Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by death of motor neurons leading to muscle wasting, paralysis, and death, usually within 2–3 years of ...symptom onset. The causes of ALS are not completely understood, and the neurodegenerative processes involved in disease progression are diverse and complex. There is substantial evidence implicating oxidative stress as a central mechanism by which motor neuron death occurs, including elevated markers of oxidative damage in ALS patient spinal cord and cerebrospinal fluid and mutations in the antioxidant enzyme superoxide dismutase 1 (SOD1) causing approximately 20% of familial ALS cases. However, the precise mechanism(s) by which mutant SOD1 leads to motor neuron degeneration has not been defined with certainty, and the ultimate trigger for increased oxidative stress in non-SOD1 cases remains unclear. Although some antioxidants have shown potential beneficial effects in animal models, human clinical trials of antioxidant therapies have so far been disappointing. Here, the evidence implicating oxidative stress in ALS pathogenesis is reviewed, along with how oxidative damage triggers or exacerbates other neurodegenerative processes, and we review the trials of a variety of antioxidants as potential therapies for ALS.
The cause(s) of amyotrophic lateral sclerosis (ALS) is not fully understood in the vast majority of cases and the mechanisms involved in motor neuron degeneration are multi-factorial and complex. ...There is substantial evidence to support the hypothesis that oxidative stress is one mechanism by which motor neuron death occurs. This theory becomes more persuasive with the discovery that mutation of the anti-oxidant enzyme, superoxide dismutase 1 (SOD1), causes disease in a significant minority of cases. However, the precise mechanism(s) by which mutant SOD1 leads to motor neuron degeneration have not been defined with certainty, and trials of anti-oxidant therapies have been disappointing. Here, we review the evidence implicating oxidative stress in ALS pathogenesis, discuss how oxidative stress may affect and be affected by other proposed mechanisms of neurodegeneration, and review the trials of various anti-oxidants as potential therapies for ALS.
Amyotrophic lateral sclerosis is a neurodegenerative disease in which death of motoneurons leads to progressive failure of the neuromuscular system resulting in death frequently within 2-3 years of ...symptom onset. Focal onset and propagation of the disease symptoms to contiguous motoneuron groups is a striking feature of the human disease progression. Recent work, using mutant superoxide dismutase 1 murine models and in vitro culture systems has indicated that astrocytes are likely to contribute to the propagation of motoneuron injury and disease progression. However, the basis of this astrocyte toxicity and/or failure of motoneuron support has remained uncertain. Using a combination of in vivo and in vitro model systems of superoxide dismutase 1-related amyotrophic lateral sclerosis, linked back to human biosamples, we set out to elucidate how astrocyte properties change in the presence of mutant superoxide dismutase 1 to contribute to motoneuron injury. Gene expression profiling of spinal cord astrocytes from presymptomatic transgenic mice expressing mutant superoxide dismutase 1 revealed two striking changes. First, there was evidence of metabolic dysregulation and, in particular, impairment of the astrocyte lactate efflux transporter, with resultant decrease of spinal cord lactate levels. Second, there was evidence of increased nerve growth factor production and dysregulation of the ratio of pro-nerve growth factor to mature nerve growth factor, favouring p75 receptor expression and activation by neighbouring motoneurons. Functional in vitro studies showed that astrocytes expressing mutant superoxide dismutase 1 are toxic to normal motoneurons. We provide evidence that reduced metabolic support from lactate release and activation of pro-nerve growth factor-p75 receptor signalling are key components of this toxicity. Preservation of motoneuron viability could be achieved by increasing lactate provision to motoneurons, depletion of increased pro-nerve growth factor levels or p75 receptor blockade. These findings are likely to be relevant to human amyotrophic lateral sclerosis, where we have demonstrated increased levels of pro-nerve growth factor in cerebrospinal fluid and increased expression of the p75 receptor by spinal motoneurons. Taken together, these data confirm that altered properties of astrocytes are likely to play a crucial role in the propagation of motoneuron injury in superoxide dismutase 1-related amyotrophic lateral sclerosis and indicate that manipulation of the energy supply to motoneurons as well as inhibition of p75 receptor signalling may represent valuable neuroprotective strategies.
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease, characterized by progressive dysfunction and death of motor neurons. Although evidence for oxidative stress in ALS ...pathogenesis is well described, antioxidants have generally shown poor efficacy in animal models and human clinical trials. We have developed an in vitro screening cascade to identify antioxidant molecules capable of rescuing NSC34 motor neuron cells expressing an ALS-associated mutation of superoxide dismutase 1. We have tested known antioxidants and screened a library of 2000 small molecules. The library screen identified 164 antioxidant molecules, which were refined to the 9 most promising molecules in subsequent experiments. Analysis of the in silico properties of hit compounds and a review of published literature on their in vivo effectiveness have enabled us to systematically identify molecules with antioxidant activity combined with chemical properties necessary to penetrate the central nervous system. The top-performing molecules identified include caffeic acid phenethyl ester, esculetin, and resveratrol. These compounds were tested for their ability to rescue primary motor neuron cultures after trophic factor withdrawal, and the mechanisms of action of their antioxidant effects were investigated. Subsequent in vivo studies can be targeted using molecules with the greatest probability of success.
Compelling evidence indicates that oxidative stress contributes to motor neuron injury in amyotrophic lateral sclerosis (ALS), but antioxidant therapies have not yet achieved therapeutic benefit in ...the clinic. The nuclear erythroid 2-related-factor 2 (Nrf2) transcription factor is a key regulator of an important neuroprotective response by driving the expression of multiple cytoprotective genes via its interaction with the antioxidant response element (ARE). Dysregulation of the Nrf2-ARE system has been identified in ALS models and human disease. Taking the Nrf2-ARE pathway as an attractive therapeutic target for neuroprotection in ALS, we aimed to identify CNS penetrating, small molecule activators of Nrf2-mediated transcription in a library of 2000 drugs and natural products. Compounds were screened extensively for Nrf2 activation, and antioxidant and neuroprotective properties in vitro. S+-Apomorphine, a receptor-inactive enantiomer of the clinically approved dopamine-receptor agonist (R–-apomorphine), was identified as a nontoxic Nrf2 activating molecule. In vivo S+-apomorphine demonstrated CNS penetrance, Nrf2 induction, and significant attenuation of motor dysfunction in the SOD1G93A transgenic mouse model of ALS. S+-apomorphine also reduced pathological oxidative stress and improved survival following an oxidative insult in fibroblasts from ALS patients. This molecule emerges as a promising candidate for evaluation as a potential neuroprotective agent in ALS patients in the clinic.
The articles included in this issue take into consideration the relationship between television and education in its broadest sense, offering historical studies of television programming, national ...policies, audience attitudes and evolving socio-political contexts. It includes case studies of different broadcasters, specific educational programming initiatives, government or state education policy delivered through the television medium, the intersections between broadcast programmes and what is retained in television archives. They cover Turkey, Germany, Italy, the UK, and Finland and map the period from the 1960s to the present day. All of this material helps situate educational provision on television within broader histories of both television as a form and education as an overarching idea or objective.
This study guide is intended to provide a starting point for those seeking to use film as a source. It is aimed at those who want to use film and moving image as the basis for research and offers ...advice on research methods, theory and methodology, archival work and film-based analysis.
Familial amyotrophic lateral sclerosis (FALS) is caused, in 20% of cases, by mutations in the Cu/Zn superoxide dismutase gene (SOD1). Although motor neuron injury occurs through a toxic gain of ...function, the precise mechanism(s) remains unclear. Using an established NSC34 cellular model for SOD1-associated FALS, we investigated the effects of mutant SOD1 specifically in cells modelling the vulnerable cell population, the motor neurons, without contamination from non-neuronal cells present in CNS. Using gene expression profiling, 268 transcripts were differentially expressed in the presence of mutant human G93A SOD1. Of these, 197 were decreased, demonstrating that the presence of mutant SOD1 leads to a marked degree of transcriptional repression. Amongst these were a group of antioxidant response element (ARE) genes encoding phase II detoxifying enzymes and antioxidant response proteins (so-called ‘programmed cell life’ genes), the expression of which is regulated by the transcription factor NRF2. We provide evidence that dysregulation of Nrf2 and the ARE, coupled with reduced pentose phosphate pathway activity and decreased generation of NADPH, represent significant and hitherto unrecognized components of the toxic gain of function of mutant SOD1. Other genes of interest significantly altered in the presence of mutant SOD1 include several previously implicated in neurodegeneration, as well as genes involved in protein degradation, the immune response, cell death/survival and the heat shock response. Preliminary studies on isolated motor neurons from SOD1-associated motor neuron disease cases suggest key genes are also differently expressed in the human disease.
This article explores local film censorship in Northern Ireland, examining the ways in which individual local authorities and committees imposed their own conceptions of what was acceptable for the ...cinema-going public. Drawing on material from the Public Records Office Northern Ireland (PRONI) this work begins with the setting up of local censorship systems in the newly created Northern Irish state in the 1920s, and maps the interventions by a range of local councils across the decades including objections to films such as Frankenstein, The Outlaw and Garden of Eden. It offers a comparative focus of a specific geographical region and argues that understandings of film censorship must move beyond a straightforward national verses local model in order to acknowledge a more nuanced picture that encompasses local sensitivities, regional politics and religious feeling.
Recent debates about media literacy and the internet have begun to acknowledge the importance of active user-engagement and interaction. It is not enough simply to access material online, but one ...must also be able to comment upon it and re-use it. Yet how do these new user expectations fit within digital initiatives which increase access to audio-visual-content but which prioritise access, preservation of archives and online research rather than active user-engagement? This article will address these issues of media literacy in relation to audio-visual content. It will consider how these issues are currently being addressed, focusing particularly on the high-profile European initiative EUscreen. EUscreen brings together 20 European television archives into a single searchable database of over 40,000 digital items. Yet creative re-use restrictions and copyright issues prevent users from re-working the material they find on the site. Instead of re-use, EUscreen offers access and detailed contextualisation of its collection of material. But if the emphasis for resources within an online environment no longer rests upon access but on user-engagement, what does EUscreen and similar sites have to offer to different users?
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