Objective: To delineate the role of NLRP3 Inflammasome activation to differential vulnerability in PD and to assess the therapeutic efficacy of PD180970 in targeting this pathway.

Background: Our previous study demonstrated that fibrinogen and complement factor H (CFAH) induce Parkinsonian features in mice. Alongside, a targeted ELISA-based analysis identified a panel of inflammasome-associated cytokines as putative serum biomarkers for Parkinson’s disease (PD). Activation of the NLRP3 inflammasome drives caspase-1 dependent maturation of IL-1β/IL-18, propagating neuroinflammatory cascades. Despite growing evidence linking the inflammasome to PD, its role in determining susceptibility remains unclear. Here we aim to validate the findings noted in the human samples in an in-vivo model using MPTP-susceptible C57BL/6J and MPTP-resistant CD-1 mice.

Method: Two mice strains C57BL/6J and CD-1 were used for the study (n=8/strain/group, 15-17 wks; both genders). They received either saline or MPTP (15 mg/kg, i.p., 4 divided doses at 2-hr intervals). PD180970 (5 mg/kg, i.p.) was administered from D4 post-MPTP for 7 consecutive days. Motor performance was evaluated using pole test and Noldus Catwalk Gait Analysis system. At the terminal endpoint, blood was collected and sera were analyzed using ELISA. Molecular networking was assessed using Cytoscape followed by Protein–Protein Interaction (PPI) using STRING database.

Results: Network pharmacology analysis predicted the potential targets and pathways of PD180970 in PD. In the in-vivo models, C57BL/6J-MPTP showed higher NLRP3 levels than CD-1 (C57BL/6J vs CD-1; ****p<0.0001). PD180970 treatment partially reverted inflammasome levels and motor deficits in C57BL/6J, whereas CD-1 showed an almost complete reversal in the time to descend on the pole. Gait analysis revealed complete recovery of stride length in both the hind limbs of CD-1, while it was partial in C57BL/6J (Con vs. C57BL/6J ***p<0.001).

Conclusion: Higher NLRP3/caspase-1 levels and more pronounced motor deficits, both of which were only partially reversed by PD180970 in C57BL/6J. In contrast, PD180970 elicited better motor performance in CD-1,suggesting strain-dependent differences in the responses to a therapeutic agent. The strain-specific variability underscores a need to personalize therapeutic approaches in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeting-the-nlrp3-inflammasome-by-pd180970-based-on-differential-susceptibility-to-mptp/