Targeting the inflammasome

Along with evidence that increased microglial activation could be a key driver of Parkinsons’s Disease, the inflammasome is emerging as a potential therapeutic target in neurodegeneration. Trent Martin Woodruff and colleagues from the University of Queensland, Australia, have been investigating pathways and activators that may lead to the development of disease-modifying therapies.

Activation of inflammasome, intracellular protein complexes that sense cellular metabolic stress, leads to production of cytokines that underly inflammatory processes. Increasing evidence suggests the NLRP3 inflammasome is involved in neurodegenerative diseases such as Parkinson’s. Its activation leads to production of the active caspase-1 form of the protease and then to expression of IL-1beta and IL-18.

Dr Woodruff and colleagues have produced evidence that there is inflammasome activation in post mortem brains from people with PD. For example, there is increased caspase-1 cleavage. And immunostaining shows that NLRP3 upregulation is co-localised to microglia. Further, in a mouse model of PD, animals treated with 6-hydroxydopamine show inflammasome activation, with increased NLRP3 expression.

Is targeting the cascade neuroprotective?

Such findings have led efforts to see if an orally active small molecule inhibitor of NLRP3 might have neuroprotective effects. To date, there is evidence that the small molecule inhibits microglia and reduces IL-1beta production. The agent crosses into brain tissue and once daily dosing can lead to sustained inflammasome inhibition.

Furthermore, in the 6-hydroxydopamine mouse model, animals treated with the NLRP3 inhibitor remain almost completely free of motor deficits and do not show loss of dopaminergic neurons.

Additional pieces of the jigsaw are being put in place by studying the pathogenetic pathways linked to PD. α-synuclein-treated microglia show activation of the inflammasome, with generation of cleaved caspase-1. This activation is dependent on NLRP3 and can be prevented by treatment with NLRP3 inhibitors .

In an in vivo model too, intrastriatal injection of α-synuclein produces activation of the inflammasome. NLRP3 inhibitors prevents this, and also prevents the development of abnormal motor behavior evident, for example, in crossing a balance beam. The small molecule also seems capable of restoring dopamine function.

Further work is under way to clarify the mechanisms underlying the apparently neuroprotective effects of NLRP3 inhibitor nd to look at the activity of analogs that might have greater therapeutic potential.

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