| 41. |
- Lerner, Renata P., et al.
(author)
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Levodopa-induced abnormal involuntary movements correlate with altered permeability of the blood-brain-barrier in the basal ganglia
- 2017
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
-
Journal article (peer-reviewed)abstract
- Chronic levodopa treatment leads to the appearance of dyskinesia in the majority of Parkinson's disease patients. Neurovascular dysregulation in putaminal and pallidal regions is thought to be an underlying feature of this complication of treatment. We used microPET to study unilaterally lesioned 6-hydroxydopamine rats that developed levodopa-induced abnormal involuntary movements (AIMs) after three weeks of drug treatment. Animals were scanned with [15O]-labeled water and [18F]-fluorodeoxyglucose, to map regional cerebral blood flow and glucose metabolism, and with [11C]-isoaminobutyric acid (AIB), to assess blood-brain-barrier (BBB) permeability, following separate injections of levodopa or saline. Multitracer scan data were acquired in each animal before initiating levodopa treatment, and again following the period of daily drug administration. Significant dissociation of vasomotor and metabolic levodopa responses was seen in the striatum/globus pallidus (GP) of the lesioned hemisphere. These changes were accompanied by nearby increases in [11C]-AIB uptake in the ipsilateral GP, which correlated with AIMs scores. Histopathological analysis revealed high levels of microvascular nestin immunoreactivity in the same region. The findings demonstrate that regional flow-metabolism dissociation and increased BBB permeability are simultaneously induced by levodopa within areas of active microvascular remodeling, and that such changes correlate with the severity of dyskinesia.
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| 42. |
- Li, Chang, et al.
(author)
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Structural-functional properties of direct-pathway striatal neurons at early and chronic stages of dopamine denervation
- 2024
-
In: European Journal of Neuroscience. - 0953-816X. ; 59:6, s. 1227-1241
-
Journal article (peer-reviewed)abstract
- The dendritic arbour of striatal projection neurons (SPNs) is the primary anatomical site where dopamine and glutamate inputs to the basal ganglia functionally interact to control movement. These dendritic arbourisations undergo atrophic changes in Parkinson's disease. A reduction in the dendritic complexity of SPNs is found also in animal models with severe striatal dopamine denervation. Using 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle as a model, we set out to compare morphological and electrophysiological properties of SPNs at an early versus a chronic stage of dopaminergic degeneration. Ex vivo recordings were performed in transgenic mice where SPNs forming the direct pathway (dSPNs) express a fluorescent reporter protein. At both the time points studied (5 and 28 days following 6-OHDA lesion), there was a complete loss of dopaminergic fibres through the dorsolateral striatum. A reduction in dSPN dendritic complexity and spine density was manifest at 28, but not 5 days post-lesion. At the late time point, dSPN also exhibited a marked increase in intrinsic excitability (reduced rheobase current, increased input resistance, more evoked action potentials in response to depolarising currents), which was not present at 5 days. The increase in neuronal excitability was accompanied by a marked reduction in inward-rectifying potassium (Kir) currents (which dampen the SPN response to depolarising stimuli). Our results show that dSPNs undergo delayed coordinate changes in dendritic morphology, intrinsic excitability and Kir conductance following dopamine denervation. These changes are predicted to interfere with the dSPN capacity to produce a normal movement-related output.
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| 43. |
- Lindgren, Hanna, et al.
(author)
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Putaminal Upregulation of FosB/Delta FosB-Like Immunoreactivity in Parkinson's Disease Patients with Dyskinesia
- 2011
-
In: Journal of Parkinson's Disease. - 1877-718X. ; 1:4, s. 347-357
-
Journal article (peer-reviewed)abstract
- The transcription factor Delta FosB is a mediator of maladaptive neuroplasticity in animal models of Parkinson's disease (PD) and L-DOPA-induced dyskinesia. Using an antibody that recognizes all known isoforms of FosB and Delta FosB, we have examined the expression of these proteins in post-mortem basal ganglia sections from PD patients. The patient cases were classified as being dyskinetic or non-dyskinetic based on their clinical records. Sections from neurologically healthy controls were also included in the study. Compared to both controls and non-dyskinetic cases, the dyskinetic group showed a higher density of FosB/Delta FosB-immunopositive cells in the posterior putamen, which represents the motor region of the striatum in primates. In contrast, the number of FosB/Delta FosB-positive cells did not differ significantly among the groups in the caudate, a region primarily involved with the processing of cognitive and limbic-related information. Only sparse FosB/Delta FosB immunoreactivity was found in the in the pallidum externum and internum, and no significant group differences were detected in these nuclei. The putaminal elevation of FosB/Delta FosB-like immunoreactivity in patients who had been affected by L-DOPA-induced dyskinesia is consistent with results from both rat and non-human primate models of this movement disorder. The present findings support the hypothesis of an involvement of Delta FosB-related transcription factors in the molecular mechanisms of L-DOPA-induced dyskinesia.
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| 44. |
- Lindgren, Hanna S., et al.
(author)
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Dyskinesia - Advances in the understanding of pathophysiology and possible treatment options
- 2010
-
In: European Neurological Review. - 1758-3837. ; 5:2, s. 34-40
-
Journal article (peer-reviewed)abstract
- The degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease gives rise to tremor and slowness of movement, cardinal motor symptoms of the disease that can be alleviated by the dopamine precursor L-DOPA. Despite this, long-term L-DOPA treatment is hampered by the development of abnormal involuntary movements, i.e. dyskinesia, in the majority of patients. The pathophysiology of dyskinesia is complex and multifactorial, but excessive swings in extracellular dopamine causing aberrant plasticity in dopaminoceptive neurons are attributed a primary role. To date there are few effective treatment alternatives for patients with Parkinson's disease experiencing dyskinesia, representing an unmet therapeutic need in the treatment strategy of the disease. This article reviews recent findings from both clinical and pre-clinical studies and their impact on the search for novel therapeutic approaches to levodopa-induced dyskinesia.
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| 45. |
- Moenne-Loccoz, Cristobal, et al.
(author)
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Cortico-Striatal Oscillations Are Correlated to Motor Activity Levels in Both Physiological and Parkinsonian Conditions
- 2020
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In: Frontiers in Systems Neuroscience. - : Frontiers Media S.A.. - 1662-5137. ; 14
-
Journal article (peer-reviewed)abstract
- Oscillatory neural activity in the cortico-basal ganglia-thalamocortical (CBGTC) loop is associated with the motor state of a subject, but also with the availability of modulatory neurotransmitters. For example, increased low-frequency oscillations in Parkinson's disease (PD) are related to decreased levels of dopamine and have been proposed as biomarkers to adapt and optimize therapeutic interventions, such as deep brain stimulation. Using neural oscillations as biomarkers require differentiating between changes in oscillatory patterns associated with parkinsonism vs. those related to a subject's motor state. To address this point, we studied the correlation between neural oscillatory activity in the motor cortex and striatum and varying degrees of motor activity under normal and parkinsonian conditions. Using rats with bilateral or unilateral 6-hydroxydopamine lesions as PD models, we correlated the motion index (MI)-a measure based on the physical acceleration of the head of rats-to the local field potential (LFP) oscillatory power in the 1-80 Hz range. In motor cortices and striata, we observed a robust correlation between the motion index and the oscillatory power in two main broad frequency ranges: a low-frequency range [5.0-26.5 Hz] was negatively correlated to motor activity, whereas a high-frequency range [35.0-79.9 Hz] was positively correlated. We observed these correlations in both normal and parkinsonian conditions. In addition to these general changes in broad-band power, we observed a more restricted narrow-band oscillation [25-40 Hz] in dopamine-denervated hemispheres. This oscillation, which seems to be selective to the parkinsonian state, showed a linear frequency dependence on the concurrent motor activity level. We conclude that, independently of the parkinsonian condition, changes in broad-band oscillatory activities of cortico-basal ganglia networks (including changes in the relative power of low- and high-frequency bands) are closely correlated to ongoing motions, most likely reflecting he operations of these neural circuits to control motor activity. Hence, biomarkers based on neural oscillations should focus on specific features, such as narrow frequency bands, to allow differentiation between parkinsonian states and physiological movement-dependent circuit modulation.
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| 46. |
- Outeiro, Tiago F., et al.
(author)
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From iPS Cells to Rodents and Nonhuman Primates : Filling Gaps in Modeling Parkinson's Disease
- 2021
-
In: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 36:4, s. 832-841
-
Journal article (peer-reviewed)abstract
- Parkinson's disease (PD) is primarily known as a movement disorder because of typical clinical manifestations associated with the loss of dopaminergic neurons in the substantia nigra. However, it is now widely recognized that PD is a much more complex condition, with multiple and severe nonmotor features implicating additional brain areas and organs in the disease process. Pathologically, typical forms of PD are characterized by the accumulation of α-synuclein-rich protein inclusions known as Lewy bodies and Lewy neurites, although other types of protein inclusions are also often present in the brain. Familial forms of PD have provided a wealth of information about molecular pathways leading to neurodegeneration, but only to add to the complexity of the problem and uncover new knowledge gaps. Therefore, modeling PD in the laboratory has become increasingly challenging. Here, we discuss knowledge gaps and challenges in the use of laboratory models for the study of a disease that is clinically heterogeneous and multifactorial. We propose that the combined use of patient-derived cells and animal models, along with current technological tools, will not only expand our molecular and pathophysiological understanding of PD, but also assist in the identification of therapeutic strategies targeting relevant pathogenic pathways.
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| 47. |
- Petersson, Per, et al.
(author)
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Significance and Translational Value of High-Frequency Cortico-Basal Ganglia Oscillations in Parkinson's Disease
- 2019
-
In: Journal of Parkinson's Disease. - : IOS Press. - 1877-7171 .- 1877-718X. ; 9:1, s. 183-196
-
Journal article (peer-reviewed)abstract
- The mechanisms and significance of basal ganglia oscillations is a fundamental research question engaging both clinical and basic investigators. In Parkinson's disease (PD), neural activity in basal ganglia nuclei is characterized by oscillatory patterns that are believed to disrupt the dynamic processing of movement-related information and thus generate motor symptoms. Beta-band oscillations associated with hypokinetic states have been reviewed in several excellent previous articles. Here we focus on faster oscillatory phenomena that have been reported in association with a diverse range of motor states. We review the occurrence of different types of fast oscillations and the evidence supporting their pathophysiological role. We also provide a general discussion on the definition, possible mechanisms, and translational value of synchronized oscillations of different frequencies in cortico-basal ganglia structures. Revealing how oscillatory phenomena are caused and spread in cortico-basal ganglia-thalamocortical networks will offer a key to unlock the neural codes of both motor and non-motor symptoms in PD. In preclinical therapeutic research, recording of oscillatory neural activities holds the promise to unravel mechanisms of action of current and future treatments.
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| 48. |
- Picconi, B, et al.
(author)
-
Abnormal Ca2+-calmodulin-dependent protein kinase II function mediates synaptic and motor deficits in experimental parkinsonism
- 2004
-
In: The Journal of Neuroscience. - 1529-2401. ; 24:23, s. 5283-5291
-
Journal article (peer-reviewed)abstract
- The NMDA receptor complex represents a key molecular element in the pathogenesis of long-term synaptic changes and motor abnormalities in Parkinson's disease (PD). Here we show that NMDA receptor 1 (NR1) subunit and postsynaptic density (PSD)-95 protein levels are selectively reduced in the PSD of dopamine (DA)-denervated striata. These effects are accompanied by an increase in striatal levels of alphaCa(2+)-calmodulin-dependent protein kinase II (alphaCaMKII) autophosphorylation, along with a higher recruitment of activated alphaCaMKII to the regulatory NMDA receptor NR2A-NR2B subunits. Acute treatment of striatal slices with R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine hydrochloride, but not with L-sulpiride, mimicked the effect of DA denervation on both alphaCaMKII autophosphorylation and corticostriatal synaptic plasticity. In addition to normalizing alphaCaMKII autophosphorylation levels as well as assembly and anchoring of the kinase to the NMDA receptor complex, intrastriatal administration of the CaMKII inhibitors KN-93 (N-[2-[[[3-(4-chlorophenyl)-2-propenyl] methylamino] methyl] phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide) and antennapedia autocamtide-related inhibitory peptide II is able to reverse both the alterations in corticostriatal synaptic plasticity and the deficits in spontaneous motor behavior that are found in an animal model of PD. The same beneficial effects are produced by a regimen of L-3,4-dihydroxyphenylalanine(L-DOPA) treatment, which is able to normalize alphaCaMKII autophosphorylation. These data indicate that abnormal alphaCaMKII autophosphorylation plays a causal role in the alterations of striatal plasticity and motor behavior that follow DA denervation. Normalization of CaMKII activity may be an important underlying mechanism of the therapeutic action of L-DOPA in PD.
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| 49. |
- Refolo, Violetta, et al.
(author)
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Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy : translational implications for interventional therapies
- 2018
-
In: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 6:1, s. 1-24
-
Journal article (peer-reviewed)abstract
- Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive striatonigral degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive striatonigral degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA.
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| 50. |
- Schuster, Stefan, et al.
(author)
-
Antagonizing L-type Ca2+ Channel Reduces Development of Abnormal Involuntary Movement in the Rat Model of L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia
- 2009
-
In: Biological Psychiatry. - : Elsevier BV. - 0006-3223. ; 65:6, s. 518-526
-
Journal article (peer-reviewed)abstract
- Background: Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia. Methods: The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion. Fourteen days later, L-DOPA treatment was initiated. Results: Isradipine-treated animals displayed a dose-dependent reduction in L-DOPA-induced rotational behavior and abnormal involuntary movements. Dendritic spine counting at electron microscopy level showed that isradipine (.2 mg/kg/day) prevented the 6-OHDA-induced spine loss and normalized preproenkephalin-A messenger RNA expression. Involuntary movements were not reduced when isradipine treatment was started concomitantly with L-DOPA. Conclusions: These results indicate that isradipine, at a therapeutically relevant dose, might represent a treatment option for preventing L-DOPA-induced dyskinesia in PD.
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