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| 2. |
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| 3. |
- Bäckström, Torbjörn, et al.
(författare)
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Allopregnanolone and mood disorders
- 2014
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 0301-0082 .- 1873-5118. ; 113, s. 88-94
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Tidskriftsartikel (refereegranskat)abstract
- Certain women experience negative mood symptoms during the menstrual cycle and progesterone addition in estrogen treatments. In women with PMDD increased negative mood symptoms related to allopregnanolone increase during the luteal phase of ovulatory menstrual cycles. In anovulatory cycles no symptom or sex steroid increase occurs. This is unexpected as positive modulators of the GABA-A receptor are generally increasing mood. This paradoxical effect has brought forward a hypothesis that the symptoms are provoked by allopregnanolone the GABA-A receptor system. GABA-A is the major inhibitory system in the brain. Positive modulators of the GABA-A receptor include the progesterone metabolites allopregnanolone and pregnanolone, benzodiazepines, barbiturates, and alcohol. GABA-A receptor modulators are known, in low concentrations to induce adverse, anxiogenic effects whereas in higher concentrations show beneficial, calming properties. Positive GABA-A receptor modulators induce strong paradoxical effects e.g. negative mood in 3-8% of those exposed, while up to 25% have moderate symptoms thus similar as the prevalence of PMDD, 3-8% among women in fertile ages, and up to 25% have moderate symptoms of premenstrual syndrome (PMS). The mechanism behind paradoxical reaction might be similar among them who react on positive GABA-A receptor modulators and in women with PMDD. In women the severity of these mood symptoms are related to the allopregnanolone serum concentrations in an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. Low to moderate progesterone/allopregnanolone concentrations in women increases the activity in the amygdala (measured with fMRI) similar to the changes seen during anxiety reactions. Higher concentrations give decreased amygdala activity similar as seen during benzodiazepine treatment with calming anxiolytic effects. Patients with PMDD show decreased sensitivity in GABA-A receptor sensitivity to diazepam and pregnanolone while increased sensitivity to allopregnanolone. This agrees with findings in animals showing a relation between changes in alpha4 and delta subunits of the GABA-A receptor and anxiogenic effects of allopregnanolone. Conclusion: These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor.(c) 2013 Elsevier Ltd. All rights reserved.
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| 5. |
- Dunning, Christopher, et al.
(författare)
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Can Parkinson's disease pathology be propagated from one neuron to another?
- 2012
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 97, s. 205-219
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease is the second most prevalent neurodegenerative disease, yet despite this, very little is known about the underlying cellular mechanisms. Initially it was thought to be a disease primarily involving loss of dopaminergic neurons in the substantia nigra pars compacta. Recent studies, however, have focused on observations that aggregated α-synuclein protein, the major component of Lewy bodies, is found throughout the nervous system. It is speculated that misfolded α-synuclein transfers between cells in a prion-like manner, thereby mediating the spread of the neuropathology. In this review, we discuss the staging (according to Braak) of Parkinson pathology and the concept describing the disease progression from one region of the brain to the other. We highlight how α-synuclein might be responsible for the spread of the disease. We compare the idea of a prion-like mechanism contributing to Parkinson's disease to emerging concepts that other proteins participate in similar processes in other neurodegenerative diseases. We then examine the future implications of a critical role in disease pathogenesis of α-synuclein for the classification, diagnosis and treatment of Parkinson's disease in the future.
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| 7. |
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| 8. |
- Ghavami, Saeid, 1965-, et al.
(författare)
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Autophagy and Apoptosis Dysfunction in Neurodegenerative Disorders
- 2014
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Ingår i: Progress in Neurobiology. - Kidlington, Oxford, United Kingdom : Pergamon Press. - 0301-0082 .- 1873-5118. ; 112, s. 24-49
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Forskningsöversikt (refereegranskat)abstract
- Autophagy and apoptosis are basic physiologic processes contributing to the maintenance of cellular homeostasis. Autophagy encompasses pathways that target long-lived cytosolic proteins and damaged organelles. It involves a sequential set of events including double membrane formation, elongation, vesicle maturation and finally delivery of the targeted materials to the lysosome. Apoptotic cell death is best described through its morphology. It is characterized by cell rounding, membrane blebbing, cytoskeletal collapse, cytoplasmic condensation, and fragmentation, nuclear pyknosis, chromatin condensation/fragmentation, and formation of membrane-enveloped apoptotic bodies, that are rapidly phagocytosed by macrophages or neighboring cells. Neurodegenerative disorders are becoming increasingly prevalent, especially in the Western societies, with larger percentage of members living to an older age. They have to be seen not only as a health problem, but since they are care-intensive, they also carry a significant economic burden. Deregulation of autophagy plays a pivotal role in the etiology and/or progress of many of these diseases. Herein, we briefly review the latest findings that indicate the involvement of autophagy in neurodegenerative diseases. We provide a brief introduction to autophagy and apoptosis pathways focusing on the role of mitochondria and lysosomes. We then briefly highlight pathophysiology of common neurodegenerative disorders like Alzheimer's diseases, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Then, we describe functions of autophagy and apoptosis in brain homeostasis, especially in the context of the aforementioned disorders. Finally, we discuss different ways that autophagy and apoptosis modulation may be employed for therapeutic intervention during the maintenance of neurodegenerative disorders.
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| 9. |
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| 10. |
- Hampel, Harald, et al.
(författare)
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Biomarkers for Alzheimer's disease therapeutic trials.
- 2011
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Ingår i: Progress in neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 95:4, s. 579-593
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Forskningsöversikt (refereegranskat)abstract
- The development of disease-modifying treatments for Alzheimer's disease requires innovative trials with large numbers of subjects and long observation periods. The use of blood, cerebrospinal fluid or neuroimaging biomarkers is critical for the demonstration of disease-modifying therapy effects on the brain. Suitable biomarkers are those which reflect the progression of AD related molecular mechanisms and neuropathology, including amyloidogenic processing and aggregation, hyperphosphorylation, accumulation of tau and neurofibrillary tangles, progressive functional, metabolic and structural decline, leading to neurodegeneration, loss of brain tissue and cognitive symptoms. Biomarkers should be used throughout clinical trial phases I-III of AD drug development. They can be used to enhance inclusion and exclusion criteria, or as baseline predictors to increase the statistical power of trials. Validated and qualified biomarkers may be used as outcome measures to detect treatment effects in pivotal clinical trials. Finally, biomarkers can be used to identify adverse effects. Questions regarding which biomarkers should be used in clinical trials, and how, are currently far from resolved. The Oxford Task Force continues and expands the work of our previous international expert task forces on disease-modifying trials and on endpoints for Alzheimer's disease clinical trials. The aim of this initiative was to bring together a selected number of key international opinion leaders and experts from academia, regulatory agencies and industry to condense the current knowledge and state of the art regarding the best use of biological markers in Alzheimer's disease therapy trials and to propose practical recommendations for the planning of future AD trials.
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| 11. |
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| 14. |
- Nässel, Dick R., et al.
(författare)
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Drosophila neuropeptides in regulation of physiology and behavior
- 2010
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 0301-0082 .- 1873-5118. ; 92, s. 42-104
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Tidskriftsartikel (refereegranskat)abstract
- Studies of neuropeptide and peptide hormone signaling are coming of age in Drosophila due to rapid developments in molecular genetics approaches that overcome the difficulties caused by the small size of the fly. In addition we have genome-wide information on genes involved in peptide signaling, and growing pools of peptidomics data. A large number of different neuropeptides has been identified in a huge variety of neuron types in different parts of the Drosophila nervous system and cells in other locations. This review addresses questions related to peptidergic signaling in the Drosophila nervous system, especially how peptides regulate physiology and behavior during development and in the mature fly. We first summarize novel findings on neuropeptide precursor genes, processed bioactive peptides and their cognate receptors. Thereafter we provide an overview of the physiological and behavioral roles of peptide signaling in Drosophila. These roles include regulation of development, growth, feeding, metabolism, reproduction, homeostasis, and longevity, as well as neuromodulation in learning and memory, olfaction and locomotor control. The substrate of this signaling is the peptide products of about 42 precursor genes expressed in different combinations in a variety of neuronal circuits or that act as circulating hormones. Approximately 45 G-protein-coupled peptide receptors are known in Drosophila and for most of these the ligands have been identified. Functions of some peptides are better understood than others, and much work remains to reveal the spectrum of roles neuropeptides and peptide hormones play in the daily life of a fly
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| 15. |
- Olsson, Bob, 1969, et al.
(författare)
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Biomarker-based dissection of neurodegenerative diseases.
- 2011
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Ingår i: Progress in neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 95:4, s. 520-534
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Forskningsöversikt (refereegranskat)abstract
- The diagnosis of neurodegenerative diseases within neurology and psychiatry are hampered by the difficulty in getting biopsies and thereby validating the diagnosis by pathological findings. Biomarkers for other types of disease have been readily adopted into the clinical practice where for instance troponins are standard tests when myocardial infarction is suspected. However, the use of biomarkers for neurodegeneration has not been fully incorporated into the clinical routine. With the development of cerebrospinal fluid (CSF) biomarkers that reflect pathological events within the central nervous system (CNS), important clinical diagnostic tools are becoming available. This review summarizes the most promising biomarker candidates that may be used to monitor different types of neurodegeneration and protein inclusions, as well as different types of metabolic changes, in living patients in relation to the clinical phenotype and disease progression over time. Our aim is to provide the reader with an updated lexicon on currently available biomarker candidates, how far they have come in development and how well they reflect pathogenic processes in different neurodegenerative diseases. Biomarkers for specific pathogenetic processes would also be valuable tools both to study disease pathogenesis directly in patients and to identify and monitor the effect of novel treatment strategies.
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| 16. |
- Salminen, Antero, et al.
(författare)
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Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer's disease
- 2012
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 0301-0082 .- 1873-5118. ; 96:1, s. 87-95
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Forskningsöversikt (refereegranskat)abstract
- The p62/sequestosome-1 is a multifunctional protein containing several protein-protein interaction domains. Through these interactions p62 is involved in the regulation of cellular signaling and protein trafficking, aggregation and degradation. p62 protein can bind through its UBA motif to ubiquitinated proteins and control their aggregation and degradation via either autophagy or proteasomes. p62 protein has been reported to be seen in association with the intracellular inclusions in primary and secondary tauopathies, α-synucleinopathies and other neurodegenerative brain disorders displaying inclusions with misfolded proteins. In Alzheimer's disease (AD), p62 protein is associated with neurofibrillary tangles composed primarily of hyperphosphorylated tau protein and ubiquitin. Increasing evidence indicates that p62 has an important role in the degradation of tau protein. The lack of p62 protein expression provokes the tau pathology in mice. Recent studies have demonstrated that the p62 gene expression and cytoplasmic p62 protein levels are significantly reduced in the frontal cortex of AD patients. Decline in the level of p62 protein can disturb the signaling pathways of Nrf2, cyclic AMP and NF-κB and in that way increase oxidative stress and impair neuronal survival. We will review here the molecular and functional characteristics of p62 protein and outline its potential role in the regulation of Alzheimer's pathogenesis.
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| 17. |
- Semple, Bridgette D, et al.
(författare)
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Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species.
- 2013
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Ingår i: Progress in neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 106-107, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxic-ischemic and traumatic brain injuries are leading causes of long-term mortality and disability in infants and children. Although several preclinical models using rodents of different ages have been developed, species differences in the timing of key brain maturation events can render comparisons of vulnerability and regenerative capacities difficult to interpret. Traditional models of developmental brain injury have utilized rodents at postnatal day 7-10 as being roughly equivalent to a term human infant, based historically on the measurement of post-mortem brain weights during the 1970s. Here we will examine fundamental brain development processes that occur in both rodents and humans, to delineate a comparable time course of postnatal brain development across species. We consider the timing of neurogenesis, synaptogenesis, gliogenesis, oligodendrocyte maturation and age-dependent behaviors that coincide with developmentally regulated molecular and biochemical changes. In general, while the time scale is considerably different, the sequence of key events in brain maturation is largely consistent between humans and rodents. Further, there are distinct parallels in regional vulnerability as well as functional consequences in response to brain injuries. With a focus on developmental hypoxic-ischemic encephalopathy and traumatic brain injury, this review offers guidelines for researchers when considering the most appropriate rodent age for the developmental stage or process of interest to approximate human brain development.
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| 18. |
- Sgambato-Faure, Veronique, et al.
(författare)
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Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson's disease
- 2012
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 96:1, s. 69-86
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Forskningsöversikt (refereegranskat)abstract
- Dyskinesias represent a major complication of dopamine replacement therapy in Parkinson's disease (PD) and have prompted a search for alternative treatments. The most radical advances in this field have been provided by surgical manipulations of the deep basal ganglia nuclei, and particularly by deep brain stimulation (DBS) of the subthalamic nucleus (STN). Although being very effective, high-frequency stimulation (HFS) of the STN is a poorly understood treatment. Besides its anti-akinetic activity, it can be pro-dyskinetic above a certain stimulation intensity. Accumulating evidence indicates that dyskinesias induced by STN-HFS and dopamine replacement therapy are linked to dysregulation of glutamate transmission in the basal ganglia. In rat models of PD, both types of dyskinesia are associated with increased concentrations of extracellular glutamate and altered expression of glutamate transporters in the substantia nigra pars reticulata and the striatum. Furthermore, a vast and ever growing literature has revealed changes in the expression, phosphorylation state, and/or subcellular distribution of specific subtypes of glutamate receptors in these dyskinetic conditions. Both types of dyskinesias are linked to an increased phosphorylation of NR2B-containing NMDA receptors in critical basal ganglia circuits. We conclude that disruption of glutamate homeostasis and activation of perisynaptic and extra-synaptic glutamate receptors are an important pathophysiological component of these treatment-induced dyskinesias in PD. These findings lay the ground for therapeutic development initiatives targeting dysfunctional components of glutamate transmission in the basal ganglia. (C) 2011 Elsevier Ltd. All rights reserved.
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| 19. |
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| 20. |
- Strömberg, Ingrid, et al.
(författare)
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Grafted dopamine neurons : Morphology, neurochemistry, and electrophysiology
- 2010
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 0301-0082 .- 1873-5118. ; 90:2, s. 190-197
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Tidskriftsartikel (refereegranskat)abstract
- Grafting of dopamine-rich tissue to counteract the symptoms in Parkinson's disease became a promising tool for future treatment. This article discusses how to improve the functional outcome with respect to graft outgrowth and functions of dopamine release and electrophysiological responses to graft implantation in the host brain striatal target. It has been documented that a subpopulation of the dopamine neurons innervates the host brain in a target-specific manner, while some of the grafted dopamine neurons never project to the host striatum. Neurochemical studies have demonstrated that the graft-induced outgrowth synthesize, store, metabolize and release dopamine and possibly other neurotransmitters such as 5-HT. Furthermore, the released dopamine affects the dopamine-depleted brain in areas that are larger than the graft-derived nerve fibers reach. While stem cells will most likely be the future source of cells to be used in grafting, it is important to find the guiding cues for how to reinnervate the dopamine-depleted striatum in a proper way with respect to the dopamine subpopulations of A9 and A10 to efficiently treat the motor abnormalities seen in Parkinson's disease.
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| 21. |
- Vargas-Martinez, F., et al.
(författare)
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Neuropeptides as neuroprotective agents: Oxytocin a forefront developmental player in the mammalian brain
- 2014
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 0301-0082 .- 1873-5118. ; 123, s. 37-78
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Forskningsöversikt (refereegranskat)abstract
- Oxytocin (OT) plays a major role in the establishment of social bonds. Social bonds are linked to the activation of cell signaling pathways that promote neurotrophic and synaptic maturation, plasticity and memory changes. Anti-social behavior is often associated with abnormalities of cell signaling pathways and/or defective function of brain neurotransmitters within behavioral CNS circuits due to unproper environmental and social factors, such as, diet, stress, chemical, air pollution, and noise, during gestational period or/and during early postnatal development. OT exerts an important regulatory functions in maternity and parental behaviors, lactation, attachment, bonding, trust, and sensorial functions such as: homeostatic cardiovascular control, satiety, touch, pain, analgesia and sexual behavior. Noteworthy, OT displays important neuroprotective properties against fetal programmed hypertension when administered during early postnatal life, added to its known anabolic properties shown in adult rats, e.g. body weight control, reduces blood pressure, and increases analgesia. This review focuses on the new evidences supporting OT's role as a major neuroprotective nonapeptide provided by its quality to reverse hypertension programmed in utero by undernutrition. (C) 2014 Elsevier Ltd. All rights reserved.
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| 22. |
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| 23. |
- Sundström, Anna, 1969-, et al.
(författare)
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Stressful negative life events and amalgam-related complaints
- 2011
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Ingår i: Community Dentistry and Oral Epidemiology. - : Wiley. - 0301-5661 .- 1600-0528. ; 39:1, s. 12-18
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The role of stressful life events in the onset of self-reported amalgam-related complaints is unclear. The aim of this study was to examine the relationship between life events and amalgam-related complaints. Method: The participants were selected from a longitudinal population-based study. One-to-one matching of 337 participants with amalgam-related complaints to 337 participants without such complaints was performed. For 81 of the participants with amalgam-related complaints and their matched controls, data was also available approximately 5 years before the onset of complaints, making longitudinal analysis possible. All participants completed questionnaires assessing the occurrence of 55 life events. Results: The results showed that many participants with amalgam-related complaints experienced negative life events before and at the onset of amalgam-related complaints. They also reported more unexpected and uncontrollable events difficult to adjust to in comparison with controls. The groups did not differ on positive or neutral life events. Somatic illness or surgical operation was the most common life event. Death of a very close family member and a major change in financial situation were also commonly reported. Conclusions: This study indicates that adverse negative life events could play a vital role in understanding and explaining amalgam-related complaints.
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