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image of Neuroinflammatory Human Brain Organoids Enable Comprehensive Drug Screening Studies: Fingolimod and its Analogues in Focus
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Abstract

Introduction

The absence of physiologically relevant models for neuroinflammatory brain disorders, such as multiple sclerosis (MS), highlights the need for improved drug screening platforms. To bridge this gap, this study aimed to develop a human brain organoid (hBO) model incorporating essential neural cell types, including astrocytes, microglia, and oligodendrocytes.

Methods

hBOs were generated from H9 stem cells, and neuroinflammatory characteristics were elicited by lipopolysaccharide (LPS). The expression of specific neuronal and inflammatory markers was assessed through qRT-PCR, immunofluorescence staining (IFS), and ELISA.

Results

IFS of mature hBOs with anti-SOX2, anti-SATB2, anti-MAPT, anti-GFAP, anti-MBP, and anti-IBA1 antibodies and images collected with the confocal microscope confirmed the differentiation of H9 cells into cortical neurons, astrocytes, microglia, and oligodendrocyte cell types. Elevated GFAP, IBA1, NF-κB, and IL-6 levels, along with reduced CNPase expression with LPS treatment, were considered reflective of MS-like pathology and were used to test fingolimod and its derivatives. Fingolimod and all its derivatives, specifically ST-1505, decreased MAPT (2.1-fold in ELISA, 1.7-fold in IFS), GFAP (1.8-fold in IFS), TNFα (5.4-fold in qRT-PCR), and FABP (1.5-fold in ELISA) levels, and increased IL-10 (11-fold in qRT-PCR) and MBP (2.9-fold in IFS) levels.

Discussion

The present data collectively showed LPS to evoke neuroinflammation in the hBO model, while fingolimod and its derivatives, particularly ST-1505, exhibited significant anti-inflammatory and neuroprotective properties by counteracting these evoked changes in the hBO model.

Conclusion

The findings supported the applicability of brain organoids as a model system for drug screening studies for neuroinflammatory brain diseases.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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/content/journals/cmc/10.2174/0109298673435364251002112630
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Neuroinflammatory Human Brain Organoids Enable Comprehensive Drug Screening Studies: Fingolimod and its Analogues in Focus
Bentham Science Publishers ; https://doi.org/10.2174/0109298673435364251002112630
/content/journals/cmc/10.2174/0109298673435364251002112630
/content/journals/cmc/10.2174/0109298673435364251002112630
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  • Article Type:     Research Article
Keywords: fingolimod derivatives ; fingolimod ; anti-inflammatory ; multiple sclerosis ; drug screening ; Brain organoid

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