1.
Lindgren, Hanna, et al.
(author)
L-DOPA-induced dopamine efflux in the striatum and the substantia nigra in a rat model of Parkinson's disease: temporal and quantitative relationship to the expression of dyskinesia.
2010
In: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 112:6, s. 1465-76
Journal article (peer-reviewed) abstract
Abstract L-DOPA-induced dyskinesia in Parkinson's Disease (PD) is associated with large increases in brain dopamine (DA) levels following drug dosing, but the precise significance of this phenomenon is not understood. Here we compare DA efflux and metabolism in the striatum and the substantia nigra (SN) in dyskinetic and non-dyskinetic animals following a standard dose of L-DOPA. Rats with 6-OHDA lesions were treated chronically with L-DOPA, monitored on the abnormal involuntary movements (AIMs) scale, and then subjected to intracerebral microdialysis under freely-moving conditions. Following s.c. L-DOPA injection, peak extracellular DA levels in both striatum and SN were twice as large in dyskinetic animals compared to non-dyskinetic rats. This effect was not attributable to differences in DOPA levels or DA metabolism. The larger DA efflux in dyskinetic animals was blunted by 5-HT1A/5-HT1B receptor agonists and TTX infusion, reflecting release from serotonin neurons. Striatal levels of serotonin and its main metabolite, 5-hydroxyindolacetic acid were indeed elevated in dyskinetic animals compared to non-dyskinetic rats, indicating a larger serotonergic innervation density in the former group. High DA release was, however, not sufficient to explain dyskinesia. The AIMs output per unit concentration of striatal extracellular DA was indeed much larger in dyskinetic animals compared to non-dyskinetic cases at most time points examined. The present results indicate that both a high DA release post L-DOPA administration and an increased responsiveness to DA must coexist for a full expression of dyskinesia.
2.
Alcacer, Cristina, et al.
(author)
Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson's disease therapy
2017
In: Journal of Clinical Investigation. - 0021-9738. ; 127:2, s. 720-734
Journal article (peer-reviewed) abstract
Parkinson's disease (PD) patients experience loss of normal motor function (hypokinesia), but can develop uncontrollable movements known as dyskinesia upon treatment with L-DOPA. Poverty or excess of movement in PD has been attributed to overactivity of striatal projection neurons forming either the indirect (iSPNs) or the direct (dSPNs) pathway, respectively. Here, we investigated the two pathways' contribution to different motor features using SPN type-specific chemogenetic stimulation in rodent models of PD (PD mice) and L-DOPA-induced dyskinesia (LID mice). Using the activatory Gq-coupled human M3 muscarinic receptor (hM3Dq), we found that chemogenetic stimulation of dSPNs mimicked, while stimulation of iSPNs abolished the therapeutic action of L-DOPA in PD mice. In LID mice, hM3Dq stimulation of dSPNs exacerbated dyskinetic responses to L-DOPA, while stimulation of iSPNs inhibited these responses. In the absence of L-DOPA, only chemogenetic stimulation of dSPNs mediated through the Gs-coupled modified rat muscarinic M3 receptor (rM3Ds) induced appreciable dyskinesia in PD mice. Combining D2 receptor agonist treatment with rM3Ds-dSPN stimulation reproduced all symptoms of LID. These results demonstrate that dSPNs and iSPNs oppositely modulate both therapeutic and dyskinetic responses to dopamine replacement therapy in PD. We also show that chemogenetic stimulation of different signaling pathways in dSPNs leads to markedly different motor outcomes. Our findings have important implications for the design of effective antiparkinsonian and antidyskinetic drug therapies.
3.
4.
Andersson, M, et al.
(author)
Time course of striatal DeltaFosB-like immunoreactivity and prodynorphin mRNA levels after discontinuation of chronic dopaminomimetic treatment.
2003
In: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 17:3, s. 661-666
Journal article (peer-reviewed) abstract
DFosB-like proteins are particularly stable transcription factors that accumulate in the brain in response to chronic perturbations. In this study we have compared the time-course of striatal FosB/DFosB-like immunoreactivity and prodynorphin mRNA expression after discontinuation of chronic cocaine treatment to intact rats and chronic L-DOPA treatment to unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats. The animals were killed between 3 h and 16 days after the last drug injection. In both treatment paradigms, the druginduced FosB/DFosB immunoreactivity remained significantly elevated in the caudate putamen even at the longest withdrawal period examined. The concomitant upregulation of prodynorphin mRNA, a target of DFosB, paralleled the time-course of DFosB-like immunoreactivity in the 6-OHDA-lesion/L-DOPA model, but was more transient in animals treated with cocaine. These results suggest that DFosB-like proteins have exceptional in vivo stability. In the dopamine-denervated striatum, these proteins may exert sustained effects on the expression of their target genes long after discontinuation of L-DOPA pharmacotherapy.
5.
Angela Cenci-Nilsson, M., et al.
(author)
Oral and infusion levodopa therapy in the management of Parkinson’s disease
2016
In: Parkinson's Disease : Current and Future Therapeutics and Clinical Trials - Current and Future Therapeutics and Clinical Trials. - 9781107053861 - 9781107284210 ; , s. 63-75
Book chapter (peer-reviewed) abstract
Introduction: The clinical diagnosis of Parkinson’s disease (PD) is based on the identification of bradykinesia and at least one additional feature among rigidity, resting tremor and postural instability. These clinical features have been estimated to appear when at least 50% of the nigral dopamine neurons and 70% of putaminal dopamine tissue contents are lost [1]. Dopaminergic imaging suggests that at least 30% of the dopamine storage capacity (measured by 18 F-DOPA uptake) and 50% of putamen dopamine transporters have been lost by the onset of contralateral limb bradykinesia and rigidity [2]. In addition to the above motor symptoms, a number of nonmotor symptoms are associated with PD. These include gastrointestinal, cardiovascular, urological and psychiatric symptoms, as well as problems with vision, pain and sleep [3]. There is general agreement that the typical motor features of PD depend on putaminal dopamine depletion. Indeed, these features respond well to dopaminergic treatments, the most effective being levodopa (l-DOPA), a dopamine precursor that can cross the blood-brain barrier. Treatment with levodopa contributes significantly to improvements in the quality of life of people with PD and increases their expected life length (reviewed in [4]). Moreover, treatment with peroral levodopa is relatively well tolerated and inexpensive [5]. Many of nonmotor symptoms may also respond to levodopa treatment [3]. Because of the above reasons, levodopa is currently considered the “gold standard” for the symptomatic treatment of PD [4, 5]. However, the response to levodopa changes with disease progression, becoming complicated by motor fluctuations and dyskinesias in a majority of patients within a few years. As will be discussed below, these motor complications can become disabling, calling for a reduction in oral levodopa dosage and/or for its replacement with advanced invasive treatments. Moreover, levodopa is poorly effective against clinical features that mainly depend on the degeneration of nondopaminergic systems. These include some nonmotor symptoms as well as motor features that occur in advanced disease stages, such as freezing of gait and falls [6]. In this chapter, we will review the history of levodopa pharmacotherapy in PD, the complications of this therapy, the options currently available to optimize oral treatment with levodopa, and recent advances in developing methods for a more continuous levodopa delivery.
6.
Bez, Francesco, et al.
(author)
Dramatic differences in susceptibility to L-DOPA-induced dyskinesia between mice that are aged before or after a nigrostriatal dopamine lesion
2016
In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 94, s. 213-225
Journal article (peer-reviewed) abstract
Mice with striatal 6-hydroxydopamine (6-OHDA) lesions are widely used as a model to study the effects of neurorestorative, symptomatic, or antidyskinetic treatments for Parkinson's disease (PD). The standard praxis is to utilize young adult mice with relatively acute 6-OHDA lesions. However, long post-lesion intervals may be required for longitudinal studies of treatment interventions, and the long-term stability of the model's behavioral and cellular phenotypes is currently unknown. In this study, C57Bl/6J mice sustained unilateral striatal 6-OHDA lesions at approx. 2 months of age, and were allowed to survive for 1, 10 or 22 months. Another group of mice sustained the lesion at the age of 23 months and survived for one month thereafter. Baseline and drug-induced motor behaviors were examined using a battery of tests (utilizing also a novel video-based methodology). The extent of nigral dopamine cell loss was stable across post-lesion intervals and ages. However, a prominent sprouting of both dopaminergic and serotonergic fibers was detected in the caudate-putamen in animals that survived until 10 and 22 months post-lesion. This phenomenon was associated with a recovery of baseline motor deficits, and with a lack of dyskinetic responses upon treatment with either L-DOPA or apomorphine. By contrast, mice sustaining the lesion at 23 months of age showed a striking susceptibility to the dyskinetic effects of both L-DOPA and apomorphine, which was associated with a pronounced drug-induced upregulation of ∆FosB in the ventrolateral striatum. The results reveal a remarkable compensatory capacity of a damaged nigrostriatal pathway in ageing mice, and how this impacts on the response to dopaminergic therapies for PD.
7.
Bimpisidis, Zisis, et al.
(author)
Differential effects of gaseous versus injectable anesthetics on changes in regional cerebral blood flow and metabolism induced by l-DOPA in a rat model of Parkinson's disease
2017
In: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 292, s. 113-124
Journal article (peer-reviewed) abstract
Preclinical imaging of brain activity requires the use of anesthesia. In this study, we have compared the effects of two widely used anesthetics, inhaled isoflurane and ketamine/xylazine cocktail, on cerebral blood flow and metabolism in a rat model of Parkinson's disease and l-DOPA-induced dyskinesia. Specific tracers were used to estimate regional cerebral blood flow (rCBF - [(14)C]-iodoantipyrine) and regional cerebral metabolic rate (rCMR - [(14)C]-2-deoxyglucose) with a highly sensitive autoradiographic method. The two types of anesthetics had quite distinct effects on l-DOPA-induced changes in rCBF and rCMR. Isoflurane did not affect either the absolute rCBF values or the increases in rCBF in the basal ganglia after l-DOPA administration. On the contrary, rats anesthetized with ketamine/xylazine showed lower absolute rCBF values, and the rCBF increases induced by l-DOPA were masked. We developed a novel improved model to calculate rCMR, and found lower metabolic activities in rats anesthetized with isoflurane compared to animals anesthetized with ketamine/xylazine. Both anesthetics prevented changes in rCMR upon l-DOPA administration. Pharmacological challenges in isoflurane-anesthetized rats indicated that drugs mimicking the actions of ketamine/xylazine on adrenergic or glutamate receptors reproduced distinct effects of the injectable anesthetics on rCBF and rCMR. Our results highlight the importance of anesthesia in studies of cerebral flow and metabolism, and provide novel insights into mechanisms mediating abnormal neurovascular responses to l-DOPA in Parkinson's disease.
8.
9.
Brehm, Nadine, et al.
(author)
A Genetic Mouse Model of Parkinson’s Disease Shows Involuntary Movements and Increased Postsynaptic Sensitivity to Apomorphine
2015
In: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 52:3, s. 1152-1164
Journal article (peer-reviewed) abstract
Alpha-synuclein (SNCA) protein aggregation plays a causal role in Parkinson's disease (PD). The SNCA protein modulates neurotransmission via the SNAP receptor (SNARE) complex assembly and presynaptic vesicle trafficking. The striatal presynaptic dopamine deficit is alleviated by treatment with levodopa (L-DOPA), but postsynaptic plastic changes induced by this treatment lead to a development of involuntary movements (dyskinesia). While this process is currently modeled in rodents harboring neurotoxin-induced lesions of the nigrostriatal pathway, we have here explored the postsynaptic supersensitivity of dopamine receptor-mediated signaling in a genetic mouse model of early PD. To this end, we used mice with prion promoter-driven overexpression of A53T-SNCA in the nigrostriatal and corticostriatal projections. At a symptomatic age (18 months), mice were challenged with apomorphine (5 mg/kg s.c.) and examined using both behavioral and molecular assays. After the administration of apomorphine, A53T-transgenic mice showed more severe stereotypic and dystonic movements in comparison with wild-type controls. Molecular markers of extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and dephosphorylation, and Fos messenger RNA (mRNA), were examined in striatal tissue at 30 and 100 min after apomorphine injection. At 30 min, wild-type and transgenic mice showed a similar induction of phosphorylated ERK1/2, Dusp1, and Dusp6 mRNA (two MAPK phosphatases). At the same time point, Fos mRNA was induced more strongly in mutant mice than in wild-type controls. At 100 min after apomorphine treatment, the induction of both Fos, Dusp1, and Dusp6 mRNA was significantly larger in mutant mice than wild-type controls. At this time point, apomorphine caused a reduction in phospho-ERK1/2 levels specifically in the transgenic mice. Our results document for the first time a disturbance of ERK1/2 signaling regulation associated with apomorphine-induced involuntary movements in a genetic mouse model of synucleinopathy. This mouse model will be useful to identify novel therapeutic targets that can counteract abnormal dopamine-dependent striatal plasticity during both prodromal and manifest stages of PD.
10.
Burguillos Garcia, Miguel, et al.
(author)
Apoptosis-inducing factor mediates dopaminergic cell death in response to lps-induced inflammatory stimulus Evidence in Parkinson's disease patients.
2011
In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 41, s. 177-188
Journal article (peer-reviewed) abstract
We show that intranigral lipopolysaccharide (LPS) injection, which provokes specific degeneration of DA neurons, induced caspase-3 activation in the rat ventral mesencephalon, which was mostly associated with glial cells. In contrast, nigral DA neurons exhibited AIF nuclear translocation in response to LPS. A significant decrease of the Bcl-2/Bax ratio in nigral tissue after LPS injection was observed. We next developed an in vitro co-culture system with the microglial BV2 and the DA neuronal MN9D murine cell lines. The silencing of caspase-3 or AIF by small interfering RNAs exclusively in the DA MN9D cells demonstrated the key role of AIF in the LPS-induced death of DA cells. In vivo chemical inhibition of caspases and poly(ADP-ribose)polymerase-1, an upstream regulator of AIF release and calpain, proved the central role of the AIF-dependent pathway in LPS-induced nigral DA cell death. We also observed nuclear translocation of AIF in the ventral mesencephalon of Parkinson's disease subjects.
