By 2040, the World Health Organization expects neurodegenerative diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease, to surpass cancer as the second most common cause of death worldwide. Currently, only treatments for symptoms of these diseases are available. Thus, research is critical to alleviate this public health burden by elucidating the pathogenic processes and developing novel therapies. While exact mechanisms by which these heterogeneous neuropathological conditions become manifest in patients remain unclear, growing evidence suggests that oxidative stress (OS) makes a significant contribution to neuronal dysfunction and apoptosis in all major neurodegenerative diseases. Recently, the gene oxidation resistance 1 (Oxr1) has emerged as a critical regulator of neuronal survival in response to OS. Oxr1 is expressed throughout the central nervous system, and its highly conserved TLDc domain protects neurons from oxidative damage through an unknown mechanism. This thesis aimed to define mechanisms by which Oxr1 confers neuronal sensitivity to OS, and to determine its role in neurodegenerative diseases. I found that Oxr1 mediates cytoplasmic localization of ALS-associated proteins Fused in Sarcoma (FUS) and transactive response DNA binding protein 43 kDa (TDP-43) through a TLDc domain- and arginine methylation-dependent pathway. Next, I investigated in vivo neuroprotective functions of Oxr1, and demonstrated that neuronal Oxr1 over-expression extends survival and ameliorates behavioural dysfunction and pathology of an ALS mouse model. In particular, neuronal Oxr1 over-expression strikingly delays neuroinflammation during ALS pathogenesis. Finally, I characterised a mouse model that specifically deletes Oxr1 from motor neurons. While loss of Oxr1 in ChAT-positive motor neurons does not cause overt neurodegeneration in the spinal cord, constitutive loss of Oxr1 leads to neuroinflammation in the cerebellum and spinal cord. Taken together, these studies illuminate functions of Oxr1 in the complex antioxidant defence network and present implications for future therapeutic strategies.

Lipids are important for structural and physiological functions of neuronal cell membranes. They exhibit a range of biological effects many are bioactive lipid mediators derived from polyunsaturated fatty acids such as sphingolipids, fatty acid ethanolamides (FA-EA) and endocannabinoids (EC). These lipid mediators and oxysterols elicit potent bioactive functions in many physiological and pathological processes of the brain and neuronal tissues. They have been investigated for biomarker discovery of ageing, neuroinflammation and neurodegenerative disorders. The n-3 fatty acids EPA and DPA are thought to exhibit a range of neuroprotective effects many of which are mediated through production of such lipid mediators. The aims of this study were to evaluate the effects of n-3 EPA and n-3 DPA supplementation on RBC membranes and in this way assess dietary compliance and to investigate brain sphingomyelin species of adult and aged rats supplemented with n-3 EPA and n-3 DPA to evaluate the effects and benefits on age-related changes in the brain. Furthermore, to study the effects of lithium on the brain FA-EAs and ECs to further understand the neuroprotective effects of lithium neuroprotective action on neuroinflammation as induced by LPS. Finally to examine if circulating oxysterols are linked to the prevalence of ALS and whether RBC fatty acids are markers of this action in relation to age and disease stages. These analytes were extracted from tissue samples and analysed with GC, LC/ESI-MS/MS and GC-MS. It was found that aged rats exhibited a significant increase in brain AA and decrease in Σn-3 and Σn-6 PUFAs when compared to adult animals. The observed increase of brain AA was reversed following n-3 EPA and n-3 DPA supplementation. Sphingomyelin was significantly increased when aged animals were supplemented with n-3 DPA. LPS treatment following lithium supplementation increased LA-EA and ALA-EA, while it decreased DHA-EA. Both oxysterols 24-OH and 27-OH increased in ALS patients and SOD1-mice. Eicosadienoic acid was different in ASL-patients compared to aged SOD1-mice. These studies demonstrated that dietary intake of n-3 EPA and n-3DPA significantly altered RBC fatty acids and sphingolipids in rat brain. They suggest that n-3 DPA can be a potential storage form for EPA, as shown by retro-conversion of n-3 DPA into EPA in erythrocyte membranes, ensuring supply of n-3 EPA. Also, n-3 EPA and n-3 DPA supplementation can contribute to an increase in brain sphingomyelin species with implications for age effects and regulation of brain development. Effects of lithium highlight novel anti-neuroinflammatory treatment pathways. Both 24-hydroxycholesterol and eicosadienoic acid may be used as biomarkers in ALS thereby possibly helping to manage the progressive stages of disease.

Made available in DSpace on 2015-07-22T20:50:46Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-05-25 / Stanich P. Relevância dos aspectos nutricionais na sobrevida de pacientes com Doença do Neurônio Motor. São Paulo; 2001. [Tese de Doutorado- Escola Paulista de Medicina – Universidade Federal de São Paulo]. Objetivos. Avaliar o efeito dos aspectos nutricionais na sobrevida de pacientes com Doença do Neurônio Motor (DNM) e apresentar as variáveis preditivas para a indicação de terapia nutricional enteral, por gastrostomia endoscópica percutânea (GEP). Material e Métodos. Foi um estudo longitudinal tipo coorte retrospectiva, de 2000 a 2008, e a casuística constituída por 128 pacientes com DNM. Variáveis clínicas, nutricionais e respiratórias foram analisadas. As análises foram conduzidas adotando-se a sobrevida como variável dependente. A sobrevida foi avaliada pela Curva de Kaplain - Meier. As variáveis que apresentaram nível de significância de 20% (p< 0,20) foram selecionadas para o modelo de regressão proporcional de Cox. Resultados. Cento e onze pacientes realizaram a gastrostomia, sendo 59 com a forma apendicular (ELA) e 52 com a forma bulbar (PBP). A desnutrição estava presente em 32% da população antes da GEP, com maior frequência nos pacientes com ELA. O tempo de sobrevida após a GEP foi de 11 meses para os pacientes com PBP e 16 meses para ELA (p< 0,05). As variáveis associadas à sobrevida foram: precocidade na indicação da GEP; redução de CVF %, idade e IMC antes da GEP (hazard ratio de 0, 254 e p = 0, 007) para os pacientes com ELA e exclusão da alimentação por via oral e traqueostomia (hazard ratio de 0, 345 e p= 0, 014) para os pacientes com PBP. Ao final do modelo as variáveis mais associadas com a sobrevida foram precocidade na indicação de GEP, exclusão da alimentação por via oral, para os pacientes com PBP e estado nutricional antes da GEP para os pacientes com ELA. Conclusões. A inserção precoce de gastrostomia endoscópica percutânea, a partir do momento diagnóstico, foi fator protetor para a sobrevida dos pacientes. A desnutrição foi fator prognóstico ruim, especialmente para os pacientes com ELA. Vigilância nutricional durante a evolução da doença pode melhorar os resultados quando o objetivo é aumentar a sobrevida de pacientes com DNM/ELA. / Aims. To evaluate the effect of nutrition on survival of patients with Motor Neurone Disease (MND) and present the predictor variables for indications of nutritional therapy, percutaneous endoscopic gastrostomy (PEG). Methods. It was a retrospective longitudinal cohort study, from 2000 to 2008, and the sample consisted of 128 patients with MND. The variables investigated were clinical, nutritional and respiratory were analysed. Analyses were conducted by adopting the survival as the dependent variable. The survival curve was evaluated by Kaplain - Meier. The variables that had a significance level of 20% (p <0.20) were selected for the proportional regression model of Cox. Results. One hundred and eleven patients underwent gastrostomy, and 59 limb onset (ALS) and 52 with bulbar onset (PBP). Malnutrition was present in 32% of the population before PEG, most frequently in patients with limb onset. The survival time after PEG was 10.5 months for patients with PBP and 16 months for ALS (p <0.05). Variables associated with survival were: early indication in the PEG, for ALS and PBP; reduction of FVC% and BMI before PEG (hazard ratio of 0, 254, p = 0, 007) for patients with limb onset and exclusion of oral feeding and tracheostomy (hazard ratio of 0, 345, p = 0, 014) for patients with bulbar onset. Conclusions. Early insertion of percutaneous endoscopic gastrostomy, from the time diagnosis was a protective factor for patient survival. Malnutrition was a bad prognostic factor, especially for patients with limb onset. Nutritional surveillance for disease progression may improve results when the goal is to increase the survival of patients with MND / ALS. / TEDE / BV UNIFESP: Teses e dissertações

Lipids are important for structural and physiological functions of neuronal cell membranes. They exhibit a range of biological effects many are bioactive lipid mediators derived from polyunsaturated fatty acids such as sphingolipids, fatty acid ethanolamides (FA-EA) and endocannabinoids (EC). These lipid mediators and oxysterols elicit potent bioactive functions in many physiological and pathological processes of the brain and neuronal tissues. They have been investigated for biomarker discovery of ageing, neuroinflammation and neurodegenerative disorders. The n-3 fatty acids EPA and DPA are thought to exhibit a range of neuroprotective effects many of which are mediated through production of such lipid mediators. The aims of this study were to evaluate the effects of n-3 EPA and n-3 DPA supplementation on RBC membranes and in this way assess dietary compliance and to investigate brain sphingomyelin species of adult and aged rats supplemented with n-3 EPA and n-3 DPA to evaluate the effects and benefits on age-related changes in the brain. Furthermore, to study the effects of lithium on the brain FA-EAs and ECs to further understand the neuroprotective effects of lithium neuroprotective action on neuroinflammation as induced by LPS. Finally to examine if circulating oxysterols are linked to the prevalence of ALS and whether RBC fatty acids are markers of this action in relation to age and disease stages. These analytes were extracted from tissue samples and analysed with GC, LC/ESI-MS/MS and GC-MS. It was found that aged rats exhibited a significant increase in brain AA and decrease in ¿n-3 and ¿n-6 PUFAs when compared to adult animals. The observed increase of brain AA was reversed following n-3 EPA and n-3 DPA supplementation. Sphingomyelin was significantly increased when aged animals were supplemented with n-3 DPA. LPS treatment following lithium supplementation increased LA-EA and ALA-EA, while it decreased DHA-EA. Both oxysterols 24-OH and 27-OH increased in ALS patients and SOD1-mice. Eicosadienoic acid was different in ASL-patients compared to aged SOD1-mice. These studies demonstrated that dietary intake of n-3 EPA and n-3DPA significantly altered RBC fatty acids and sphingolipids in rat brain. They suggest that n-3 DPA can be a potential storage form for EPA, as shown by retro-conversion of n-3 DPA into EPA in erythrocyte membranes, ensuring supply of n-3 EPA. Also, n-3 EPA and n-3 DPA supplementation can contribute to an increase in brain sphingomyelin species with implications for age effects and regulation of brain development. Effects of lithium highlight novel anti-neuroinflammatory treatment pathways. Both 24-hydroxycholesterol and eicosadienoic acid may be used as biomarkers in ALS thereby possibly helping to manage the progressive stages of disease. / Libyan Government