Lipopolysaccharide mouse models for Parkinson's disease research: a critical appraisal.
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ABSTRACT:
SUBMITTER: Deng I
PROVIDER: S-EPMC9120679 | biostudies-literature | 2022 Nov
REPOSITORIES: biostudies-literature
Publications
Lipopolysaccharide mouse models for Parkinson's disease research: a critical appraisal.
Deng Isaac I Bobrovskaya Larisa L
Neural regeneration research 20221101 11
Parkinson's disease, the most common movement disorder, has a strong neuroinflammatory aspect. This is evident by increased pro-inflammatory cytokines in the serum, and the presence of activated microglial cells, and inflammatory cytokines in the substantia nigra of post-mortem brains as well as cerebrospinal fluid of Parkinson's disease patients. The central and peripheral neuroinflammatory aspects of Parkinson's disease can be investigated in vivo via administration of the inflammagen lipopoly ...[more]
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Project description:BackgroundIn Parkinson's disease (PD), there is heterogeneity in the clinical presentation and underlying biology. Research on PD subtypes aims to understand this heterogeneity with potential contribution for the knowledge of disease pathophysiology, natural history and therapeutic development. There have been many studies of PD subtypes but their impact remains unclear with limited application in research or clinical practice.ObjectiveTo critically evaluate PD subtyping systems.MethodsWe conducted a systematic review of PD subtypes, assessing the characteristics of the studies reporting a subtyping system for the first time. We completed a critical appraisal of their methodologic quality and clinical applicability using standardized checklists.ResultsWe included 38 studies. The majority were cross-sectional (n = 26, 68.4%), used a data-driven approach (n = 25, 65.8%), and non-clinical biomarkers were rarely used (n = 5, 13.1%). Motor characteristics were the domain most commonly reported to differentiate PD subtypes. Most of the studies did not achieve the top rating across items of a Methodologic Quality checklist. In a Clinical Applicability Checklist, the clinical importance of differences between subtypes, potential treatment implications and applicability to the general population were rated poorly, and subtype stability over time and prognostic value were largely unknown.ConclusionSubtyping studies undertaken to date have significant methodologic shortcomings and most have questionable clinical applicability and unknown biological relevance. The clinical and biological signature of PD may be unique to the individual, rendering PD resistant to meaningful cluster solutions. New approaches that acknowledge the individual-level heterogeneity and that are more aligned with personalized medicine are needed.
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Project description:Increasing evidence suggests a pivotal role of receptor-interacting protein kinase 1 (RIPK1), an initiator of necroptosis, in neuroinflammation. However, the precise role of RIPK1 in microglial activation remains unclear. In the present study, we explored the role of RIPK1 in lipopolysaccharide (LPS)-induced neuroinflammation and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice by using RIPK1-specific inhibitors necrostatin-1 (Nec-1) and necrostatin-1 stable (Nec-1s). Nec-1/Nec-1s or RIPK1 siRNA inhibited the production of proinflammatory molecules and the phosphorylation of RIPK1-RIPK3-MLKL and cell death in LPS-induced inflammatory or LPS/QVD/BV6-induced necroptotic conditions of BV2 microglial cells. Detailed mechanistic studies showed that Nec-1/Nec-1s exerted anti-inflammatory effects by modulating AMPK, PI3K/Akt, MAPKs, and NF-κB signaling pathways in LPS-stimulated BV2 cells. Subsequent in vivo studies showed that Nec-1/Nec-1s inhibited microglial activation and proinflammatory gene expression by inhibiting the RIPK1 phosphorylation in the brains of LPS-injected mice. Furthermore, Nec-1/Nec-1s exert neuroprotective and anti-inflammatory effects in MPTP-induced PD mice. We found that p-RIPK1 is mainly expressed in microglia, and thus RIPK1 may contribute to neuroinflammation and subsequent cell death of dopaminergic neurons in MPTP-induced PD model mice. These data suggest that RIPK1 is a key regulator of microglial activation in LPS-induced neuroinflammation and MPTP-induced PD mice.
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Project description:Since the early days of the intestinal microbiota research, mouse models have been used frequently to study the interaction of microbes with their host. However, to translate the knowledge gained from mouse studies to a human situation, the major spatio-temporal similarities and differences between intestinal microbiota in mice and humans need to be considered. This is done here with specific attention for the comparative physiology of the intestinal tract, the effect of dietary patterns and differences in genetics. Detailed phylogenetic and metagenomic analysis showed that while many common genera are found in the human and murine intestine, these differ strongly in abundance and in total only 4% of the bacterial genes are found to share considerable identity. Moreover, a large variety of murine strains is available yet most of the microbiota research is performed in wild-type, inbred strains and their transgenic derivatives. It has become increasingly clear that the providers, rearing facilities and the genetic background of these mice have a significant impact on the microbial composition and this is illustrated with recent experimental data. This may affect the reproducibility of mouse microbiota studies and their conclusions. Hence, future studies should take these into account to truly show the effect of diet, genotype or environmental factors on the microbial composition.
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Project description:BackgroundMedical research is a central part of any residency training. In view of the new Saudi orthopedic committee promotion regulation that mandates each resident to participate in a research project, the challenges that stand in the way of completion of substantial research within surgical residency must be investigated. The aim of this study was to assess the practice, attitudes, perception, and limitations associated with research among residents in the Saudi orthopedic program in the central region.MethodsA cross-sectional study was conducted between June and July 2020 using an online-based survey. The total number of study participants was 128 orthopedic residents out of the 191 residents enrolled in the central region program. Data were analyzed, and descriptive statistics in the form of frequency and percentage were determined, analytical tests were performed with P < 0.05 being statistically significant.ResultsMost residents (95 %) participated in a research project during residency. Most projects (53.10 %) were case reports followed by retrospective studies (48.40 %). The majority (79.70 %) did not attend a research methods course during residency. Experience in research differed significantly (P < 0.05) by age, residency year, and center. The mean involvement score was significantly higher among males at 3 (± 1) than among females at 2 (± 0) (P < 0.001). Only 40.60 % have access to orthopedic journals, and the same percentage (40.60 %) knew how to Critique original articles. There was a statistically significant difference in the accessibility score according to the training center. Lack of faculty support and mentorship were the main barriers to medical research at 62.50 and 39.10 %, respectively. A total of 68.80 % reported that funding was not available through their institutes.ConclusionsIn Saudi Arabia, the level of meaningful clinical research and publications by orthopedic residents is still low. The results of this study should be taken into consideration before the implementation of the new promotion criteria in the centers under the umbrella of Saudi orthopedic committee.
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