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P Brundin

Publications and source records attributed to P Brundin.

At least 19 recordsLinked to original sources
PubMed2006

Working memory training decreases hippocampal neurogenesis.

The relationship between adult hippocampal neurogenesis and cognition appears more complex than suggested by early reports. We aimed to determine if the duration and task demands of spatial memory training differentially affect hippocampal neurogenesis. Adult male rats were trained in the Morris water maze in a reference memory task for 4 days, or alternatively working memory for either 4 or 14 days. Four days of maze training did not impact neurogenesis regardless of whether reference or working memory paradigms were used. Interestingly, 2 weeks of working memory training using a hidden platform resulted in fewer newborn hippocampal neurons compared with controls that received either cue training or no maze exposure. Stress is a well-established negative regulator of hippocampal neurogenesis. We found that maze training in general, and a working memory task in particular, increased levels of circulating corticosterone after 4 days of training. Our study indicates that working memory training over a prolonged period of time reduces neurogenesis, and this reduction may partially be mediated by increased stress.

Analysis of Variance↗
PubMed2006

Therapeutic potential of controlled drug delivery systems in neurodegenerative diseases.

Several compounds that exhibit a therapeutic effect in experimental models of neurodegenerative diseases have been identified over recent years. Safe and effective drug delivery to the central nervous system is still one of the main obstacles in translating these experimental strategies into clinical therapies. Different approaches have been developed to enable drug delivery in close proximity to the desired site of action. In this review, we describe biodegradable polymeric systems as drug carriers in models of neurodegenerative diseases. Biomaterials described for intracerebral drug delivery are well tolerated by the host tissue and do not exhibit cytotoxic, immunologic, carcinogenic or teratogenic effects even after chronic exposure. Behavioral improvement and normalization of brain morphology have been observed following treatment using such biomaterials in animal models of Parkinson's, Alzheimer's and Huntington's diseases. Application of these devices for neuroactive drugs is still restricted due to the relatively small volume of tissue exposed to active compound. Further development of polymeric drug delivery systems will require that larger volumes of brain tissue are targeted, with a controlled and sustained drug release that is carefully controlled so it does not cause damage to the surrounding tissue.

Alzheimer Disease↗
PubMed2006

The impact of graft size on the development of dyskinesia following intrastriatal grafting of embryonic dopamine neurons in the rat.

Intrastriatal transplants of embryonic ventral mesencephalon can cause dyskinesia in patients with Parkinson's disease (PD). We assessed the impact of transplant size on the development of graft-induced dyskinesia. Rats with unilateral 6-hydroxydopamine lesions were primed to exhibit L-DOPA-induced dyskinesia. They were then intrastriatally grafted with different quantities of embryonic ventral mesencephalic tissue to give small and large grafts. Without drug treatment, discrete dyskinetic-like movements were observed in most rats with large grafts 2-6 weeks after transplantation, but disappeared later. Amphetamine evoked severe abnormal involuntary movements (AIMs) in grafted animals, which were more striking with large grafts. The AIMs coincided with contralateral rotation, but displayed a different temporal profile and pharmacological properties. Thus, selective dopamine uptake blockade elicited rotational behavior, whereas coadministration of both dopamine and serotonin uptake blockers was required to evoke significant orolingual and limb AIMs. In conclusion, robust and reproducible AIMs were evoked in rats with large grafts by blockade of monoamine reuptake. These AIMs may provide a new tool for assessing dyskinetic effects of neural grafting.

Amphetamine↗
PubMed2006

High-fat diet impairs hippocampal neurogenesis in male rats.

High fat diets and obesity pose serious health problems, such as type II diabetes and cardiovascular disease. Impaired cognitive function is also associated with high fat intake. In this study, we show that just 4 weeks of feeding a diet rich in fat ad libitum decreased hippocampal neurogenesis in male, but not female, rats. There was no obesity, but male rats fed a diet rich in fat exhibited elevated serum corticosterone levels compared with those fed standard rat chow. These data indicate that high dietary fat intake can disrupt hippocampal neurogenesis, probably through an increase in serum corticosterone levels, and that males are more susceptible than females.

Animals↗
PubMed2005

Synaptic dysfunction in Huntington's disease: a new perspective.

Huntington's disease (HD) is caused by a polyglutamine expansion in the protein huntingtin and is characterized by intraneuronal inclusions and widespread neuronal death at the late stage of the disease. In research, most of the emphasis has been on understanding the cell death and its mechanisms. Until recently, it was believed that the vast majority, if not all, of the symptoms in HD are a direct consequence of neurodegeneration. However, increasing evidence shows that subtle alterations in synaptic function could underlie the early symptoms. It is of particular interest to understand the nature of this neuronal dysfunction. Normal huntingtin interacts with various cytoskeletal and synaptic vesicle proteins that are essential for exocytosis and endocytosis. Altered interactions of mutant huntingtin with its associated partners could contribute to abnormal synaptic transmission in HD. This review describes recent advances in understanding synaptic dysfunction in HD.

Animals↗
PubMed2005

Platelet-derived growth factor (PDGF-BB) and brain-derived neurotrophic factor (BDNF) induce striatal neurogenesis in adult rats with 6-hydroxydopamine lesions.

The effects of i.c.v. infused platelet-derived growth factor and brain-derived neurotrophic factor on cell genesis, as assessed with bromodeoxyuridine (BrdU) incorporation, were studied in adult rats with unilateral 6-hydroxydopamine lesions. Both growth factors increased the numbers of newly formed cells in the striatum and substantia nigra to an equal extent following 10 days of treatment. At 3 weeks after termination of growth factor treatment, immunostaining of BrdU-labeled cells with the neuronal marker NeuN revealed a significant increase in newly generated neurons in the striatum. In correspondence, many doublecortin-labeled neuroblasts were also observed in the denervated striatum following growth factor treatment. Further evaluation suggested that a subset of these new neurons expresses the early marker for striatal neurons Pbx. However, no BrdU-positive cells were co-labeled with DARPP-32, a protein expressed by mature striatal projection neurons. Both in the striatum and in the substantia nigra there were no indications of any newly born cells differentiating into dopaminergic neurons following growth factor treatment, such that BrdU-labeled cells never co-expressed tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. In conclusion, our results suggest that administration of these growth factors is capable of recruiting new neurons into the striatum of hemiparkinsonian rats.

Adrenergic Agents↗
PubMed2003

Both apoptosis and necrosis occur early after intracerebral grafting of ventral mesencephalic tissue: a role for protease activation.

Neural transplantation is an experimental treatment for Parkinson's disease. Widespread clinical application of the grafting technique is hampered by a relatively poor survival (around 10%) of implanted embryonic dopamine neurones. Earlier animal studies have indicated that a large proportion of the grafted cells die during graft tissue preparation and within the first few days after intracerebral implantation. The present study was designed to reveal the prevalence of cell death in rat intrastriatal grafts at 90 min, 1, 3, 6 and 42 days after implantation. We examined apoptotic cell death using semi-thin and paraffin sections stained with methylene blue and an antibody against activated caspase 3, respectively. We identified abundant apoptotic cell death up to 3 days after transplantation. In addition, we studied calpain activation using an antibody specific for calpain-cleaved fodrin. We report a peak in calpain activity 90 min after grafting. Surprisingly, we did not observe any significant difference in the number of dopaminergic neurones over time. The present results imply that grafted cells may be victims of either an early necrotic or a later apoptotic cell death and that there is substantial cell death as early as 90 min after implantation.

Animals↗
PubMed2002

Maintenance of susceptibility to neurodegeneration following intrastriatal injections of quinolinic acid in a new transgenic mouse model of Huntington's disease.

A transgenic mouse model of Huntington's disease (R6/1 and R6/2 lines) expressing exon 1 of the HD gene with 115-150 CAG repeats resisted striatal damage following injection of quinolinic acid and other neurotoxins. We examined whether excitotoxin resistance characterizes mice with mutant huntingtin transgenes. In a new transgenic mouse with 3 kb of mutant human huntingtin cDNA with 18, 46, or 100 CAG repeats, we found no change in susceptibility to intrastriatal injections of the excitotoxin quinolinic acid, compared to wild-type littermates. The new transgenic mice were injected with the same dose of quinolinic acid (30 nmol) as had been the R6 mice. Our findings highlight the importance of studying pathogenetic mechanisms in different transgenic models of a disease.

Animals↗
PubMed2002

Evidence for dysfunction of the nigrostriatal pathway in the R6/1 line of transgenic Huntington's disease mice.

The present multidisciplinary study examined nigrostriatal dopamine and striatal amino acid transmission in the R6/1 line of transgenic Huntington's disease (HD) mice expressing exon 1 of the HD gene with 115 CAG repeats. Although the number of tyrosine hydroxylase-positive neurons was not reduced and nigrostriatal connectivity remained intact in 16-week-old R6/1 mice, the size of tyrosine hydroxylase-positive neurons in the substantia nigra was reduced by 15%, and approximately 30% of these cells exhibited aggregated huntingtin. In addition, using in vivo microdialysis, we found that basal extracellular striatal dopamine levels were reduced by 70% in R6/1 mice compared to their wild-type littermates. Intrastriatal perfusion with malonate in R6/1 mice resulted in a short-lasting, attenuated increase in local dopamine release compared to wild-type mice. Furthermore, the size of the malonate-induced striatal lesion was 80% smaller in these animals. Taken together, these findings suggest that a functional deficit in nigrostriatal dopamine transmission may contribute to the behavioral phenotype and the resistance to malonate-induced neurotoxicity characteristic of R6/1 HD mice.

Animals↗
PubMed2002

Characterisation of cell damage and death in embryonic mesencephalic tissue: a study on ultrastructure, vital stains and protease activity.

Dissociated embryonic ventral mesencephalic tissue is a source of dopaminergic neurones in both cell culture and neural transplantation studies. Around 90% of grafted dopaminergic neurones die within 1 week after transplantation. Little is known about when the cell death is triggered and what forms of cell death predominate. Using electron microscopy, we characterised ultrastructural changes in dissected embryonic day 14 rat mesencephalic tissue before and after tissue dissociation. In addition, cell viability was evaluated using Trypan Blue and Hoechst/Ethidium Homodimer. Several cells exhibited leaky outer membranes (permitting entry of vital stains) and ultrastructural degeneration already immediately after the mesencephalon was dissected, and before it was mechanically disrupted. After 2 h at room temperature, 90% of the remaining cells had intact outer membranes. However, when estimating cells lost acutely in the tissue dissociation, in addition to cells exhibiting condensed chromatin and organellar changes, we suggest that only around 14% of the cells initially dissected in the mesencephalic tissue pieces remained healthy after 2 h. There was a peak in calpain activity (specific cleavage of fodrin) immediately following tissue dissociation, and it subsided during the next few hours. Caspase-3 activity was initially low, but increased almost 20-fold 4 h after tissue disruption. Interestingly, extensive degradation of caspase-3 occurred already directly after dissection and was at least partly calpain-dependent. Our data suggest that, in addition to cells undergoing primary necrosis, some cells undergo apoptotic or related changes soon after tissue harvesting, and eventually undergo a secondary necrosis. In summary, embryonic mesencephalic cells exhibit multiple degenerative changes very early on in the neural transplant/tissue culture preparation protocol.

Animals↗
PubMed2002

Effects of antioxidant pretreatment on the survival of embryonic dopaminergic neurons in vitro and following grafting in an animal model of Parkinson's disease.

The effect of pretreating cell suspensions of embryonic rat ventral mesencephala (VM) with antioxidant combinations on the survival of dopaminergic (DA) neurons was studied in vitro and following transplantation into the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. The in vitro experiments examined the effects of two thiol antioxidants, N-acetyl-L-cysteine (NAC) and reduced glutathione (GSH), and a member of the lazaroid family of 21-aminosteroids, U-83836E, singly and in combination, on survival of DA neurons derived from dissociated E14 rat VM tissue. For in vivo studies, cell suspensions were pretreated with combinations of NAC, GSH, and U-83836E prior to transplanting into 6-OHDA-lesioned rats to investigate whether DA neuron survival could be further improved. NAC, GSH, and U-83836E individually increased DA neuron survival in vitro and a combination of all three resulted in the greatest survival. In vivo, pretreatment with U-83836E alone resulted in a significantly greater reduction in amphetamine-induced rotation 6 weeks postgrafting compared with a control group receiving nontreated graft tissue. This functional effect correlated with a significant improvement in DA neuron survival 6 weeks postgrafting. The thiol combination pretreatment of NAC and GSH, and the triple combination of NAC, GSH, and U-83836E, however, failed to improve both functional recovery and DA neuron survival when compared with the nontreated control grafts.

Acetylcysteine↗
PubMed2001

[Huntington disease--yet another mad protein?].

Huntington's disease is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat. It is characterized by motor and cognitive disturbances, as well as cellular dysfunction and loss in the basal ganglia and the cerebral cortex. The mutant protein huntingtin aggregates in cells. The toxicity of mutant huntingtin, or the loss of its normal function, causes disruption of cellular functions such as protein and calcium metabolism, transmitter release, mitochondria and gene transcription. Recent findings in basic research open up new possibilities for novel therapies.

Animals↗
PubMed2001

Expanded CAG repeats in exon 1 of the Huntington's disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration.

Huntington's disease (HD) is caused by an expanded CAG repeat in exon 1 of the gene coding for the huntingtin protein. The cellular pathway by which this mutation induces HD remains unknown, although alterations in protein degradation are involved. To study intrinsic cellular mechanisms linked to the mutation, we examined dissociated postnatally derived cultures of striatal neurons from transgenic mice expressing exon 1 of the human HD gene carrying a CAG repeat expansion. While there was no difference in cell death between wild-type and mutant littermate-derived cultures, the mutant striatal neurons exhibited elevated cell death following a single exposure to a neurotoxic concentration of dopamine. The mutant neurons exposed to dopamine also exhibited lysosome-associated responses including induction of autophagic granules and electron-dense lysosomes. The autophagic/lysosomal compartments co-localized with high levels of oxygen radicals in living neurons, and ubiquitin. The results suggest that the combination of mutant huntingtin and a source of oxyradical stress (provided in this case by dopamine) induces autophagy and may underlie the selective cell death characteristic of HD.

Animals↗
PubMed2001

Altered striatal amino acid neurotransmitter release monitored using microdialysis in R6/1 Huntington transgenic mice.

Huntington's disease is an autosomal dominant disease which presents with striatal and cortical degeneration causing involuntary movements, dementia and emotional changes. We employed 16-week-old transgenic Huntington mice (R6/1 line developed by Bates and coworkers) that express exon 1 of the mutant human Huntington gene with 115 CAG triplet repeats. At this age, R6/1 mice do not exhibit an overt neurological phenotype nor any striatal neuronal loss. Using microdialysis, we monitored basal and intrastriatal N-methyl D-aspartate (NMDA, 100 microM, 15 min)- and KCl (100 mM, 15 min)-induced increases in local aspartate, glutamate and GABA release in halothane-anaesthetized transgenic mice and wild-type controls. Basal striatal dialysate glutamate levels were reduced by 42% in R6/1 mice whilst aspartate and GABA levels did not differ from those observed in control mice. Intrastriatal NMDA was associated with significantly greater aspartate (at 15 min) and GABA (at 30 min) levels in the R6/1 mice compared to controls, whilst glutamate release rapidly increased to the same extent in both groups. Intrastriatal KCl was associated with enhanced increases (30 min) in local aspartate and glutamate release in the R6/1 mice above those observed in controls whilst the rapid increase (15 min) in GABA release was similar in both groups. The results provide compelling evidence for specific alterations in both basal, as well as NMDA- and KCl-induced, release of striatal amino acid neurotransmitters in this transgenic model of Huntington's disease, even in the absence of manifest neurodegeneration.

Amino Acids↗
PubMed2001

Mice transgenic for exon 1 of the Huntington's disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6-hydroxydopamine.

Huntington's disease is an autosomal dominant hereditary neurodegenerative disorder characterized by severe striatal cell loss. Dopamine (DA) has been suggested to play a role in the pathogenesis of the disease. We have previously reported that transgenic mice expressing exon 1 of the human Huntington gene (R6 lines) are resistant to quinolinic acid-induced striatal toxicity. In this study we show that with increasing age, R6/1 and R6/2 mice develop partial resistance to DA- and 6-hydroxydopamine-mediated toxicity in the striatum. Using electron microscopy, we found that the resistance is localized to the cell bodies and not to the neuropil. The reduction of dopamine and cAMP regulated phosphoprotein of a molecular weight of 32 kDa (DARPP-32) in R6/2 mice does not provide the resistance, as DA-induced striatal lesions are not reduced in size in DARPP-32 knockout mice. Neither DA receptor antagonists nor a N-methyl-d-aspartate (NMDA) receptor blocker reduce the size of DA-induced striatal lesions, suggesting that DA toxicity is not dependent upon DA- or NMDA receptor-mediated pathways. Moreover, superoxide dismutase-1 overexpression, monoamine oxidase inhibition and the treatment with the free radical scavenging spin-trap agent phenyl-butyl-tert-nitrone (PBN) also did not block DA toxicity. Levels of the antioxidant molecules, glutathione and ascorbate were not increased in R6/1 mice. Because damage to striatal neurons following intrastriatal injection of 6-hydroxydopamine was also reduced in R6 mice, a yet-to-be identified antioxidant mechanism may provide neuroprotection in these animals. We conclude that striatal neurons of R6 mice develop resistance to DA-induced toxicity with age.

Aging↗