RESUMO
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD.
Assuntos
Antiparkinsonianos/farmacologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Doença de Parkinson/tratamento farmacológico , Receptor X Retinoide alfa/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Antiparkinsonianos/química , Antiparkinsonianos/farmacocinética , Encéfalo/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Dopamina/genética , Estabilidade de Medicamentos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/agonistas , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Multimerização Proteica , Ratos , Receptor X Retinoide alfa/agonistas , Receptor X Retinoide alfa/química , Receptor X Retinoide alfa/genéticaRESUMO
Background: Biologic agents have demonstrated efficacy in treating ulcerative colitis (UC); however, treatment failure to tumor necrosis factor inhibitors (TNFi) is common in the real world. Data on preferential sequencing in clinical practice after failure remain limited. Objectives: This study aimed to evaluate real-world outcomes of patients cycling to TNFis or switching to non-TNFi biologics following first-line failure with TNFis. Design: Retrospective cohort study in Germany. Methods: Adult patients with UC were identified using administrative claims data from 1 May 2014 to 30 June 2022 provided by a statutory sickness fund. Patients newly initiating first-line therapy with TNFis and then switching to another agent were identified. Patients were defined as within-class switched (WCS), if they cycled to another TNFi, or outside-class switchers (OCS), if they switched to a non-TNFi biologic [ustekinumab (UST) or vedolizumab (VDZ)] and followed from index (switch date) to death, insurance end, or study end on 30 June 2022. Inverse probability of treatment weighting (IPTW) was performed to adjust for differences in baseline characteristics between groups, and weighted Cox regression models were used to compare primary (time to discontinuation and second treatment switch) and secondary outcomes (corticosteroid-free drug survival). Results: We identified 166 patients initiating TNFis and switching to a subsequent treatment (mean age: 42.9 years, 49.4% female). Following IPTW, there were 71 and 76 patients in the WCS and OCS groups, respectively. Compared to OCS, WCS were more likely to discontinue the new therapy [hazard ratio (HR), 1.82, 95% confidence interval (CI), 1.14-2.89, p = 0.012], and switch a second time (HR, 3.46, 95% CI, 1.89-6.36, p < 0.001). Moreover, WCS showed an increased likelihood of initiating prolonged corticosteroid therapy (HR, 1.42, 95% CI, 0.77-2.59, p = 0.260); however, the results were not significant. Conclusion: Following first-line TNFi failure, this study suggests that real-world outcomes among patients with UC are less favorable when cycling to another TNFi, compared to switching to a non-TNFi such as UST or VDZ.
RESUMO
The most prominent pathological feature in Parkinson's disease (PD) is the progressive and selective loss of mesencephalic dopaminergic neurons of the nigrostriatal tract. The present study was conducted in order to investigate whether naive and or genetically modified neural stem/precursor cells (NPCs) can survive, differentiate and functionally integrate in the lesioned striatum. To this end, stereotaxic injections of 6-OHDA in the right ascending nigrostriatal dopaminergic pathway of mice and subsequent NPC transplantations were performed, followed by apomorphine-induced rotations and double-immunofluorescence experiments. Our results demonstrate that transplanted embryonic NPCs derived from the cortical ventricular zone of E14.5 transgenic mouse embryos expressing the green fluorescent protein (GFP) under control of the beta-actin promoter and cultured as neurospheres can survive in the host striatum for at least three weeks after transplantation. The percentage of surviving GFP-positive cells in the host striatum ranges from 0.2% to 0.6% of the total transplanted NPCs. Grafted cells functionally integrate in the striatum, as indicated by the statistically significant decrease of contralateral rotations after apomorphine treatment. Furthermore, we show that within the striatal environment GFP-positive cells differentiate into beta-III tubulin-expressing neurons, but not glial cells. Most importantly, GFP-positive cells further differentiate to dopaminergic (TH-positive) and medium size spiny (DARPP-32- positive) neuronal phenotypes. Over-expression of the cell cycle exit and neuronal differentiation protein Cend1 in NPCs enhances the generation of GABAergic, but not dopaminergic, neuronal phenotypes after grafting in the lesioned striatum. Our results encourage the development of strategies involving NPC transplantation for the treatment of neurodegenerative diseases.