Objective: The present study aimed to elucidate the molecular mechanism underlying bidirectional olfactory–brain dysfunction mediated through NLRP3 inflammasome activation in cellular models of PD and to evaluate the neuroprotective potential of betulin.

Background: Parkinson’s disease (PD) is characterized by progressive dopaminergic neurodegeneration accompanied by chronic neuroinflammation. Increasing evidence indicates that activation of the NLRP3 inflammasome signaling pathway contributes significantly to PD pathogenesis. Olfactory dysfunction is one of the earliest non-motor symptoms of PD, suggesting a potential role of the olfactory–brain axis in disease propagation. However, the molecular basis of bidirectional olfactory–brain communication mediated by inflammasome signaling remains poorly understood.

Method: Molecular docking analysis was performed to examine the interaction of betulin with key inflammasome components. In vitro experiments were conducted in MPP+-induced microglial cells to evaluate its effect on inflammasome activation, microglial responses, and neuronal differentiation. An in vivo PD model was established using MPTP administration to investigate inflammasome activation in the olfactory bulb and substantia nigra and to assess the protective efficacy of betulin.

Results: Betulin treatment significantly inhibited inflammasome assembly in MPP+-induced microglial cells, reduced phagocytic activation, and suppressed the release of pro-inflammatory cytokines such as Interleukin‑1β and Interleukin‑18. Additionally, betulin enhanced neuronal differentiation markers and promoted neurite outgrowth. In vivo, betulin administration improved olfactory and motor functions in MPTP-treated animals. Immunoblotting analysis demonstrated marked downregulation of inflammasome-associated proteins including NLRP3, Caspase‑1, and ASC in the olfactory bulb and substantia nigra.

Conclusion: Betulin exhibits significant neuroprotective potential by regulating cellular redox balance, suppressing microglial activation, and inhibiting NLRP3 inflammasome signaling. These findings highlight the role of inflammasome-mediated olfactory–brain axis dysfunction in PD and suggest that targeting NLRP3 signaling could be a promising therapeutic strategy for limiting neuroinflammation and neurodegeneration.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/deciphering-the-nlrp3-driven-olfactory-brain-axis-in-parkinsons-disease-neuroprotective-role-of-betulin/