Endogenous gasotransmitters and synthetic molecules show therapeutic potential by modulating NLRP3 inflammasome in neurodegenerative diseases

The NLRP3 inflammasome is a critical component of innate immunity, driving neuroinflammatory responses in the cytosol. Dysregulated NLRP3 activation promotes caspase-1-dependent maturation of IL-1β and IL-18, triggering GSDMD-mediated pyroptosis. This process significantly contributes to the pathogenic cascades underlying Alzheimer's disease (AD) and Parkinson's disease (PD). Current therapeutic strategies often fall short in effectively targeting this core inflammatory driver, highlighting a need for novel approaches that can precisely modulate NLRP3 activity.

This comprehensive review integrates current insights into NLRP3 inflammasome-driven pathology in age-associated neurodegenerative disorders. It highlights the regulatory roles of endogenous gasotransmitters, specifically hydrogen sulfide (H2S) and nitric oxide (NO), in modulating NLRP3 activity. The review also evaluates the therapeutic potential of various synthetic molecules designed for pharmacological inhibition of the NLRP3 inflammasome, discussing their molecular mechanisms and emerging clinical relevance. The authors explore advanced delivery platforms, such as peptide conjugates, for controlled gasotransmitter release.

Endogenous gasotransmitters, including H2S and NO, emerge as crucial modulators of redox homeostasis, mitochondrial function, and inflammatory signaling pathways, directly or indirectly regulating NLRP3 inflammasome activity. Accumulating evidence suggests these gaseous mediators exert potent neuroprotective effects by attenuating inflammasome activation, limiting oxidative and nitrosative stress, and preserving neuronal integrity.

Despite their therapeutic potential, the pleiotropic and concentration-dependent actions of gasotransmitters pose substantial challenges for precise delivery and controlled bioavailability, suggesting a need for advanced delivery systems like peptide conjugates. Synthetic compounds designed to inhibit the NLRP3 inflammasome have shown significant promise. Preclinical and emerging clinical studies demonstrate that such agents effectively modulate inflammasome-associated downstream signaling events through diverse molecular mechanisms, offering a targeted approach to neuroinflammation.