Parthenolide attenuates neuroinflammation by targeting NLRP3 inflammasome & mitochondrial dysfunction in experimental...

Diabetic Neuropathy (DN) is one of the most common complications of diabetes induced by intricate mechanisms including oxidative stress, mitochondrial dysfunction, and chronic inflammation, primarily driven by NLRP3 inflammasome activation. Current treatments provide mostly symptomatic relief, necessitating the quest for therapies addressing underlying mechanisms of diabetic neuropathy.

This study evaluated the therapeutic potential of Parthenolide, a sesquiterpene lactone with anti-inflammatory and mitochondrial protective properties, in mitigating diabetic neuropathy.

Molecular docking studies assessed Parthenolide binding with NLRP3, DRP1, and OPA1. High-glucose-exposed SH-SY5Y cells were used to explore Parthenolide effects on oxidative stress, mitochondrial function, and inflammasome activity. In vivo, diabetes in rats induced with Streptozotocin (55 mg/kg) were treated with Parthenolide at 0.25 mg/kg and 0.5 mg/kg for two weeks. Neurobehavioral tests, nerve conduction studies, and analyses of oxidative stress markers, mitochondrial integrity, and inflammation were conducted.

Parthenolide exhibited strong binding affinities with NLRP3 (-8.3 kcal/mol), DRP1 (-7.4 kcal/mol), and OPA1 (-6.7 kcal/mol). In vitro, Parthenolide reduced ROS levels, restored mitochondrial membrane potential, and enhanced mitochondrial protective proteins (SIRT1, FIS1, OPA1) while suppressing NLRP3 activation. In vivo, Parthenolide significantly improved nerve function (motor nerve conduction velocity and nerve blood flow), and alleviated sensorimotor changes. It enhanced antioxidant defences (GSH, SOD2), upregulated mitochondrial regulators (OPA1, PGC1α, NRF1), and reduced oxidative damage (MDA). Parthenolide also lowered inflammasome markers (NLRP3, ASC, and Caspase-1) and pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, and IL-18.

Parthenolide showed neuroprotective potential against experimental DN by reducing oxidative stress, mitochondrial dysfunction, and inflammasome activation.