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| 2. |
- Berglöf, Elisabet, et al.
(författare)
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Locus coeruleus promotes survival of dopamine neurons in ventral mesencephalon : An in oculo grafting study
- 2009
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 216:1, s. 158-165
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease is a neurodegenerative disorder where dopamine neurons in the substantia nigra of ventral mesencephalon undergo degeneration. In addition to the loss of dopamine neurons, noradrenaline neurons in the locus coeruleus degenerate, actually to a higher extent than the dopamine neurons. The interaction between these two nuclei is yet not fully known, hence this study was undertaken to investigate the role of locus coeruleus during development of dopamine neurons utilizing the intraocular grafting model. Fetal ventral mesencephalon and locus coeruleus were implanted either as single grafts or co-grafts, placed in direct contact or at a distance. The results revealed that the direct attachment of locus coeruleus to ventral mesencephalon enhanced graft volume and number of tyrosine hydroxylase (TH)-positive neurons in ventral mesencephalic grafts. Cell counts of subpopulations of TH-positive neurons also immunoreactive for aldehyde dehydrogenase 1-A1 (ALDH1) or calbindin, revealed improved survival of ALDH1/TH-positive neurons. However, the number of calbindin/TH-positive neurons was not affected. High density of dopamine-beta-hydroxylase (DBH)-positive innervation in the ventral mesencephalon placed adjacent to locus coeruleus was correlated to the improved survival. Ventral mesencephalic tissue, implanted at a distance to locus coeruleus, did not demonstrate improved survival, although DBH-positive nerve fibers were detected. In conclusion, the direct contact of locus coeruleus resulting in dense noradrenergic innervation of ventral mesencephalon is beneficial for the survival of ventral mesencephalic grafts. Thus, when trying to rescue dopamine neurons in Parkinson's disease, improving the noradrenergic input to the substantia nigra might be worth considering.
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| 3. |
- Brys, Ivani, et al.
(författare)
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Neurophysiological effects in cortico-basal ganglia-thalamic circuits of antidyskinetic treatment with 5-HT1A receptor biased agonists
- 2018
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 302, s. 155-168
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Tidskriftsartikel (refereegranskat)abstract
- Recently, the biased and highly selective 5-HT1A agonists, NLX-112, F13714 and F15599, have been shown to alleviate dyskinesia in rodent and primate models of Parkinson's disease, while marginally interfering with antiparkinsonian effects of levodopa. To provide more detailed information on the processes underlying the alleviation of dyskinesia, we have here investigated changes in the spectral contents of local field potentials in cortico-basal ganglia-thalamic circuits following treatment with this novel group of 5-HT1A agonists or the prototypical agonist, 8-OH-DPAT. Dyskinetic symptoms were consistently associated with 80 Hz oscillations, which were efficaciously suppressed by all 5-HT1A agonists and reappeared upon co-administration of the antagonist, WAY100635. At the same time, the peak-frequency of fast 130 Hz gamma oscillations and their cross-frequency coupling to low-frequency delta oscillations were modified to a different extent by each of the 5-HT1A agonists. These findings suggest that the common antidyskinetic effects of these drugs may be chiefly attributable to a reversal of the brain state characterized by 80 Hz gamma oscillations, whereas the differential effects on fast gamma oscillations may reflect differences in pharmacological properties that might be of potential relevance for non-motor symptoms.
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| 6. |
- Eusebio, Alexandre, et al.
(författare)
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Effects of low-frequency stimulation of the subthalamic nucleus on movement in Parkinson's disease.
- 2008
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 209:1, s. 125-30
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Tidskriftsartikel (refereegranskat)abstract
- Excessive synchronization of basal ganglia neural activity at low frequencies is considered a hallmark of Parkinson's disease (PD). However, few studies have unambiguously linked this activity to movement impairment through direct stimulation of basal ganglia targets at low frequency. Furthermore, these studies have varied in their methodology and findings, so it remains unclear whether stimulation at any or all frequencies < or = 20 Hz impairs movement and if so, whether effects are identical across this broad frequency band. To address these issues, 18 PD patients chronically implanted with deep brain stimulation (DBS) electrodes in both subthalamic nuclei were stimulated bilaterally at 5, 10 and 20 Hz after overnight withdrawal of their medication and the effects of the DBS on a finger tapping task were compared to performance without DBS (0 Hz). Tapping rate decreased at 5 and 20 Hz compared to 0 Hz (by 11.8+/-4.9%, p=0.022 and 7.4+/-2.6%, p=0.009, respectively) on those sides with relatively preserved baseline task performance. Moreover, the coefficient of variation of tap intervals increased at 5 and 10 Hz compared to 0 Hz (by 70.4+/-35.8%, p=0.038 and 81.5+/-48.2%, p=0.043, respectively). These data suggest that the susceptibility of basal ganglia networks to the effects of excessive synchronization may be elevated across a broad low-frequency band in parkinsonian patients, although the nature of the consequent motor impairment may depend on the precise frequencies at which synchronization occurs.
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| 7. |
- Fowler, Christopher J, et al.
(författare)
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Modulation of the endocannabinoid system : neuroprotection or neurotoxicity?
- 2010
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Ingår i: Experimental Neurology. - : Elsevier. - 0014-4886 .- 1090-2430. ; 224:1, s. 37-47
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Forskningsöversikt (refereegranskat)abstract
- There is now a large volume of data indicating that compounds activating cannabinoid CB(1) receptors, either directly or indirectly by preventing the breakdown of endogenous cannabinoids, can protect against neuronal damage produced by a variety of neuronal "insults". Given that such neurodegenerative stimuli result in increased endocannabinoid levels and that animals with genetic deletions of CB(1) receptors are more susceptible to the deleterious effects of such stimuli, a case can be made for an endogenous neuroprotective role of endocannabinoids. However, this is an oversimplification of the current literature, since (a) compounds released together with the endocannabinoids can contribute to the neuroprotective effect; (b) other proteins, such as TASK-1 and PPARalpha, are involved; (c) the CB(1) receptor antagonist/inverse agonist rimonabant has also been reported to have neuroprotective properties in a number of animal models of neurodegenerative disorders. Furthermore, the CB(2) receptor located on peripheral immune cells and activated microglia are potential targets for novel therapies. In terms of the clinical usefulness of targeting the endocannabinoid system for the treatment of neurodegenerative disorders, data are emerging, but important factors to be considered are windows of opportunity (for acute situations such as trauma and ischemia) and the functionality of the target receptors (for chronic neurodegenerative disorders such as Alzheimer's disease).
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| 8. |
- Kingham, Paul J, et al.
(författare)
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Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro.
- 2007
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Ingår i: Exp Neurol. - : Elsevier BV. - 0014-4886. ; 207:2, s. 267-74
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Tidskriftsartikel (refereegranskat)abstract
- Experimentally, peripheral nerve repair can be enhanced by Schwann cell transplantation but the clinical application is limited by donor site morbidity and the inability to generate a sufficient number of cells quickly. We have investigated whether adult stem cells, isolated from adipose tissue, can be differentiated into functional Schwann cells. Rat visceral fat was enzymatically digested to yield rapidly proliferating fibroblast-like cells, a proportion of which expressed the mesenchymal stem cell marker, stro-1, and nestin, a neural progenitor protein. Cells treated with a mixture of glial growth factors (GGF-2, bFGF, PDGF and forskolin) adopted a spindle-like morphology similar to Schwann cells. Immunocytochemical staining and western blotting indicated that the treated cells expressed the glial markers, GFAP, S100 and p75, indicative of differentiation. When co-cultured with NG108-15 motor neuron-like cells, the differentiated stem cells enhanced the number of NG108-15 cells expressing neurites, the number of neurites per cell and the mean length of the longest neurite extended. Schwann cells evoked a similar response whilst undifferentiated stem cells had no effect. These results indicate adipose tissue contains a pool of regenerative stem cells which can be differentiated to a Schwann cell phenotype and may be of benefit for treatment of peripheral nerve injuries.
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| 9. |
- Luis-Ravelo, Diego, et al.
(författare)
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Pramipexole reduces soluble mutant huntingtin and protects striatal neurons through dopamine D3 receptors in a genetic model of Huntington's disease
- 2018
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 299, s. 137-147
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is a neurodegenerative disorder caused by abnormal expansion of the polyglutamine tract in the huntingtin protein (HTT). The toxicity of mutant HTT (mHTT) is associated with intermediate mHTT soluble oligomers that subsequently form intranuclear inclusions. Thus, interventions promoting the clearance of soluble mHTT are regarded as neuroprotective. Striatal neurons are particularly vulnerable in HD. Their degeneration underlies motor symptoms and striatal atrophy, the anatomical hallmark of HD. Recent studies indicate that autophagy may be activated by dopamine D-2 and D-3 receptor (D2R/D3R) agonists. Since autophagy plays a central role in the degradation of misfolded proteins, and striatal neurons express D2R and D3R, D2R/D3R agonists may promote the clearance of mHTT in striatal neurons. Here, this hypothesis was tested by treating 8 week old R6/1 mice with the D2R/D3R agonist pramipexole for 4 weeks. Pramipexole reduced striatal levels of soluble mHTT and increased the size of intranuclear inclusions in R6/1 mice. Furthermore, striatal DARPP-32 levels and motor functions were recovered. These effects were accompanied by an increase in LC3-II and a decrease in p62 in the striatum. Tollip, a selective adaptor of ubiquitinated polyQ proteins to LC3, was also reduced in the striata of R6/lmice but not in their wild-type littermates. No changes were detected in the cerebral cortex where D3R expression is very low, and behavioral and biochemical effects in the striatum were prevented by a D3R antagonist. The findings indicate that PPX protects striatal neurons by promoting the clearance of soluble mHTT through a D3R-mediated mechanism. The evidence of autophagy markers suggests that autophagy is activated, although it is not efficient at removing all mHTT recruited by the autophagic machinery as indicated by the increase in the size of intranuclear inclusions.
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| 10. |
- Moldovan, Mihai, et al.
(författare)
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Nerve excitability changes related to axonal degeneration in amyotrophic lateral sclerosis : insights from the transgenic SOD1(G127X) mouse model
- 2012
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 233:1, s. 408-420
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Tidskriftsartikel (refereegranskat)abstract
- Motor nerve excitability studies by "threshold tracking" in amyotrophic lateral sclerosis (ALS) revealed heterogeneous abnormalities in motor axon membrane function possibly depending on disease stage. It remains unclear to which extent the excitability deviations reflect a pathogenic mechanism in ALS or are merely a consequence of axonal degeneration. We investigated motor axon excitability in presymptomatic and symptomatic SOD1(G127X) mutants, a mouse model of ALS with late clinical onset and rapid disease progression. After clinical onset, there was a rapid loss of functional motor units associated with an increase in rheobase and strength-duration time constant, an increase in refractoriness at the expense of the superexcitability, larger than normal threshold deviations during both depolarizing and hyperpolarizing threshold electrotonus with impaired accommodation and reduction of the input conductance. These abnormalities progressed rapidly over a few days and were associated with morphological evidence of ongoing axonal degeneration. Presymptomatic mice with unaltered motor performance at rotor-rod measurement also had an increase in refractoriness at the expense of the superexcitability during the recovery cycle. This was, however, associated with smaller than normal deviations during threshold electrotonus, and a steeper resting current-threshold slope indicating slight axonal depolarization in agreement with motoneuronal hyperexcitability indicated by enhanced F-waves. Our data suggest that SOD1(G127X) motor axons undergo a state of membrane depolarization; however, during rapid motoneuron loss disease-specific nerve excitability measures are confounded by excitability changes in degenerating but still conducting axons. These findings should be considered in the interpretation of disease-stage-related nerve excitability changes in ALS. (C) 2011 Elsevier Inc. All rights reserved.
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