| 31. |
- Fieblinger, Tim, et al.
(författare)
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Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia.
- 2014
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- The striatum is widely viewed as the fulcrum of pathophysiology in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). In these disease states, the balance in activity of striatal direct pathway spiny projection neurons (dSPNs) and indirect pathway spiny projection neurons (iSPNs) is disrupted, leading to aberrant action selection. However, it is unclear whether countervailing mechanisms are engaged in these states. Here we report that iSPN intrinsic excitability and excitatory corticostriatal synaptic connectivity were lower in PD models than normal; L-DOPA treatment restored these properties. Conversely, dSPN intrinsic excitability was elevated in tissue from PD models and suppressed in LID models. Although the synaptic connectivity of dSPNs did not change in PD models, it fell with L-DOPA treatment. In neither case, however, was the strength of corticostriatal connections globally scaled. Thus, SPNs manifested homeostatic adaptations in intrinsic excitability and in the number but not strength of excitatory corticostriatal synapses.
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| 32. |
- Fieblinger, Tim, et al.
(författare)
-
Non‐Apoptotic Caspase‐3 Activation Mediates Early Synaptic Dysfunction of Indirect Pathway Neurons in the Parkinsonian Striatum
- 2022
-
Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:10
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Tidskriftsartikel (refereegranskat)abstract
- Non‐apoptotic caspase‐3 activation is critically involved in dendritic spine loss and synaptic dysfunction in Alzheimer’s disease. It is, however, not known whether caspase‐3 plays similar roles in other pathologies. Using a mouse model of clinically manifest Parkinson’s disease, we provide the first evidence that caspase‐3 is transiently activated in the striatum shortly after the degeneration of nigrostriatal dopaminergic projections. This caspase‐3 activation concurs with a rapid loss of dendritic spines and deficits in synaptic long‐term depression (LTD) in striatal projection neurons forming the indirect pathway. Interestingly, systemic treatment with a caspase inhibitor prevents both the spine pruning and the deficit of indirect pathway LTD without interfering with the ongoing dopaminergic degeneration. Taken together, our data identify transient and non‐apoptotic caspase activation as a critical event in the early plastic changes of indirect pathway neurons following dopamine denervation.
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| 33. |
- Francardo, Veronica, et al.
(författare)
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Investigating the molecular mechanisms of L-DOPA-induced dyskinesia in the mouse
- 2014
-
Ingår i: Parkinsonism and Related Disorders. - 1353-8020. ; 20:SUPPL.1, s. 20-22
-
Tidskriftsartikel (refereegranskat)abstract
- L-DOPA-induced dyskinesia (LID) is a major complication of the pharmacotherapy of Parkinson's disease (PD). Animal models of LID are essential for investigating pathogenic pathways and therapeutic targets. While non-human primates have been the preferred species for pathophysiological studies, mouse models of LID have been recently produced and characterized to facilitate molecular investigations. Most of these studies have used mice with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal projection sustaining treatment with L-DOPA for 1-4 weeks. Mice with complete medial forebrain bundle lesions have been found to develop dyskinetic movements of maximal severity associated with a pronounced post-synaptic supersensitivity of D1-receptor dependent signaling pathways throughout the striatum. In contrast, mice with striatal 6-OHDA lesions have been found to exhibit a variable susceptibility to LID and a regionally restricted post-synaptic supersensitivity. Genetic mouse models of PD have just started to be used for studies of LID, providing an opportunity to dissect the impact of genetic factors on the maladaptive neuroplasticity that drives the development of treatment-induced involuntary movements in PD.
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| 34. |
- Francardo, Veronica, et al.
(författare)
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Neuroprotection and neurorestoration as experimental therapeutics for Parkinson's disease
- 2017
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 298:Pt. B, s. 137-147
-
Tidskriftsartikel (refereegranskat)abstract
- Disease-modifying treatments remain an unmet medical need in Parkinson's disease (PD). Such treatments can be operationally defined as interventions that slow down the clinical evolution to advanced disease milestones. A treatment may achieve this outcome by either inhibiting primary neurodegenerative events ("neuroprotection") or boosting compensatory and regenerative mechanisms in the brain ("neurorestoration"). Here we review experimental paradigms that are currently used to assess the neuroprotective and neurorestorative potential of candidate treatments in animal models of PD. We review some key molecular mediators of neuroprotection and neurorestoration in the nigrostriatal dopamine pathway that are likely to exert beneficial effects on multiple neural systems affected in PD. We further review past and current strategies to therapeutically stimulate these mediators, and discuss the preclinical evidence that exercise training can have neuroprotective and neurorestorative effects. A future translational task will be to combine behavioral and pharmacological interventions to exploit endogenous mechanisms of neuroprotection and neurorestoration for therapeutic purposes. This type of approach is likely to provide benefit to many PD patients, despite the clinical, etiological, and genetic heterogeneity of the disease.
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| 35. |
- Francardo, Veronica, et al.
(författare)
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Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson’s Disease
- 2019
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Ingår i: Neurotherapeutics. - : Springer Science and Business Media LLC. - 1933-7213 .- 1878-7479. ; 16:2, s. 465-479
-
Tidskriftsartikel (refereegranskat)abstract
- Pridopidine is a small molecule in clinical development for the treatment of Huntington’s disease. It was recently found to have high binding affinity to the sigma-1 receptor, a chaperone protein involved in cellular defense mechanisms and neuroplasticity. Here, we have evaluated the neuroprotective and neurorestorative effects of pridopidine in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of parkinsonism in mice. By 5 weeks of daily administration, a low dose of pridopidine (0.3 mg/kg) had significantly improved deficits in forelimb use (cylinder test, stepping test) and abolished the ipsilateral rotational bias typical of hemiparkinsonian animals. A higher dose of pridopidine (1 mg/kg) significantly improved only the rotational bias, with a trend towards improvement in forelimb use. The behavioral recovery induced by pridopidine 0.3 mg/kg was accompanied by a significant protection of nigral dopamine cell bodies, an increased dopaminergic fiber density in the striatum, and striatal upregulation of GDNF, BDNF, and phosphorylated ERK1/2. The beneficial effects of pridopidine 0.3 mg/kg were absent in 6-OHDA-lesioned mice lacking the sigma-1 receptor. Pharmacokinetic data confirmed that the effective dose of pridopidine reached brain concentrations sufficient to bind S1R. Our results are the first to show that pridopidine promotes functional neurorestoration in the damaged nigrostriatal system acting via the sigma-1 receptor.
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| 36. |
- Grigoriou, Sotirios, et al.
(författare)
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Comparison of dyskinesia profiles after L-DOPA dose challenges with or without dopamine agonist coadministration
- 2023
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Ingår i: Neuropharmacology. - 0028-3908. ; 237
-
Tidskriftsartikel (refereegranskat)abstract
- Many patients with Parkinson's disease (PD) experiencing L-DOPA-induced dyskinesia (LID) receive adjunct treatment with dopamine agonists, whose functional impact on LID is unknown. We set out to compare temporal and topographic profiles of abnormal involuntary movements (AIMs) after L-DOPA dose challenges including or not the dopamine agonist ropinirole. Twenty-five patients with PD and a history of dyskinesias were sequentially administered either L-DOPA alone (150% of usual morning dose) or an equipotent combination of L-DOPA and ropinirole in random order. Involuntary movements were assessed by two blinded raters prior and every 30 min after drug dosing using the Clinical Dyskinesia Rating Scale (CDRS). A sensor-recording smartphone was secured to the patients' abdomen during the test sessions. The two raters’ CDRS scores were highly reliable and concordant with models of hyperkinesia presence and severity trained on accelerometer data. The dyskinesia time curves differed between treatments as the L-DOPA-ropinirole combination resulted in lower peak severity but longer duration of the AIMs compared with L-DOPA alone. At the peak of the AIMs curve (60–120 min), L-DOPA induced a significantly higher total hyperkinesia score, whereas in the end phase (240–270 min), both hyperkinesia and dystonia tended to be more severe after the L-DOPA-ropinirole combination (though reaching statistical significance only for the item, arm dystonia). Our results pave the way for the introduction of a combined L-DOPA-ropinirole challenge test in the early clinical evaluation of antidyskinetic treatments. Furthermore, we propose a machine-learning method to predict CDRS hyperkinesia severity using accelerometer data.
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| 37. |
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| 38. |
- Iderberg, Hanna, et al.
(författare)
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Activity of serotonin 5-HT1A receptor 'biased agonists' in rat models of Parkinson's disease and l-DOPA-induced dyskinesia.
- 2015
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Ingår i: Neuropharmacology. - : Elsevier BV. - 1873-7064 .- 0028-3908. ; 93, s. 52-67
-
Tidskriftsartikel (refereegranskat)abstract
- Serotonin 5-HT1A receptor agonists reduce l-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease (PD). Here, we compared the effects of novel 5-HT1A receptor 'biased agonists' on LID in hemiparkinsonian rats. F13714 preferentially activates pre-synaptic 5-HT1A autoreceptors. F15599 preferentially activates cortical postsynaptic 5-HT1A heteroreceptors. The partial agonist, tandospirone, does not differentiate these receptor subpopulations. The drugs were also tested on rotational behavior, rotarod and cylinder test for evaluation of locomotor activity, motor coordination and forelimb akinesia. Finally, the effects of F13714 and F15599 on 5-HT, DA, glutamate, and GABA release were investigated by microdialysis. F13714 abolished l-DOPA-induced AIMs even at very low doses (0.02-0.04 mg/kg). This effect was reversed by the selective 5-HT1A receptor antagonist, WAY100635. F13714 also elicited ipsilateral rotations (which were blocked by WAY100635) and potentiated the rotational activity of a sub-threshold dose of l-DOPA (2 mg/kg). F13714 profoundly inhibited striatal 5-HT release on both sides of the brain, and slightly increased DA release on the intact side. F15599 inhibited the l-DOPA-induced AIMs only at a dose (0.16 mg/kg) that reduced 5-HT release. Tandospirone produced a modest attenuation of peak AIMs severity and did not elicit rotations. F13714, F15599 and tandospirone did not modify the action of l-DOPA in the cylinder test but impaired rotarod performance at the highest doses tested. Targeting 5-HT1A receptors with selective biased agonists exerts distinct effects in the rat model of PD and LID. Preferential activation of 5-HT1A autoreceptors could potentially translate to superior antidyskinetic and l-DOPA dose-sparing effects in PD patients.
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| 39. |
- Iderberg, Hanna, et al.
(författare)
-
Pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of Parkinson's disease and l-DOPA-induced dyskinesia: Comparison between a positive allosteric modulator and an orthosteric agonist.
- 2015
-
Ingår i: Neuropharmacology. - : Elsevier BV. - 1873-7064 .- 0028-3908. ; 95, s. 121-129
-
Tidskriftsartikel (refereegranskat)abstract
- Metabotropic glutamate receptor 4 (mGlu4) negatively modulates GABA and glutamate release in the 'indirect pathway' of the basal ganglia, and has thus been proposed as a potential target to treat motor symptoms in Parkinson's disease. Here, we present an extensive comparison of the behavioural effects produced by the mGlu4 positive allosteric modulator (PAM), VU0364770, and the mGlu4 orthosteric agonist, LSP1-2111, in rats with unilateral 6-OHDA lesions. The compounds' activity was initially assessed in a test of haloperidol-induced catalepsy in intact rats, and effective doses were then evaluated in the hemiparkinsonian animal model. Neither of the two compounds modified the development of dyskinetic behaviours elicited by chronic treatment with full doses of l-DOPA. When given together with l-DOPA to rats with already established dyskinesias, neither VU0364770 nor LSP1-2111 modified the abnormal involuntary movement scores. VU0364770 potentiated, however, the motor stimulant effect of a subthreshold l-DOPA dose in certain behavioural tests, whereas LSP1-2111 lacked this ability. Taken together, these results indicate that a pharmacological stimulation of mGlu4 lacks intrinsic antidyskinetic activity, but may have DOPA-sparing activity in Parkinson's disease. For the latter indication, mGlu4 PAMs appear to provide a better option than orthosteric agonists.
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| 40. |
- Lee, Chong S., et al.
(författare)
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Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson's disease
- 2000
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Ingår i: Brain. - 0006-8950. ; 123:7, s. 1365-1379
-
Tidskriftsartikel (refereegranskat)abstract
- We investigated the role of dopamine neurons in the manifestation of levodopa-induced dyskinesia in a rat model of Parkinson's disease. Daily treatment with a subthreshold dose of levodopa gradually induced abnormal involuntary movements (AIM) in 6-hydroxydopamine-lesioned rats, which included stereotypy and contraversive rotation. After 4 weeks of levodopa treatment, rats with mild and severe AIM were assigned to two treatment subgroups. The graft subgroup received embryonic ventral mesencephalic tissue into the striatum, whilst the sham-graft subgroup received vehicle only. Rats continued to receive levodopa treatment for 3 months post-graft. Brain sections at the level of the basal ganglia were processed for autoradiography using a ligand for dopamine transporter, and in situ hybridization histochemistry for mRNAs encoding postsynaptic markers. Levodopa-induced AIM significantly improved in grafted rats. The severity of AIM correlated inversely with the density of dopamine nerve terminals in the striatum (P < 0.001), with almost no AIM when the density of dopamine nerve terminals was > 10-20% of normal. Embryonic dopamine neuronal grafts normalized not only mRNA expression for preproenkephalin (PPE) in the indirect pathway, but also mRNA expression for prodynorphin (PDyn) in the direct pathway, which was upregulated by levodopa treatment. AIM scores correlated linearly with expression of PPE mRNA in the indirect pathway (P < 0.001) and also with PDyn mRNA in the direct pathway (P < 0.001). We conclude that embryonic dopamine neuronal grafts may improve levodopa-induced dyskinesia by restoring altered activities of postsynaptic neurons, resulting not only from dopamine denervation, but also from levodopa therapy, provided that the density of striatal dopaminergic nerve terminals is restored above a 'threshold' level.
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