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| 2. |
- 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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| 3. |
- Esmeraldo Paiva, Aislan, et al.
(författare)
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High Aspect Ratio Nanoscale Pores through BCP-Based Metal Oxide Masks and Advanced Dry Etching
- 2023
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Ingår i: ACS applied materials & interfaces. - 1944-8244. ; 15:50, s. 57960-57969
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Tidskriftsartikel (refereegranskat)abstract
- The reliable and regular modification of the surface properties of substrates plays a crucial role in material research and the development of functional surfaces. A key aspect of this is the development of the surface pores and topographies. These can confer specific advantages such as high surface area as well as specific functions such as hydrophobic properties. Here, we introduce a combination of nanoscale self-assembled block-copolymer-based metal oxide masks with optimized deep reactive ion etching (DRIE) of silicon to permit the fabrication of porous topographies with aspect ratios of up to 50. Following the evaluation of our procedure and involved parameters using various techniques, such as AFM or SEM, the suitability of our features for applications relying on high light absorption as well as efficient thermal management is explored and discussed in further detail.
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| 4. |
- Fritschi, Sarah K, et al.
(författare)
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Highly potent soluble amyloid-β seeds in human Alzheimer brain but not cerebrospinal fluid.
- 2014
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 137:11, s. 2909-2915
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Tidskriftsartikel (refereegranskat)abstract
- The soluble fraction of brain samples from patients with Alzheimer's disease contains highly biologically active amyloid-β seeds. In this study, we sought to assess the potency of soluble amyloid-β seeds derived from the brain and cerebrospinal fluid. Soluble Alzheimer's disease brain extracts were serially diluted and then injected into the hippocampus of young, APP transgenic mice. Eight months later, seeded amyloid-β deposition was evident even when the hippocampus received subattomole amounts of brain-derived amyloid-β. In contrast, cerebrospinal fluid from patients with Alzheimer's disease, which contained more than 10-fold higher levels of amyloid-β peptide than the most concentrated soluble brain extracts, did not induce detectable seeding activity in vivo. Similarly, cerebrospinal fluid from aged APP-transgenic donor mice failed to induce cerebral amyloid-β deposition. In comparison to the soluble brain fraction, cerebrospinal fluid largely lacked N-terminally truncated amyloid-β species and exhibited smaller amyloid-β-positive particles, features that may contribute to the lack of in vivo seeding by cerebrospinal fluid. Interestingly, the same cerebrospinal fluid showed at least some seeding activity in an in vitro assay. The present results indicate that the biological seeding activity of soluble amyloid-β species is orders of magnitude greater in brain extracts than in the cerebrospinal fluid.
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| 5. |
- Hansson, Oskar, et al.
(författare)
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Additive effects of caspase inhibitor and lazaroid on the survival of transplanted rat and human embryonic dopamine neurons
- 2000
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 164:1, s. 102-111
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Tidskriftsartikel (refereegranskat)abstract
- Major practical constraints on neural grafting in Parkinson's disease are the shortage of human donor tissue and the great loss of dopamine neurons during the grafting procedure. The vast majority of implanted embryonic dopamine neurons are believed to die within a few days of transplantation surgery, at least in part through apoptosis. We have previously found that survival of nigral grafts in rodents can be significantly augmented by pretreatment with the caspase inhibitor Ac-YVAD-cmk or by lazaroids (lipid peroxidation inhibitors). We now report that pretreatment with the caspase inhibitor Ac-DEVD-cmk, but not z-VAD-fmk, results in a significantly improved survival of transplanted dopamine neurons of similar magnitude to that achieved in this study using Ac-YVAD-cmk (both 220-230% of control). In addition, we found that treatment of the graft tissue with tirilazad mesylate (a lazaroid allowed for clinical use) almost doubled the survival of grafted dopamine neurons. When Ac-YVAD-cmk and tirilazad mesylate treatments were combined, the number of surviving dopamine neurons increased significantly further to 280% of control. Importantly, the same combination of neuroprotectants enhanced the survival of human dopamine neurons xenotransplanted to immunosuppressed rats (to 240% of control). In conclusion, these results suggest that combining treatments that counteract oxidative stress and caspase activation is a valuable strategy to enhance nigral graft survival that should be considered for clinical application.
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| 6. |
- Maciel, EN, et al.
(författare)
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Cyclosporin A and Bcl-2 do not inhibit quinolinic acid-induced striatal excitotoxicity in rodents
- 2003
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Ingår i: Experimental Neurology. - 0014-4886. ; 183:2, s. 430-437
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial permeability transition (MPT) is a nonselective inner membrane permeabilization that contributes to neuronal cell death under circumstances such as brain trauma, ischemia, and hypoglycemia. Here we study the participation of MPT and the Bcl-2-sensitive apoptotic cell death pathway in glutamate receptor-mediated excitotoxicity. Intrastriatal infusions of the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid caused massive striatal neurodegeneration in both rats and mice. Interestingly, transgenic mice overexpressing human Bcl-2 and rats systemically treated with cyclosporin A did not exhibit reduced sensitivity to quinolinic acid-induced striatal toxicity. Both Bcl-2 and cyclosporin A are inhibitors of MPT; in addition Bcl-2 also inhibits apoptotic stimuli-mediated release of mitochondrial apoptogenic factors. Isolated brain mitochondria from cyclosporin A-treated rats showed resistance to Ca2+-induced dissipation of the membrane potential, indicating protection against MPT. We conclude that quinolinic acid-mediated striatal excitotoxicity is not dependent on MPT and Bcl-2-sensitive apoptotic cell death pathways. (C) 2003 Elsevier Science (USA). All rights reserved.
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| 7. |
- Mundt-Petersen, Ulrika, et al.
(författare)
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Pretreatment with MK-801 or the lazaroid U-83836E does not enhance striatal graft survival
- 2000
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Ingår i: Cell Transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 9:1, s. 73-78
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Tidskriftsartikel (refereegranskat)abstract
- A large proportion of grafted striatal neurons die, and mechanisms by which they succumb may involve excitotoxicity and oxidative stress. We investigated the effects of pretreatment of the graft tissue with the N-methyl-D-aspartate (NMDA) receptor antagonist (+)dizocilpine hydrogen maleate (MK-801) and lipid peroxidation inhibitor lazaroid U-83836E on the survival of transplanted striatal neurons. Neither compound increased the survival of grafts, suggesting that NMDA-related excitotoxicity or oxidative stress may not be primary mediators of cell death in striatal grafts.
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| 8. |
- Schierle, Gabriele
(författare)
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Apoptosis And Excitotoxicity In The Death of Cultured And Grafted Dopaminergic Neurones
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Over the past two decades, grafting of embryonic nigral tissue has developed into a feasible therapeutic strategy for Parkinson's disease (PD). It has become apparent that the degree of restoration of dopaminergic neurotransmission by the transplanted cells is highly correlated to the symptomatic relief. However, the efficacy of the treatment is still far from optimal: More than 90% of the grafted dopaminergic neurones die during the transplantation procedure and the immediate period (first one to four days) after graft injection. Improvement in the survival of transplanted cells would increase the potential of this therapeutic approach and facilitate a more widespread use. This background provided the motivation of the research described in the present thesis. The focus here was 1), to characterise cell death occurring during nigral transplantation, and, 2), to find and evaluate novel neuroprotective strategies. In the neurone an overload of Ca2+ effects a cascade of events ultimately leading to cell death. Ca2+ entry is mainly mediated either via excitatory amino acid (EAA) receptor activation or via voltage-dependent Ca2+ channels (VDCCs). In the present work, it could be shown that a potent inhibitor of the EAA receptor N-methyl-D-aspartate (NMDA) was able to protect cultured embryonic dopaminergic neurones against stress induced by serum-deprivation. On the other hand, when this compound was applied during mesencephalic grafting, no increase in dopaminergic neurone survival was observed. This indicates that excitotoxicity plays a subordinate role in death of transplanted dopaminergic neurones. In contrast, effective inhibition of VDCCs increased the survival of grafted dopaminergic neurones to 260% compared to control. Bcl-2 is a protein which has proven effective in the prevention of apoptosis in related contexts. Here it could be shown that it protected dopaminergic neurones in cultures subjected to serum-deprivation or staurosporine (STS) insult. However, Bcl-2 overexpression did not increase dopaminergic neurone survival when embryonic ventral mesencephalic tissue from transgenic mice was xenotransplanted into rats. The caspase family of proteases promotes apoptosis and some of its members are closely linked to a Bcl-2-independent pathway. In part of the current thesis, treatment with a caspase inhibitor was found to lead to a remarkable three-to-fourfold increase in the number of surviving implanted dopaminergic neurones, and thus efficiently blocked apoptosis. Activation of poly (ADP-ribose) polymerase (PARP) which is a substrate of caspases has recently been linked to neuronal death. However, its role in the context of apoptosis is still matter of debate. In the final part of the present thesis, it was shown that PARP does not play a role in nigral cell death. The presented research sheds further light on the mechanisms leading to cell death in nigral transplantation and led to the discovery of novel neuroprotective strategies which justify further exploration regarding their relevance for clinical application.
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| 9. |
- Schierle, Gabriele, et al.
(författare)
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Caspase inhibition reduces apoptosis and increases survival of nigral transplants
- 1999
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 5:1, s. 97-100
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Tidskriftsartikel (refereegranskat)abstract
- Transplantation of embryonic nigral tissue ameliorates functional deficiencies in Parkinson disease. The main practical constraints of neural grafting are the shortage of human donor tissue and the poor survival of dopaminergic neurons grafted into patients, which is estimated at 5-10% (refs. 3,4). The required amount of human tissue could be considerably reduced if the neuronal survival was augmented. Studies in rats indicate that most implanted embryonic neurons die within 1 week of transplantation, and that most of this cell death is apoptotic. Modified peptides, such as acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloro-methylketone (Ac-YVAD-cmk), that specifically inhibit proteases of the caspase family effectively block apoptosis in a plethora of experimental paradigms, such as growth factor withdrawal, excitotoxicity, axotomy, cerebral ischemia and brain trauma. Here we examined the effects of caspase inhibition by Ac-YVAD-cmk on cell death immediately after donor tissue preparation and on long-term graft survival. Treatment of the embryonic nigral cell suspension with Ac-YVAD-cmk mitigated DNA fragmentation and reduced apoptosis in transplants. It also increased survival of dopaminergic neurons grafted to hemiparkinsonian rats, and thereby substantially improved functional recovery.
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| 10. |
- Schierle, Gabriele, et al.
(författare)
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Flunarizine improves the survival of grafted dopaminergic neurons
- 1999
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Ingår i: Neuroscience. - 1873-7544. ; 94:1, s. 17-20
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Tidskriftsartikel (refereegranskat)abstract
- Embryonic nigral grafts can survive, reinnervate the striatum and reverse functional deficits in both experimental and clinical Parkinsonism. A major drawback is that only around 10% of the implanted dopaminergic neurons survive. The underlying mechanisms leading to this 90% cell death are not fully understood, but oxidative stress and a substantial loss of neurotrophic support are likely to be involved. Hypoxia and mechanical trauma, which are unavoidable during tissue preparation, may be a trigger for cell death. Recent studies have provided evidence that the type of cell death occurring is, to a large extent, apoptotic. Flunarizine is an antagonist of L-, T- and N-type calcium channels, which permits calcium entry into cells via a voltage-dependent mechanism. Flunarizine has been shown to protect neurons against death induced by serum deprivation, nerve growth factor deprivation, oxidative stress, axotomy and ischemia. This study was designed to investigate whether flunarizine can protect grafted embryonic dopaminergic neurons from death when implanted in a rat model of Parkinson's disease. Addition of 1 microM flunarizine inhibited cell death in a suspension of cells derived from the rat's ventral mesencephalon and when such a treated suspension was injected into the neostriatum there was a 2.6-fold greater number of surviving dopaminergic neurons, a doubling of the graft volume and a doubling of the volume of the host neostriatum innervated by dopaminergic fibers from the graft, compared with suspensions not exposed to flunarizine. Furthermore, rats injected with cells that had been exposed to flunarizine displayed a greater recovery of function in the amphetamine-induced rotation test.
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