure, we aimed to synthesise compounds that display calcium channel and
NMDA receptor (NMDAR) channel inhibition, as well as selective inhibition of nNOS.
A series of compounds (-H, -NO2, -NH2, -OCH3) were obtained in yields that varied between
16.5 % and 90.25 %. These novel compounds were tested for calcium influx through VGCC
and NMDAR inhibition using synaptoneurosomes isolated from rat brain homogenate against
the reference compounds MK-801, NGP1-01, amantadine, memantine and nimodipine. A
lack of success with the synthesis of the guanidine compounds prevented the use of the
oxyhemoglobin capture assay for the determination of nNOS inhibitory activity of these
compounds.
The novel synthesised compounds display inhibitory activity towards VGCC and the
NMDAR in the micromolar range. Further tests are recommended on compounds SE-1, SE-4,
SE-11 and SE-12 as they displayed good inhibitory activity against both NMDAR- as well as
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KCl-mediated calcium influx. These novel compounds may be better therapeutic options than
amantadine and memantine as they inhibit both NMDAR and VGCC-mediated calcium
influx, whereas amantadine and memantine only inhibit NMDA-mediated calcium influx.
These novel adamantane derived compounds may possibly serve as novel leads or potential
therapeutic agents for the treatment of neurodegenerative disorders.
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Chalcone and curcumin hybrids of indole propargylamines as multifunctional neuroprotective agentsMusakwa, Lovetone January 2020 (has links)
Magister Pharmaceuticae - MPharm / Neurodegenerative disorders (NDs) are a range of chronic brain disorders that includes
amongst others motor function loss. Parkinson’s disease (PD) is one of the common NDs that
has an insidious onset and diagnosed when dopaminergic neurons in the substantia nigra are
already lost. The loss creates a deficiency of the dopamine (neurotransmitter) thereby causing
neurochemical imbalance resulting in the signs and symptoms of PD. NDs overlap at multiple
levels so some of the symptoms overlap as well. NDs currently have no cure yet and current
drug therapies only improve the quality of life of the patients by targeting the symptoms
mainly. Treatment of PD currently involves different classes of drugs and depending on the
stages of the disease, some drugs can be only used as an adjunct therapy. Anti-oxidants and
monoamine oxidase inhibitors (MAO-I) are part of the treatment options.
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An investigation into the molecular aetiology of Parkinson's disease in South African patientsGlanzmann, Brigitte 03 1900 (has links)
Thesis (MScMedSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Parkinson's disease (PD) is a severely debilitating neurodegenerative disorder that results in
motor circuit dysregulation and ultimately, causes impairment of movement. This condition
is due to the selective degradation of the dopaminergic neurons in the substantia nigra pars
compacta in the midbrain, which subsequently results in the pathological symptoms namely
bradykinesia, resting tremor, postural instability and rigidity. It was initially hypothesized
that individuals who develop PD were exposed to an environmental trigger(s) that caused the
onset of the disease, but more recently, a significant genetic component, coupled to
environmental factors have been implicated in disease pathogenesis. Currently, there are
eight genes (Parkin, PINK1, LRRK2, SNCA, DJ-1, ATP13A2, EIF4G1 and VPS35) that have
been directly implicated in PD.
Worldwide, the prevalence of neurodegenerative disorders is increasing as populations are
living longer. In Europe, Canada and USA, it has been projected that the prevalence of PD
may increase by a factor of two between 2010 and 2050; approximately a 92% increase. In
Tanzania (the only study done in sub-Saharan Africa) an even larger increase of 184%
between 2005 and 2025 is predicted, due to the fact that the speed of populations ageing in
developing countries, will exceed that of developed countries. Research into the causes and
risk factors underlying neurodegenerative disorders such as PD is therefore urgently needed
for policy makers and governments in developing nations to take appropriate action to deal
with this impending health care problem.
The aim of the present study was to investigate the molecular aetiology of a group of South
African PD patients. A total of 262 patients from various ethnic backgrounds were recruited
for the study, and 35% had a positive family history of PD with the average age at onset
(AAO) being 54.3 years of age (SD = 12.5 years). Mutation screening of the known PD
genes (Parkin, PINK1, LRRK2, SNCA and DJ-1) was performed using high resolution melt
and Sanger sequencing. Genotyping was done using fluorescently-labelled PCR primers
followed by electrophoresis on an ABI 3130xl genetic analyser (for CTG repeats in JPH3)
and with a KASP™ Genotyping Assay (for a 16bp indel in DJ-1). In order to identify a
novel PD-causing gene, whole exome sequencing (WES) was conducted on three Afrikaner
probands with an Illumina Genome Hiseq 2000TM and the sequences were aligned using the NCBI Human Reference Genome 37.2. The BORG (Bio-Ontological Relationship Graph)
semantic database, which models the relationship of human and model organism genes to
functions, pathways and phenotypes, was used to filter and prioritise genetic variants shared
between the three PD exomes.
It was determined that the known PD genes do not play a significant role in disease
pathogenesis in the South African patients as only 15/262 (5.7%) of the patients harboured
mutations: seven in Parkin, one in PINK1, six in LRRK2 and one in SNCA. Only one of the
patients harboured a 16bp indel variant at the transcription start site of DJ-1. None of the
Black PD patients had pathogenic repeat expansions in JPH3 thereby excluding Huntington
disease-like 2 as a cause of the disease phenotype.
Genealogical analysis revealed that six of the apparently unrelated Afrikaner PD probands
were related to a founder couple that immigrated to South Africa in the 1600s which suggests
that there is a possible founder effect for the disease. Bioinformatics analysis of WES data
on three of the probands identified 21 variants in 12 genes that were present in all three PD
exomes and fulfilled various criteria. Sanger sequencing was used for verification of five
variants and of these, two (in CDC27 and NEDD4) were found to be artefacts. The
remaining three (in HECDT1, TBCC and RNF40) were excluded based on the lack of cosegregation
with disease and the high frequency of the allele in controls. Further work is
necessary to verify the presence of the remaining sixteen variants and to characterise each of
them for their possible pathogenicity.
The discovery of novel PD-causing genes is important as this may shed light on the pathways
or processes that are involved. A current hypothesis implicates the lysosome-dependent
pathway as a unifying biochemical pathway that can account for the phenotypic spectrum
within PD. Notably, although Mendelian forms are thought to account for only about 10-
15% of cases, the study of Mendelian inherited variants is likely to provide insight into the
pathophysiology of the more common sporadic form of this condition. Dissecting the key
molecular mechanisms underlying PD will provide critical information for improved
treatment strategies and drug interventions that will ultimately prevent or halt neuronal cell
loss in susceptible individuals. / AFRIKAANSE OPSOMMING: Parkinson se siekte (PS) is 'n erge neurodegeneratiewe bewegings-siekte, wat motorstroombaan
disregulasie veroorsaak. Dit lei uiteindelik tot beperkte bewegings vermoëns. Hierdie toestand
word veroorsaak weens die selektiewe agteruitgang van die dopaminergeniese neurone in die
substantia nigra pars compacta in die midbrein, wat later lei tot die patologiese simptome
naamlik: bradykinesia, rustende spiersametrekkings, posturale onstabiliteit en rigiditeit. Daar is
aanvanklik vermoed dat individue wat PS ontwikkel, aan 'n omgewingsfaktor(e) blootgestel is
wat die aanvang van die siekte veroorsaak het, terwyl meer onlangs is daar 'n aansienlike
genetiese komponent tesame met omgewingsfaktore geïdentifiseer, wat betrokke is by die
patogenese van die siekte. Tans is daar agt gene (Parkin, PINK1, LRRK2, SNCA, DJ-1,
ATP13A2, EIF4G1 en VPS35) wat direk by PS geïmpliseer is.
Wêreldwyd is daar ‗n toenemende voorkoms van neurodegeneratiewe siektes aangesien
bevolkings langer leef. In Europa, Kanada en die VSA, is daar geprojekteer dat die voorkoms
van PS tussen 2010 en 2050 met 'n faktor van twee verhoog kan word. Dit is ongeveer 'n 92%-
verhoging. In Tanzanië (die enigste studie wat tot dusver in sub-Sahara Afrika gedoen is) word
daar selfs ‗n groter toename, van 184% tussen 2005 en 2025 voorspel. Dit is te danke aan die feit
dat die bevolkings- veroudering in ontwikkelende lande die van ontwikkelde lande sal oorskry.
Ondersoeke na die oorsake en risiko-faktore onderliggend aan neurodegeneratiewe siektes,
byvoorbeeld PS, word dus dringend benodig deur beleidmakers en regerings in ontwikkelende
lande, sodat hulle die nodige stappe kan neem om hierdie dreigende gesondheidsorg-probleem op
te los.
Die doel van die huidige studie was om ondersoek in te stel na die molekulêre etiologie van 'n
groep Suid-Afrikaanse PS pasiënte. 'n Totaal van 262 pasiënte van verskillende etniese
agtergronde, is gewerf vir die studie. Hiervan het 35% 'n positiewe familiegeskiedenis van PS en
die gemiddelde aanvangs ouderdom (AAO) was 54,3 jaar (SD = 12,5 jaar). Mutasie-analise van
die bekende PS gene is uitgevoer met behulp van hoë resolusie smelt en Sanger
volgordebepaling. Genotipering is gedoen met behulp van fluoresserend geëtiketteerde PKR
inleiers met elektroforese, op 'n ABI 3130xl genetiese analiseerder (CTG herhalings in JPH3), en
met 'n KASP ™ Genotipering toets (vir 'n 16bp indel in DJ-1). Ten einde, om 'n nuwe PSveroorsakende
geen te identifiseer was heel eksoom volgordebepaling (WES) uitgevoer op drie
Afrikaner PS positiewe pasiënte met 'n Illumina Genome Hiseq 2000™ en die volgorders is gerangskik met behulp van die NCBI Menslike Verwysings Genoom 37.2. Die BORG (Bio-
Ontologiese Verhoudings Grafiek) semantiese databasis, wat gebaseer is op die verhouding van
die mens en model organisme gene funksies, paaie en fenotipes, en is gebruik om genetiese
variante, wat gedeel word tussen die drie PS exome te filtreer en te prioritiseer.
Daar is vasgestel dat die bekende PS gene nie 'n belangrike rol in die patogenese van die siekte
in die Suid-Afrikaanse pasiënte speel nie. Dit is aangesien slegs 15/262 (5.7%) van die pasiënte
bekende mutasies dra: sewe in Parkin, een in PINK1, ses in LRRK2 en een in SNCA. Slegs een
van die pasiënte het 'n 16bp delesie variant in die transkripsie promotor area van DJ-1 gedra.
Geen van die Swart PS pasiënte het patogeniese herhalings in JPH3 vertoon nie. Gevolglik is
Huntington siekte-agtige 2 uitgesluit as 'n oorsaak van die siekte fenotipe.
Genealogiese analise het getoon dat ses van die skynbaar onverwante Afrikaner PS pasiënte
verwant is aan 'n stigter paartjie wat in die 1600's na Suid-Afrika geïmigreer het, wat daarop dui
dat daar 'n moontlike stigter effek vir die siekte is. Bioinformatiese analise van WES data vir drie
van die pasiënte, het 21 variante in 12 gene geïdentifiseer, wat in al drie PS exome teenwoordig
was en verskeie kriteria vervul het. Sanger volgordebepaling is gebruik vir die bevestiging van
vyf variante en van hierdie, is twee (in CDC27 en NEDD4) bevind om artefakte te wees. Die
oorblywende drie (in HECDT1, TBCC en RNF40) is uitgesluit gebaseer op die gebrek aan
gesamentlike-segregasie met die siekte en die hoë frekwensie van die allele in die kontrole groep.
Verdere werk is nodig om die teenwoordigheid van die oorblywende variante te verifieer en om
elkeen van hulle te karakteriseer vir hulle moontlike patogenisiteit.
Die ontdekking van die nuwe PS-veroorsakende gene is belangrik aangesien dit lig kan werp op
die stelsels of prosesse wat betrokke is. 'n Huidige hipotese impliseer die lisosoom-afhanklike pad
as 'n verenigende biochemiese padweg, wat verantwoordelik is vir die fenotipiese spektrum binne
PS. Alhoewel Mendeliese vorms vermoedelik verantwoordelik is vir slegs omgeveer 10-15% van
die gevalle, is die studie van Mendelse gene geneig om insig te verkry in die patofisiologie van
die meer algemene sporadiese vorm van hierdie toestand. Ontleding van die kern molekulêre
meganismes onderliggend aan PS sal kritiese inligting vir beter strategieë vir behandeling en
geneesmiddel-intervensies voorsien, wat gevolglik neuronale sel verlies in vatbare individue sal
voorkom of beëindig. / Medical Research Council / National Research Foundation / Harry Crossley Foundation
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A Network View on Neurodegenerative DisordersChandrasekaran, Sreedevi 01 May 2013 (has links)
Neurodegeneration is a chronic, progressive and debilitating condition that affects majority of the World's elderly population who are at greater risk. Numerous scientific studies suggest that there could be a common underlying molecular mechanism that promotes the degeneration and the subsequent neuronal loss, however so far the progress in this direction is rather limited. Abnormal protein misfoldings, as well as protein plaque formations in the brain, are some of the hallmark characteristic features of neurodegenerative disorders (NDDs). Genetic and environmental factors, oxidative stress, excessive reactive oxygen species formation, mitochondrial dysfunction, energy depletion and autophagy disruption etc. are some of the widely suspected mechanisms that manifest the cognitive, motor and emotional symptoms of these NDDs. Motivated by some molecular traits found in common in several NDDs, network-based systems biology tools and techniques were used in this study to identify critical molecular players and underlying biological processes that are common for Parkinson's, Alzheimer's and Huntington's disease. Utilizing multiple microarray gene expression datasets, several biomolecular networks such as direct interaction, shortest path, and microRNA regulatory networks were constructed and analyzed for each of the disease conditions. The network-based analysis revealed 26 genes of potential interest in Parkinson's, 16 in Alzheimer's and 30 in Huntington's disease. Many new microRNA-target regulatory interactions were identified. For each disorder, several routes for possible disease initiation and protection scenarios were uncovered. A unified neurodegeneration mechanism network was constructed by utilizing the significantly differentially expressed genes found in common in Parkinson's, Alzheimer's and Huntington's microarray datasets. In this integrated network many key molecular partakers and several biological processes that were significantly affected in all three NDDs were uncovered. The integrated network also revealed complex dual-level interactions that occur between disease contributing and protecting entities. Possibilities of microRNA-target interactions were explored and many such pairs of potential interest in NDDs were suggested. Investigating the integrated network mechanism, we have identified several routes for disease initiating, as well as alleviating ones that could be utilized in common for Parkinson's, Alzheimer's and Huntington's disease. Finding such crucial and universal molecular players in addition to maintaining a delicate balance between neurodegeneration promoters and protectors is vital for restoring the homeostasis in the three NDDs.
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Polycyclic compounds as carriers for neuroactive non- steroidal anti-inflammatory drugsAbaniwonda, Modupe January 2017 (has links)
Magister Pharmaceuticae - MPharm / Recent scientific findings have highlighted the beneficial roles of polycyclic cage compounds in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Further interest into the chemistry of these compounds is stimulated by their remarkable ability to improve the pharmacokinetics profile of known neuroprotective agents. As potent lipophilic scaffolds, they can be employed to target the brain delivery of desired compounds.
Inflammation is a key mediator of neuronal cell's degeneration as activated microglia and other inflammatory mediators propagate oxidative damage and neuronal loss. Epidemiological and clinical evidence suggests that non-steroidal anti-inflammatory drugs (NSAIDs) slow down the progression and onset of neurodegenerative diseases. The beneficial effects of NSAIDs in ND can be attributed to their ability to inhibit cyclooxygenase enzymes thereby halting the biosynthesis of prostaglandins (PG) which are powerful mediators of inflammation. NSAIDs also inhibit the expression of pro- inflammatory genes. Despite their potential neuroprotective activity, NSAIDs are poorly lipophilic due to the presence of polar carboxylic acid groups and will therefore ionise at physiological pH, deterring them from reaching the desired site of action in the central nervous system (CNS).
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