Objective: Parkinson’s disease (PD) is a distressing neurodegenerative disorder effecting nearly 2-3% of the total population greater than 65 years old . Several mechanisms have been forwarded to explain the neuronal loss among which chronic neuroinflammation, mitochondrial dysfunction, are of chief importance. However the molecular mechanisms of neurodegeneration are still controversial and proper mechanism is yet to be elucidated.

Background: Inflammation in the brain has become an important factor in driving microglial-mediated release of inflammatory cytokines. NLRP3 is the most extensively researched inflammasomes complex in connection with PD and is the main perpetrator behind the production of active IL-1β and IL-18. Mitochondrial dysfunction has became a key pathophysiological process in several neurodegenerative disorders including PD, where damaged mitochondria  produces large amount reactive oxygen species (ROS) and other sterile insults which positively regulate NLRP3 inflammasome activation. Hence inhibiting ROS generation might provide a prospective therapy in controlling inflammasome activation.

Method: Mouse microglia (N9) cells were treated with lipopolysaccharide (LPS) and 1-Methyl-4-phenylpyridinium (MPP+) to activate the NLRP3 Inflammasome complex. MPP+ was used as a mitochondrial complex-I inhibitor which causes generation of large amount of ROS and other insults which activate inflammasome complex. Similarly in animal model MPTP was given to cause neuronal damage in the substantia nigra par compacta (SNpc) region of the brain. Andrographolide treatment was given in both in-vitro and in-vivo models to evaluate its anti-inflammatory activity.

Results: Andrographolide treatment ameliorates motor deficits and dopamine reduction in MPTP treated mice. NLRP3 inhibition by Andrographolide abrogates microglial activation both in vitro and in vivo model. MPTP mediated mitochondrial superoxide generation was responsible for NLRP3 inflamasomes in microglia both in-vitro and in-vivo model. Impaired mitochondrial dysfunction and clearance was seen to further aggravate microglia activation which was ameliorated by Andrographolide treatment.

Conclusion: Collectively, our findings disclose that Andrographolide can inhibit microglial activation by inhibiting ROS generation which might be a promising future therapeutic target for PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/andrograholide-protect-microglial-activation-via-inhibiting-mitochondrial-ros-generation-and-nlrp3-inflammasome-activation-in-in-vitro-and-in-vivo-model-of-parkinsons-disease/