Lipopolysaccharide-Induced Animal Models for Neuroinflammation: An Overview
Choosing the Right LPS Paradigm
Neuroinflammation is a pathological mechanism that contributes to neurodegenerative diseases, and its in-depth characterisation relies on animal models able to reproduce the behavioural dysfunctions and cellular mechanisms associated with brain inflammation. Among these, the most widely used is the model induced by exposure to lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria that, once recognised by the microglial TLR4-MD-2 complex, triggers a signalling cascade culminating in the release of pro-inflammatory cytokines. Despite its broad adoption, this model yields markedly heterogeneous results across studies, which makes comparing and interpreting outcomes difficult. Starting from this problem, the present review gathers and characterises the different experimental paradigms used to reproduce neuroinflammation through LPS, aiming to guide the choice of the model best suited to each research question.
To that end, the authors systematise an extensive body of in vivo studies in a comprehensive table, detailing for each one the species, age, and sex of the animals, the LPS serotype, the route and dose of administration, the sacrifice time point, and the neuroinflammatory changes observed. The analysis shows that the intraperitoneal route is the most frequent and consistently increases pro-inflammatory biomarkers such as IL-6, IL-1β, iNOS, and TNF-α, alongside reductions in anti-inflammatory markers, most notably IL-10, while the intracerebroventricular route produces broadly similar outcomes. The sex of the animals also shapes the response, with evidence that females are more resistant to LPS, possibly through a protective effect of hormones such as estrogen, which is why most studies rely on males. Age is likewise determinant, with an exacerbated inflammatory response in aged animals. Dose and exposure time, in turn, stand out as the variables contributing most to the observed heterogeneity, since they span a very wide range of paradigms, from low doses up to very high values.
In conclusion, although the LPS model is technically straightforward to implement and remains the most frequently used approach to study neuroinflammation, the diversity of experimental parameters compromises the homogeneity of results and limits comparability between studies. By laying out the available paradigms and their respective outcomes in a structured way, this review offers a practical tool for researchers to select the paradigm best matched to their specific aim, contributing to a more robust and reproducible evaluation in the field of neuroinflammation, with particular relevance for the study of neurodegenerative diseases such as Parkinson’s disease.