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- Fredholm, BB, et al.
(författare)
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Consequences of eliminating adenosine A(1) receptors in mice
- 2003
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Ingår i: Drug Development Research (Proceedings of the Seventh International Symposium on Adenosine and Adenine Nucleotides - Part 1). - : Wiley. - 1098-2299 .- 0272-4391. ; 58, s. 350-
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Konferensbidrag (refereegranskat)abstract
- The second coding exon of the adenosine A, receptor gene was eliminated by homologous recombination. The phenotype of mice (mixed C57B6/129OlaHsd background) was studied, using siblings from matings of heterozygous mice. Among the offspring the ratio between+/+, +/-and -/-animals was 1:2:1. Over the first half-year-at least-growth and viability were the same in all genotypes. Binding of A(1) ligands was eliminated in-/-mice and halved in+/-mice. Blood pressure was increased in-/-mice and this was paralleled by an increase in plasma renin. Heart rate was unaffected, as was contractility. Furthermore, the response of the perfused heart to ischemia was similar in+/+and -/-hearts. However, remote preconditioning was eliminated in-/-mouse hearts. Tubuloglomerular feedback in the kidney was also lost in-/-mice. The analgesic response to a non-selective adenosing receptor agonist was lost in-/-mice, which also showed hyperalgesia in the tail-flick test. There was a slight hypoactivity in-/-mice, but responses to caffeine were essentially normal. The inhibition of excitatory neurotransmission in hippocampus by adenosine was lost in-/-mice and reduced in+/-mice. Responses to ATP were affected similarly. Hypoxic depression of synaptic transmission was essentially eliminated in hippocampus and hypoxic decrease in spinal respiratory neuron firing was markedly reduced. These results show that adenosine A, receptors play a physiologically important role in the kidney, spinal cord, and hippocampus and that they are critically important in the adaptive responses to hypoxia. (C) 2003 Wiley-Liss, Inc.
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- Petzold, Axel, et al.
(författare)
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Diagnosis and classification of optic neuritis
- 2022
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Ingår i: Lancet Neurology. - : ELSEVIER SCIENCE INC. - 1474-4422 .- 1474-4465. ; 21:12, s. 1120-1134
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Forskningsöversikt (refereegranskat)abstract
- There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Epidemiological data show that, cumulatively, optic neuritis is most frequently caused by many conditions other than multiple sclerosis. Worldwide, the cause and management of optic neuritis varies with geographical location, treatment availability, and ethnic background. We have developed diagnostic criteria for optic neuritis and a classification of optic neuritis subgroups. Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups.
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- Satir, Tugce Munise, et al.
(författare)
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Partial reduction of amyloid β production by β-secretase inhibitors does not decrease synaptic transmission
- 2020
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease (AD) is the most common form of age-related neurodegenerative diseases. Cerebral deposition of Aβ peptides, especially Aβ42, is considered the major neuropathological hallmark of AD and the putative cause of AD-related neurotoxicity. Aβ peptides are produced by sequential proteolytic processing of APP, with β-secretase (BACE) being the initiating enzyme. Therefore, BACE has been considered an attractive therapeutic target in AD research and several BACE inhibitors have been tested in clinical trials, but so far, all have had negative outcomes or even led to worsening of cognitive function. AD can be triggered by Aβ years before the first symptoms appear and one reason for the failures could be that the clinical trials were initiated too late in the disease process. Another possible explanation could be that BACE inhibition alters physiological APP processing in a manner that impairs synaptic function, causing cognitive deterioration. Methods: The aim of this study was to investigate if partial BACE inhibition, mimicking the putative protective effect of the Icelandic mutation in the APP gene, could reduce Aβ generation without affecting synaptic transmission. To investigate this, we used an optical electrophysiology platform, in which effects of compounds on synaptic transmission in cultured neurons can be monitored. We employed this method on primary cortical rat neuronal cultures treated with three different BACE inhibitors (BACE inhibitor IV, LY2886721, and lanabecestat) and monitored Aβ secretion into the cell media. Results: We found that all three BACE inhibitors tested decreased synaptic transmission at concentrations leading to significantly reduced Aβ secretion. However, low-dose BACE inhibition, resulting in less than a 50% decrease in Aβ secretion, did not affect synaptic transmission for any of the inhibitors tested. Conclusion: Our results indicate that Aβ production can be reduced by up to 50%, a level of reduction of relevance to the protective effect of the Icelandic mutation, without causing synaptic dysfunction. We therefore suggest that future clinical trials aimed at prevention of Aβ build-up in the brain should aim for a moderate CNS exposure of BACE inhibitors to avoid side effects on synaptic function. © 2020 The Author(s).
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