Objective: Parkinson’s disease (PD) affects around 2-3% population of age greater than 65 and is the second most common neurogenerative disorder. The molecular mechanism underpinning the disease still remains controversial but  chronic neuroinflammation are the key players in the initiation and the progression of the neuronal deaths in PD.

Background: Microglia, helps in maintaining cellular homeostasis by phagocytosing any foreign or sterile insults. Excessive and persistent injury can activate microglia whereby they release a large number of cytokines andchemokines  which hampers neuronal survival. NLRP3 inflammasomes are widely studied in correlation with inflammation and are triggered by a variety of stimuli and disrupted mitochondrial potential is one of the causes of its activation.

Method: Neurobehavior paradigms were assessed to evaluate the neuroprotective role of perillyl alcohol in MPTP treated mice. N9 mouse microglial cells were used to check the NLRP3 expression and how mitochondrial dysfunction could potentiate NLRP3 inflammasomes complex formation. Further histology and western blot were done to check the particular pathway of inflammasomes activation. Neurotransmitter estimation was done as to check the levels of Dopamine, HIAA, 5-HT and Nor-epinephrine and mitochondrial damage was assessed by Mitochondrial membrane potential, DCFDA, mitosox assay.

Results: Treatment with Mito-tempo, PA  was seen to rescue disrupted mitochondrial membrane potential progressively and inhibit ROS generation in LPS+ATP stimulated cells. Mito-tempo-PA combination was seen to be synergistic in nature in reducing  NLRP3 activation which consecutively reduced the IL-1β, IL-18 and pyroptosis markers. Mouse treated with PA at a dose of 200mg/kg body weight improved MPTP induced neuro deficit scores and other behavioral parameters. In-vivo data further supports in-vitro studies showing that PA inhibits NLRP3 inflammasomes activation in mice brain by promoting mitochondrial biogenesis .

Conclusion: PA was shown to have a neuroprotective activity in both in-vitro and in-vivo models of PD, further pre-clinical toxicity studies warrant the use of PA as nutraceutical to prevent the progression of oxidative stress or inflammation induced PD. Thus, targeting mitochondrial dysfunction could be an efficient strategy to cure NLRP3-related diseases.

References: 1. Hirsch EC, Vyas S, Hunot S. Neuroinflammation in Parkinson’s disease. Parkinsonism & related disorders. 2012 Jan 1;18:S210-2. 2. Tansey MG, Goldberg MS. Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiology of disease. 2010 Mar 1;37(3):510-8. 3. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE. Parkinson disease. Nature reviews Disease primers. 2017 Mar 23;3:17013. 4. Hu Q, Wang G. Mitochondrial dysfunction in Parkinson’s disease. Translational neurodegeneration. 2016 Dec;5(1):14. 5. Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. Oxidative stress and Parkinson’s disease. Frontiers in neuroanatomy. 2015 Jul 8;9:91.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/perillyl-alcohol-restores-mitochondrial-dysfunction-and-abridge-nlrp3-inflammasomes-activation-in-in-vitro-and-in-vivo-model-of-parkinsons-disease/