Objective: To evaluate the possible neuroprotective effects of mitochondrial NLRP3 inflammasome inhibition in a 6-hydroxydopamine mouse model of Parkinson’s Disease.

Background: Overactivation of brain immune cells (microglia) is known to be associated with the neurodegeneration that occurs with the onset of Parkinson’s disease (PD) symptoms. Dopaminergic neuronal dysfunction in the brain is one of the common cause of Parkinsonism. Understanding neuroinflammation processes, a key contributor of PD pathology may help to detect, prevent, or cure the increasing number of patients with the disease. Recent evidence indicates that NLRP3 inflammasome play a key role in the inflammatory response seen in various neurodegenerative diseases where improved therapies are highly needed.

Method: Adult male NLRP3 knockout mice (8 – 9 weeks old) were used in this study. All mice underwent behavioral tests to assess pre-clinical signs of PD. The neurotoxin 6-OHDA (5µg in 2µL saline) was stereotaxically infused in the medial forebrain bundle to mimic core behavioral and clinical symptoms close to PD. Mice were sacrificed 3, 5, 7, and 14 days post-lesion with 6-OHDA. Blood and brain tissues (striatum, prefrontal cortex, and hippocampus) was collected at each time point for analysis. Behavioral symptoms (e.g., muscle strength, motor dysfunction) and clinical deficits (e.g., dopamine, TH, Neutrophils, IL-1β, IL-6, TNF-α, IL-10, NLRP3) were analyzed to track the underlying mechanism in our PD model. Immunohistochemical/immunofluorescence and stereological technique of brain areas were used to visualize and quantify the markers of the neurodegeneration.

Results: Overall, we found that, mitochondrial NLRP3 inhibition reduced dopaminergic cell death in the striatum. Moreover, it is possible that mitochondrial NLRP3 inhibition ameliorates neuroinflammatory responses and delay pre- and clinical symptoms associated with PD.

Conclusion: Inhibition of mitochondrial NLRP3 inflammasome may be neuroprotective to dopaminergic neurons that degenerate during PD, hence, may be used as a novel treatment therapy for patients with early- and/or late-onset PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-inhibition-of-mitochondrial-nlrp3-inflammasome-decreases-dopaminergic-cell-death-in-a-6-ohda-mouse-model-of-parkinsons-disease/