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/kg, i.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/kg, i.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/kg, i.p.) and eliminated stress-induced ultrasonic vocalization at 0.08mg/kg, i.p., effects consistent with potential antidepressant- and anxiolytic-like properties.
In other tests, NLX-112 (0.01–0.16mg/kg, i.p.) did not impair the ability of l-DOPA to rescue forepaw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and forepaw treading which are typical of 5-HT1A agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63mg/kg, i.p., twice a day), flat body posture and forepaw 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.
•NLX-112 is a highly-selective and efficacious serotonin 5-HT1A receptor agonist.•NLX-112 potently and completely abolishes l-DOPA-induced dyskinesia (LID) in rat.•NLX-112 also stimulates rotations and exhibits antidepressant-like properties.•NLX-112 inhibits 5-HT neurons mediating ‘false neurotransmitter’ dopamine release.•NLX-112 is a promising clinical candidate to treat LID in Parkinson's disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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.
•5-HT1A receptor agonists were tested on rat l-DOPA-induced dyskinesia (LID).•F13714 is a ‘biased agonist’ that preferentially activates 5-HT1A autoreceptors.•F13714 abolished LID, stimulated rotations and inhibited serotonin release.•F15599, a preferential postsynaptic 5-HT1A receptor agonist, was less active.•Preferential targeting 5-HT1A autoreceptors is a novel strategy for LID treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Socioeconomic status, origin or demographic attributes shall not determine the quality of healthcare delivery, according to e.g. United Nations and European Union rules. Health equity has been ...defined as the absence of systematic disparities and unwarranted differences between groups defined by differences in social advantages. A study was performed to investigate whether this was applicable to type 1 diabetes mellitus (T1D) care in a setting with universal, tax-funded healthcare.
This retrospective registry-study was based on patient-level data from individuals diagnosed with T1D during 2010-2011 (n = 16,367) in any of seven Swedish county councils (covering ~65% of the Swedish population). Health equity in T1D care was analysed through multivariate regression analyses on absolute HbA1c level at one-year follow-up, one-year change in estimated glomerular filtration rate (eGFR) and one-year change in cardiovascular risk score, using selected sociodemographic dimensions as case-mix factors.
Higher educational level was consistently associated with lower levels of HbA1c, and so was being married. Never married was associated with worse eGFR development, and lower educational level was associated with higher cardiovascular risk. Women had higher HbA1c levels than men, and glucose control was significantly worse in patients below the age of 25.
Patients' sociodemographic profile was strongly associated with absolute levels of risk factor control in T1D, but also with an increased annual deterioration in eGFR. Whether these systematic differences stem from patient-related problems or healthcare organisational shortcomings is a matter for further research. The results, though, highlight the need for intensified diabetes management education and secondary prevention directed towards T1D patients, taking sociodemographic characteristics into account.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The transcription factor ΔFosB 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 ΔFosB, 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/ΔFosB-immunopositive cells in the posterior putamen, which represents the motor region of the striatum in primates. In contrast, the number of FosB/ΔFosB-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/ΔFosB 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/ΔFosB-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 ΔFosB-related transcription factors in the molecular mechanisms of L-DOPA-induced dyskinesia.
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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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
Lumbar spinal stenosis (LSS) can be surgically treated, with variable outcome. Studies have linked socioeconomic factors to outcome, but no nation-wide studies have been performed. This ...register-based study, including all patients surgically treated for LSS during 2008–2012 in Sweden, aimed to determine predictive factors for the outcome of surgery.
Methods
Clinical and socioeconomic factors with impact on outcome in LSS surgery were identified in several high-coverage registers, e.g., the national quality registry for spine surgery (Swespine, FU-rate 70–90%). Multivariate regression analyses were conducted to assess their effect on outcome. Two patient-reported outcome measures, Global Assessment of leg pain (GA) and the Oswestry Disability Index (ODI), as well as length of sick leave after surgery were analyzed.
Results
Clinical and socioeconomic factors significantly affected health outcome (both GA and ODI). Some predictors of a good outcome (ODI) were: being born in the EU, reporting no back pain at baseline, a high disposable income and a high educational level. Some factors predicting a worse outcome were previous surgery, having had back pain more than 2 years, having comorbidities, being a smoker, being on social welfare and being unemployed.
Conclusions
The study highlights the relevance of adding socioeconomic factors to clinical factors for analysis of patient-reported outcomes, although the causal pathway of most predictors’ impact is unknown. These findings should be further investigated in the perspective of treatment selection for individual LSS patients. The study also presents a foundation of case mix algorithms for predicting outcome of surgery for LSS.
Graphical abstract
These slides can be retrieved under Electronic Supplementary Material.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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.
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.
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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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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