| 1. |
- Araujo, IM, et al.
(författare)
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Calpain activation is involved in early caspase-independent neurodegeneration in the hippocampus following status epilepticus
- 2008
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 105:3, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- Evidence for increased calpain activity has been described in the hippocampus of rodent models of temporal lobe epilepsy. However, it is not known whether calpains are involved in the cell death that accompanies seizures. In this work, we characterized calpain activation by examining the proteolysis of calpain substrates and in parallel we followed cell death in the hippocampus of epileptic rats. Male Wistar rats were injected with kainic acid (KA; 10 mg/kg) intraperitoneally and sacrificed 24h later, after development of grade 5 seizures. We observed a strong Fluoro-Jade labelling in the CA1 and CA3 areas of the hippocampus in the rats that received KA, as compared to saline-treated rats. Immunohistochemistry and Western blot analysis for the calpain-derived breakdown products of spectrin (SBDP) showed evidence of increased calpain activity in the same regions of the hippocampus where cell death is observed. No evidence was found for caspase activation, in the same conditions. Treatment with the calpain inhibitor MDL 28170 significantly prevented the neurodegeneration observed in CA1. Taken together, our data suggest that early calpain activation, but not caspase activation, is involved in neurotoxicity in the hippocampus after status epilepticus.
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| 2. |
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| 3. |
- Bacos, Karl, et al.
(författare)
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Islet beta-cell area and hormone expression are unaltered in Huntington's disease.
- 2008
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Ingår i: Histochemistry and Cell Biology. - : Springer Science and Business Media LLC. - 1432-119X .- 0948-6143. ; 129, s. 623-629
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Tidskriftsartikel (refereegranskat)abstract
- Neurodegenerative disorders are often associated with metabolic alterations. This has received little attention, but might be clinically important because it can contribute to symptoms and influence the course of the disease. Patients with Huntington's disease (HD) exhibit increased incidence of diabetes mellitus (DM). This is replicated in mouse models of HD, e.g., the R6/2 mouse, in which DM is primarily caused by a deficiency of beta-cells with impaired insulin secretion. Pancreatic tissue from HD patients has previously not been studied and, thus, the pathogenesis of DM in HD is unclear. To address this issue, we examined pancreatic tissue sections from HD patients at different disease stages. We found that the pattern of insulin immunostaining, levels of insulin transcripts and islet beta-cell area were similar in HD patients and controls. Further, there was no sign of amyloid deposition in islets from HD patients. Thus, our data show that pancreatic islets in HD patients appear histologically normal. Functional studies of HD patients with respect to insulin secretion and islet function are required to elucidate the pathogenesis of DM in HD. This may lead to a better understanding of HD and provide novel therapeutic targets for symptomatic treatment in HD.
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| 4. |
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| 5. |
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| 6. |
- Björkqvist, Maria, et al.
(författare)
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Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease
- 2006
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 15:10, s. 1713-1721
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is characterized by a triad of motor, psychiatric and cognitive symptoms. Although many of these symptoms are likely to be related to central nervous system pathology, others may be due to changes in peripheral tissues. The R6/2 mouse, a transgenic model of HD expressing exon 1 of the human HD gene, develops progressive alterations in the hypothalamic-pituitary-adrenal axis, reminiscent of a Cushing-like syndrome. We observed muscular atrophy, reduced bone mineral density, abdominal fat accumulation and insulin resistance in the mice. All these changes could be consequences of increased glucocorticoid levels. Indeed, hypertrophy of the adrenal cortex and a progressive increase in serum and urine corticosterone levels were found in R6/2 mice. In addition, the intermediate pituitary lobe was markedly enlarged and circulating adreno-corticotrophic hormone (ACTH) increased. Under normal conditions dopamine represses the ACTH expression. In the R6/2 mice, however, the expression of pituitary dopamine D2 receptors was reduced by half, possibly explaining the increase in ACTH. Urinary samples from 82 HD patients and 68 control subjects were analysed for cortisol: in accord with the observations in the R6/2 mice, urinary cortisol increased in parallel with disease progression. This progressive increase in cortisol may contribute to the clinical symptoms, such as muscular wasting, mood changes and some of the cognitive deficits that occur in HD.
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| 7. |
- Björkqvist, Maria, et al.
(författare)
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The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient {beta}-cell mass and exocytosis.
- 2005
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 14:5, s. 565-574
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes frequently develops in Huntington's disease (HD) patients and in transgenic mouse models of HD such as the R6/2 mouse. The underlying mechanisms have not been clarified. Elucidating the pathogenesis of diabetes in HD would improve our understanding of the molecular mechanisms involved in HD neuropathology. With this aim, we examined our colony of R6/2 mice with respect to glucose homeostasis and islet function. At week 12, corresponding to end-stage HD, R6/2 mice were hyperglycemic and hypoinsulinemic and failed to release insulin in an intravenous glucose tolerance test. In vitro, basal and glucose-stimulated insulin secretion was markedly reduced. Islet nuclear huntingtin inclusions increased dramatically over time, predominantly in ß-cells. ß-cell mass failed to increase normally with age in R6/2 mice. Hence, at week 12, ß-cell mass and pancreatic insulin content in R6/2 mice were 35±5 and 16±3% of that in wild-type mice, respectively. The normally occurring replicating cells were largely absent in R6/2 islets, while no abnormal cell death could be detected. Single cell patch-clamp experiments revealed unaltered electrical activity in R6/2 ß-cells. However, exocytosis was virtually abolished in ß- but not in {alpha}-cells. The blunting of exocytosis could be attributed to a 96% reduction in the number of insulin-containing secretory vesicles. Thus, diabetes in R6/2 mice is caused by a combination of deficient ß-cell mass and disrupted exocytosis.
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| 8. |
- Brundin, Patrik, et al.
(författare)
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Graft survival
- 1999
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Ingår i: Journal of Neurosurgery. - 0022-3085. ; 90:4, s. 804-805
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Tidskriftsartikel (refereegranskat)
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| 9. |
- Brundin, Patrik, et al.
(författare)
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Improving the survival of grafted dopaminergic neurons: a review over current approaches
- 2000
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Ingår i: Cell Transplantation. - 1555-3892. ; 9:2, s. 179-195
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Tidskriftsartikel (refereegranskat)abstract
- Neural transplantation is developing into a therapeutic alternative in Parkinson's disease. A major limiting factor is that only 3-20% of grafted dopamine neurons survive the procedure. Recent advances regarding how and when the neurons die indicate that events preceding actual tissue implantation and during the first week thereafter are crucial, and that apoptosis plays a pivotal role. Triggers that may initiate neuronal death in grafts include donor tissue hypoxia and hypoglycemia, mechanical trauma, free radicals, growth factor deprivation, and excessive extracellular concentrations of excitatory amino acids in the host brain. Four distinct phases during grafting that can involve cell death have been identified: retrieval of the embryo; dissection and preparation of the donor tissue; implantation procedure followed by the immediate period after graft injection; and later stages of graft maturation. During these phases, cell death processes involving free radicals and caspase activation (leading to apoptosis) may be triggered, possibly involving an increase in intracellular calcium. We review different approaches that reduce cell death and increase survival of grafted neurons, typically by a factor of 2-4. For example, changes in transplantation procedure such as improved media and implantation technique can be beneficial. Calcium channel antagonists such as nimodipine and flunarizine improve nigral graft survival. Agents that counteract oxidative stress and its consequences, such as superoxide dismutase overexpression, and lazaroids can significantly increase the survival of transplanted dopamine neurons. Also, the inhibition of apoptosis by a caspase inhibitor has marked positive effects. Finally, basic fibroblast growth factor and members of the transforming growth factor-beta superfamily, such as glial cell line-derived neurotrophic factor, significantly improve the outcome of nigral transplants. These recent advances provide hope for improved survival of transplanted neurons in patients with Parkinson's disease, reducing the need for human embryonic donor tissue and increasing the likelihood of a successful outcome.
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| 10. |
- Gil, Joana, et al.
(författare)
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Asialoerythropoetin is not effective in the R6/2 line of Huntington's disease mice
- 2004
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Ingår i: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in the HD gene. Both excitotoxicity and oxidative stress have been proposed to play important roles in the pathogenesis of HD. Since no effective treatment is available, this study was designed to explore the therapeutic potential of erythropoietin (EPO), a cytokine that has been found to prevent excitotoxicity, and to promote neurogenesis. To avoid the side effects of a raised hematocrit, we used asialoerythropoietin (asialoEPO), a neuroprotective variant of EPO that lacks erythropoietic effects in mice. R6/2 transgenic HD mice were treated with this cytokine from five to twelve weeks of age. Results: We provide new evidence that cell proliferation in the dentate gyrus of the R6/2 hippocampus is reduced by 50% compared to wild-type littermate controls. However, we found that the asialoEPO treatment did not affect the progression of motor symptoms, weight loss or the neuropathological changes. Furthermore, cell proliferation was not enhanced. Conclusions: We conclude that the chosen protocol of asialoEPO treatment is ineffective in the R6/2 model of HD. We suggest that reduced hippocampal cell proliferation may be an important and novel neuropathological feature in R6 HD mice that could be assessed when evaluating potential therapies.
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