ArticleJournal of neuroinflammation2026
Clinically advanced NLRP3 inhibitor modulates microglial transcriptome and alleviates α-synuclein-induced progression of parkinsonism.
Article in Journal of neuroinflammation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Small-Molecule NANT Therapeutics Targeting the Brain-Immune Axis in Alzheimer's Disease: Mechanisms, Clinical Progress, and Translational Challenges.Molecules (Basel, Switzerland) · 2026Review
- Multiple system atrophy: cure and care.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- The neuroimmune system and cognition.Nature immunology · 2026Review
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10 authors.
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Abstract
backgroundParkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, and the rare disorder multiple system atrophy (MSA), are both characterized by intracellular accumulation of α-synuclein fibrils and early, sustained microglial reactivity in parallel to the neurodegeneration. Activation of the NLRP3 inflammasome in disease-associated reactive microglia is increasingly recognized as a key pathogenic driver and a promising therapeutic target in synucleinopathies. Dapansutrile (OLT1177®) is a selective, orally bioavailable NLRP3 inhibitor with a favorable safety profile in clinical trials for non-neurological indications. Here, we evaluated the therapeutic potential of dapansutrile in preclinical models of PD and MSA and explored the predictive and translational value of its effects.
methodsTwo established mouse models of synucleinopathy with nigral neurodegeneration were employed: the α-synuclein preformed fibril (PFF) propagation model and the transgenic PLP-α-syn model expressing human wild-type α-synuclein in oligodendrocytes. Pharmacokinetic analyses assessed plasma and brain exposure after oral administration. The efficacy of six-month dapansutrile treatment was examined in both preventive (post-PFF injection) and therapeutic (PLP-α-syn mice) paradigms, using behavioral, histopathological, and molecular readouts. Transcriptomic profiling of striatal and midbrain microglia identified differentially expressed genes (DEGs) associated with treatment and compared them with post-mortem transcriptomic signatures of disease-associated microglia in PD patients. Plasma IL-18 and neurofilament light chain (NfL) levels were evaluated as translational biomarkers.
resultsChronic oral dapansutrile treatment at clinically relevant doses improved motor performance, reduced α-synuclein inclusions, attenuated gliosis, and mitigated nigral neurodegeneration in both models. Microglial transcriptomic analyses revealed that dapansutrile reversed key transcriptional signatures characteristic of PD-associated reactive microglia. Moreover, plasma IL-18 and NfL levels correlated with neuropathological and functional outcomes, supporting their potential as biomarkers of target engagement and treatment efficacy.
conclusionsThese data identify chronic NLRP3 activation as a shared and targetable mechanism in PD and MSA and highlight dapansutrile as a CNS-penetrant, clinically advanced candidate for disease modification in α-synucleinopathies. The observed transcriptomic reprogramming of microglia and the parallel changes in blood biomarkers provide a strong translational bridge to clinical development.
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