Background.Huntington's disease (HD) is a rare familial autosomal dominant neurodegenerative disorder characterized by progressive degeneration of medium spiny neurons (MSNs) located in the striatum.Currently available treatments of HD are only limited to alleviating symptoms; therefore, high expectations for an effective therapy are associated with potential replacement of lost neurons through stimulation of postnatal neurogenesis.One of the drugs of potential interest for the treatment of HD is riluzole, which may act as a positive modulator of adult neurogenesis, promoting replacement of damaged MSNs.The aim of this study was to evaluate the effects of chronic riluzole treatment on a novel HD-like transgenic mouse model, based on the genetic ablation of the transcription factor TIF-IA.This model is characterized by selective and progressive degeneration of MSNs.Methods.Selective ablation of TIF-IA in MSNs (TIF-IA D1RCre mice) was achieved by Cre-based recombination driven by the dopamine 1 receptor (D1R) promoter in the C57Bl/6N mouse strain.Riluzole was administered for 14 consecutive days (5 mg/kg, i.p.; 1x daily) starting at 6 weeks of age.Behavioral analysis included a motor coordination test performed on 13-week-old animals on an accelerated rotarod (4 to 40 r.p.m.; 5 min).To visualize the potential effects of riluzole treatment, the striata of the animals were stained by immunohistochemistry (IHC) and/or immunofluorescence (IF) with Ki67 (marker of proliferating cells), neuronal markers (NeuN, MAP2, DCX), and markers associated with neurodegeneration (GFAP, 8OHdG, FluoroJade C).Additionally, the morphology of dendritic spines of neurons was assessed by a commercially available FD Rapid Golgi Stain™ Kit. Results.A comparative analysis of IHC staining patterns with chosen markers for the neurodegeneration process in MSNs did not show an effect of riluzole on delaying the progression of MSN cell death despite an observed enhancement of cell proliferation as visualized by the Ki67 marker.A lack of a riluzole effect was also reflected by the behavioral phenotype associated with MSN degeneration.Moreover, the analysis of dendritic spine morphology did not show differences between mutant and control animals.Discussion.Despite the observed increase in newborn cells in the subventricular zone (SVZ) after riluzole administration, our study did not show any differences between riluzole-treated and non-treated mutants, revealing a similar extent of the neurodegenerative phenotype evaluated in 13-week-old TIF-IA D1RCre animals.This could be due to either the treatment paradigm (relatively low dose of riluzole used for this study) or the possibility that the effects were simply too weak to have any functional meaning.Nevertheless, this study is in line with others that question the effectiveness of riluzole in animal models and raise concerns about the utility of this drug due to its rather modest clinical efficacy.
Our data give evidence that CXCR3 ligands exhibit pronociceptive properties and play an important role in the initiation, development and maintenance of neuropathic pain. Moreover, intrathecal administration of each CXCR3 ligand induced hypersensitivity reactions in naive mice and of its neutralizing antibodies diminished neuropathic pain syndrome in CCI-exposed mice. Furthermore, our results indicate that selective CXCR3 antagonist (±)-NBI-74330 reduced the neuropathic pain-related behaviour and also enhanced morphine analgesic potency in CCI-exposed rats. Interestingly, our data show that (±)-NBI-74330 administration diminished the spinal IBA1 and, in parallel, downregulated CXCL4, CXCL9 and CXCL10. In addition, CXCR3 antagonist increased the spinal GFAP, what correlates with upregulation of CXCR3 and CXCL11. Moreover, in DRG (±)-NBI-74330 did not change IBA1 and GFAP positive cells activation, however downregulated also CXCL9. CXCR3 and CXCL10 were co-localized predominantly with neuronal marker in the spinal cord. Summing up, chronic (±)-NBI-74330 intrathecal injection promotes beneficial analgesic effects in rat neuropathic pain model, as described in details in "Pharmacological blockade of CXCR3 by (±)-NBI-74330 reduces neuropathic pain and enhances opioid effectiveness - evidence from in vivo and in vitro studies" (Piotrowska et al., 2018).
Dataset from the project investigating the presence of nonmotor symptoms of Parkinson's disease in a mouse model of progressive loss of dopaminergic neurons (namely,TIF-IADATCreERT2 strain). Mice were tested for executive and cognitive functions (males: Operant Sensation Seeking test, OSS; females: Probabilistic Reversal Learning Task in Intellicages), olfactory acuity (males: buried food test), saccharin preference (males and females), and motor performance (males and females: test using CatWalk apparatus). The dataset includes files used to perform statistical analyses but their names may vary from the ones used in the scripts. For the purpose of recreating our analyses, please refer to the GitHub page, where both scripts and input data file names are compliant: https://github.com/annaradli/tif-pd-behavior. Description of files: animals_info.csv - animals data: genotype, sex, age, Intellicage tag identifier catwalk_run_statistics_all_females.csv - data recorded in CatWalk apparatus for females catwalk_run_statistics_all_males.csv - data recorded in CatWalk apparatus for males females_weight_raw_data.csv - females' body weight intellicage_raw_data.csv - data recorded in IntelliCage exported to .csv format intellicage_raw_data_R.RData - data recorded in IntelliCage in .RData format males_weight_raw_data.csv - males' body weight olfactory_time_digging_raw_data.csv - time to start digging at the right place in the buried food test olfactory_time_retrieve_raw_data.csv- time to retrieve cracker in the buried food test oss_raw_data.csv - data recorded in the OSS test saccharin_preference_males_raw_data.csv - saccharin preference test results for males v2 contains the corrected 'animals_info.csv' file without an unnecessary column.
