| 1. |
- Francardo, Veronica, et al.
(författare)
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Chapter 22 - Rodent Models of Treatment-Related Complications in Parkinson Disease
- 2014. - 2nd
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Ingår i: Movement Disorders : Genetics and Models - Genetics and Models. - 9780124051959 ; , s. 373-386
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Bokkapitel (refereegranskat)abstract
- Dopamine replacement therapy effectively relieves the typical motor features of Parkinson disease (PD), but it can cause complications that limit its utility. Dyskinesia (abnormal involuntary movements) and motor fluctuations (abrupt changes in the patients' motor status) occur in most PD patients after a few years of 3,4-dihydroxyphenyl-. l-alanine (l-DOPA) pharmacotherapy. Animal models reproducing these motor complications can be obtained in mice and rats if the nigrostriatal dopamine pathway is severely damaged. Within the large arsenal of neurotoxic and genetic models of PD, rodents with unilateral 6-hydroxydopamine lesions have the best characteristics for the sake of modeling l-DOPA-induced dyskinesia. When treated chronically with high doses of l-DOPA, these rodent models may also display motor response alterations reminiscent of the wearing-off fluctuations that occur in PD patients. Because of research performed on these animal models, our understanding of the molecular and biochemical mechanisms of l-DOPA-induced dyskinesia has made great advances, and several pharmacological approaches to treatment have been recently identified and successfully tested in proof-of-concept trials in PD patients. It is now well recognized that dopaminergic therapies for PD also cause nonmotor fluctuations (e.g., abrupt changes in mood and cognitive performance) and impulse control disorders. Valid rodent models of these nonmotor complications need to be developed as an important tool for basic and translational research on the cognitive and psychiatric features of PD.
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| 2. |
- Lindgren, Hanna, et al.
(författare)
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Putaminal Upregulation of FosB/Delta FosB-Like Immunoreactivity in Parkinson's Disease Patients with Dyskinesia
- 2011
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Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 1:4, s. 347-357
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Bergqvist, Jenny, et al.
(författare)
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Healthcare resource use, comorbidity, treatment and clinical outcomes for patients with primary intracranial tumors : a Swedish population-based register study
- 2017
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Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 56:3, s. 405-414
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Tidskriftsartikel (refereegranskat)abstract
- Background: Primary intracranial tumors are relatively uncommon and heterogeneous, which make them challenging to study. We coupled data from unique Swedish population-based registries in order to deeper analyze the most common intracranical tumor types. Patient characteristics (e.g. comorbidities), care process measures like adherence to national guidelines, healthcare resource use and clinical outcome was evaluated.Materials and methods: A register-based study including several population-based registries for all patients living in Stockholm-Gotland, diagnosed with primary intracranial tumor between 2001 and 2013 was performed. Patient characteristics were captured and investigated in relation to survival, healthcare resource use (inpatient-, outpatient- and primary care) and treatment process.Results: High-grade glioma and meningioma were the most common tumor types and most patients (76%) were above the age of 40 in the patient population (n = 3664). Older age, comorbidity (Elixhauser comorbidity index) and type of tumor (high-grade glioma) were associated with lower survival rate and increased use of healthcare resources, analyzed for patients living in Stockholm (n = 3031). The analyses of healthcare use and survival showed no differences between males and females, when stratifying by tumor types. Healthcare processes were not always consistent with existing national treatment recommendations for patients with high-grade gliomas (n = 474) with regard to specified lead times, analyzed in the Swedish Brain Tumor Registry, as also observed at the national level.Conclusions: Age, comorbidity and high-grade gliomas, but not sex, were associated with decreased survival and increased use of healthcare resources. Fewer patients than aimed for in national guidelines received care according to specified lead times. The analysis of comprehensive population-based register data can be used to improve future care processes and outcomes.
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| 4. |
- Bergqvist, Jenny, et al.
(författare)
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The effects of clinical and sociodemographic factors on survival, resource use and lead times in patients with high-grade gliomas : a population-based register study
- 2018
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Ingår i: Journal of Neuro-Oncology. - : Springer. - 0167-594X .- 1573-7373. ; 139:3, s. 599-608
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous studies indicate an effect of sociodemographic factors on risk for being diagnosed with, as well as on survival of cancer in general. Our primary aim was to analyse sociodemographic factors, resource use and lead times in health care after diagnosis with high grade malignant glioma (HGG) in a large population based cohort.Methods: A register-based study using several unique high-coverage registries. All patients over the age of 18 diagnosed with HGG in the Swedish Stockholm-Gotland region between 2001 and 2013 (n=1149) were included.Results: In multivariable cox proportional hazard model of survival, older age, male sex and high tumour grade were associated with worse survival. No significant differences could be seen related to country of birth. A high disposable income was associated with better survival and fewer occasions of pre-diagnostic inpatient care. Older age and comorbidities were correlated with a significantly increased number of outpatient visits the year before HGG diagnosis. In addition, male sex, being born outside Sweden was associated to a higher number of outpatient visits the year after diagnosis in multivariable analysis. Leadtime from diagnosis (first suspicion on brain scan) to surgery showed that the oldest patients, patients with comorbidity and patients born outside Europe had to wait longer for surgery.Conclusions: Sociodemographic factors like education, income and country of birth have impact on care processes both before and after the diagnosis HGG. This needs to be acknowledged in addition to important clinical factors like age, comorbidity and tumour grade, in order to accomplish more equal cancer care.
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| 5. |
- 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
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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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| 6. |
- Iderberg, Hanna, et al.
(författare)
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Animal models of l-DOPA-induced dyskinesia: an update on the current options.
- 2012
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Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 211, s. 13-27
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Tidskriftsartikel (refereegranskat)abstract
- Major limitations to the pharmacotherapy of Parkinson's disease (PD) are the motor complications resulting from l-DOPA treatment. Abnormal involuntary movements (dyskinesia) affect a majority of the patients after a few years of l-DOPA treatment and can become troublesome and debilitating. Once dyskinesia has debuted, an irreversible process seems to have occurred, and the movement disorder becomes almost impossible to eliminate with adjustments in peroral pharmacotherapy. There is a great need to find new pharmacological interventions for PD that will alleviate parkinsonian symptoms without inducing dyskinesia. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate model is an excellent symptomatic model of PD and was the first model used to reproduce l-DOPA-induced dyskinesia experimentally. As it recapitulates the motor features of human dyskinesia, that is, chorea and dystonia, it is considered a reliable animal model to define novel therapies. Over the last decade, rodent models of l-DOPA-induced dyskinesia have been developed, having both face validity and predictive validity. These models have now become the first-line experimental tool for therapeutic screening purposes. The application of classical 6-hydroxydopamine (6-OHDA) lesion procedures to produce rodent models of dyskinesia has provided the field with more dynamic tools, since the versatility of toxin doses and injection coordinates allows for mimicking different stages of PD. This article will review models developed in non-human primate and rodents to reproduce motor complications induced by dopamine replacement therapy. The recent breakthroughs represented by mouse models and the relevance of rodents in relation to non-human primate models will be discussed. This article is part of a Special Issue entitled: Neuroscience Disease Models.
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| 7. |
- Iderberg, Hanna
(författare)
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Emerging pharmacotherapies for Parkinson's Disease: Experimental studies in the rat
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson´s disease (PD) is a neurodegenerative disorder characterized by the typical motor symptoms, akinesia/bradykinesia, rigidity and resting tremor. These symptoms are caused by a deficiency of dopamine (DA) in the brain, which depends on degeneration of DA neurons in the substantia nigra. The most effective treatment for PD is the DA precursor, L-DOPA. Unfortunately, within a few years, L-DOPA causes dyskinesias (abnormal involuntary movements) that are debilitating and treatment-limiting. In experimental models of PD, L-DOPA-induced dyskinesia (LID) can be improved through pharmacological modulation of glutamate or serotonin (5-HT) transmission. However, the applicability of either approach, and the underlying mechanisms, have remained unclear. This thesis work has examined the effects of novel glutamate- and 5-HT modulators in animal models of PD and LID. In a first study, we evaluated Fenobam, a clinically approved antagonist of metabotropic glutamate receptor type 5 (mGluR5) in parkinsonian rats and monkeys. Compared with animals treated with L-DOPA, rats cotreated with Fenobam and L-DOPA exhibited a reduced peak severity of LID but a maintained an antiparkinsonian-like motor response. Similar results were obtained in the monkey model of PD. In a second study, we examined the antiakinetic and antidyskinetic potential of novel ligands of metabotropic glutamate receptor type 4 (mGluR4), which is highly expressed in the basal ganglia. We show that neither a positive allosteric modulator (PAM) nor an orthosteric agonist of mGluR4 ameliorate LID. However, the mGluR4 PAM potentiated the antiakinetic effect of low doses of L-DOPA in certain behavioral tests. In a third study, we investigated the effects of novel, potent and selective agonists of the 5-HT1A receptor, which has emerged as an important modulator of DA release in parkinsonian subjects treated with L-DOPA. The 5-HT1A agonists examined here had superior antidyskinetic efficacy to previously used compounds. Intriguingly, one agonist completely abolished LID and only slightly interfered with the antiakinetic effect of L-DOPA. This compound was shown to markedly reduce the activity of 5-HT neurons, assessed by measuring 5-HT release in the striatum. In the fourth study, we addressed the hypothesis that mGluR5 antagonists and 5-HT1A/B agonists have distinct mechanisms of action, by examining the effects of the two drug categories on involuntary movements induced by either L-DOPA or a D1 receptor agonist. D1 agonist-induced dyskinesia was responsive to mGluR5 but not 5-HT1A/B modulation. Combined mGluR5 antagonism and 5-HT1A/B agonism exerted greater-than-additive antidyskinetic effects in L-DOPA-treated rats. However, there was no advantage in combining the two drugs when dyskinesias were elicited by the D1 receptor agonist. These results prompted the interesting hypothesis that different types of PD dyskinesias may respond differently to putative antidyskinetic interventions, depending on their main underlying mechanism. To systematically address the above hypothesis, we performed a fifth study to characterize dyskinesia induced by different classes of DA receptor agonists, and examine their response to treatment. Interestingly, the phenomenology of dyskinesias was found to depend on the inducing agent. In particular, combination of D1- and D2- receptor agonists produced involuntary movements with more pronounced dystonic features. The antidyskinetic response to mGluR5 antagonism was also conditional on the inducing treatment. Only dyskinesias induced by a D1 receptor agonist, but not those induced by a D2 agonist, were significantly improved by mGluR5 antagonism. Taken together, the results of this thesis provide a robust experimental and theoretical basis for developing antidyskinetic treatments that modulate mGluR5 and 5-HT1A/B receptors.
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| 8. |
- Iderberg, Hanna, et al.
(författare)
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Modulating mGluR5 and 5-HT1A/1B receptors to treat l-DOPA-induced dyskinesia: Effects of combined treatment and possible mechanisms of action.
- 2013
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 250, s. 116-124
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Tidskriftsartikel (refereegranskat)abstract
- l-DOPA-induced dyskinesia (LID) is a major complication of the pharmacotherapy of Parkinson's disease. Emerging approaches to the treatment of LID include negative modulation of metabotropic glutamate receptor type 5 (mGluR5) and positive modulation of serotonin receptors 5-HT1A/1B. We set out to compare the efficacy of these two approaches in alleviating the dyskinesias induced by either l-DOPA or a D1 receptor agonist. Rats with unilateral 6-OHDA lesions were treated chronically with either l-DOPA or the selective D1-class receptor agonist SKF38393 to induce abnormal involuntary movements (AIMs). Rats with stable AIM scores received challenge doses of the mGluR5 antagonist, MTEP (2.5 and 5mg/kg), or the 5-HT1A/1B agonists 8-OH-DPAT/CP94253 (0.035/0.75 and 0.05/1.0mg/kg). Treatments were given either alone or in combination. In agreement with previous studies, 5mg/kg MTEP and 0.05/1.0mg/kg 8-OH-DPAT/CP94253 significantly reduced l-DOPA-induced AIM scores. The two treatments in combination achieved a significantly greater effect than each treatment alone. Moreover, a significant attenuation of l-DOPA-induced AIM scores was achieved when combining doses of MTEP (2.5mg/kg) and 8-OH-DPAT/CP94253 (0.035/0.75mg/kg) that did not have a significant effect if given alone. SKF38393-induced AIM scores were reduced by MTEP at both doses tested, but not by 0.05/1.0mg/kg 8-OH-DPAT/CP94253. The differential efficacy of MTEP and 8-OH-DPAT/CP94253 in reducing l-DOPA- versus SKF38393-induced dyskinesia indicates that these treatments have different mechanisms of action. This contention is supported by the efficacy of subthreshold doses of these compounds in reducing l-DOPA-induced AIMs. Combining negative modulators of mGluR5 with positive modulators of 5-HT1A/1B receptors may therefore achieve greater than additive antidyskinetic effects and reduce the dose requirement for these drugs in Parkinson's disease.
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| 9. |
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| 10. |
- Iderberg, Hanna, et al.
(författare)
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NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat.
- 2015
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 271:May 30, s. 335-350
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Tidskriftsartikel (refereegranskat)abstract
- L-DOPA is the gold-standard treatment for Parkinson's disease (PD), but induces troublesome dyskinesia after prolonged treatment. This is associated with the 'false neurotransmitter' conversion of L-DOPA to dopamine by serotonin neurons projecting from the raphe to the dorsal striatum. Reducing their activity by targeting pre-synaptic 5-HT1A receptors should thus be an attractive therapeutic strategy, but previous 5-HT1A agonists have yielded disappointing results. Here, we describe the activity of a novel, highly selective and potent 5-HT1A agonist, NLX-112 (also known as befiradol or F13640) in rat models relevant to PD and its associated affective disorders. NLX-112 (0.16mg/kgi.p.) potently and completely reversed haloperidol-induced catalepsy in intact rats and abolished L-DOPA-induced Abnormal Involuntary Movements (AIMs) in hemiparkinsonian rats, an effect that was reversed by the selective 5-HT1A antagonist, WAY100635. In microdialysis experiments, NLX-112 profoundly decreased striatal 5-HT extracellular levels, indicative of inhibition of serotonergic function. NLX-112 also blunted the L-DOPA-induced surge in dopamine levels on the lesioned side of the brain, an action that likely underlies its anti-dyskinetic effects. NLX-112 (0.16mg/kgi.p.) robustly induced rotations in hemiparkinsonian rats, suggesting that it has a motor facilitatory effect. Rotations were abolished by WAY100635 and were ipsilateral to the lesioned side, suggesting a predominant stimulation of the dopamine system on the non-lesioned side of the brain. NLX-112 also efficaciously reduced immobility time in the forced swim test (75% reduction at 0.16mg/kgi.p.) and eliminated stress-induced ultrasonic vocalization at 0.08mg/kgi.p., effects consistent with potential antidepressant- and anxiolytic-like properties. In other tests, NLX-112 (0.01-0.16mg/kgi.p.) did not impair the abilityof L-DOPA to rescue fore-paw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and fore-paw treading which are typical of 5-HT1A agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63mg/kgi.p., twice a day), flat body posture and fore-paw treading subsided within 4days of treatment. Taken together, these observations suggest that NLX-112 could exhibit a novel therapeutic profile, combining robust anti-dyskinetic properties without impairing the therapeutic properties of L-DOPA, and with additional beneficial effects on non-motor (affective) symptoms.
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