Purinergic P2X receptor overactivation, impaired mitophagy, and NLRP3 inflammasome-driven neuroinflammation have been increasingly implicated in Parkinson's disease (PD) pathogenesis. Suramin, a purinergic receptor antagonist, has recently attracted attention for its neuroprotective effects in several neurological disorders. However, its potential to modulate the P2X/mitophagy/NLRP3 axis in PD remains unexplored. This study evaluated the neuroprotective effects of suramin in comparison with metformin, a reported mitophagy and inflammasome modulator, in a rotenone-induced PD rat model. Rotenone (1.5 mg/kg, s.c.) was administered on alternate days for three weeks. Suramin (100 mg/kg, I.V.) was administered on days 11 and 18, while metformin (200 mg/kg, p.o.) was given from days 11 to 21. Behavioral outcomes were evaluated using the open-field, footprint, grip strength, and rotarod tests. Expression levels of selected target signals were quantified using qPCR, ELISA, and immunohistochemistry. Suramin and metformin significantly improved motor and behavioral performance, preserved dopaminergic integrity, improved tyrosine hydroxylase expression, and diminished α-synuclein accumulation, with suramin demonstrating greater efficacy. At the molecular level, suramin more effectively downregulated striatal P2X7R, P2X4R, and ROS levels and increased p-AMPK/t-AMPK ratio. Both treatments promoted mitophagy, as evidenced by increased PINK1, Parkin, and BNIP3 levels along with reduced LC3-II/I ratio. They also suppressed NLRP3 inflammasome activation and pyroptosis, with suramin showing more potent anti-inflammatory effects. Altogether, suramin's neuroprotective effects could be mediated via suppressing P2X7/P2X4 receptors, enhancing mitophagy and counteracting NLRP3-driven pyroptosis in the striatum, with its relatively stronger profile attributable to more robust P2X7/P2X4 signaling inhibition, underscoring its potential as a therapeutic candidate for PD.
Attia et al. (Fri,) studied this question.