Modulation of Inflammasome Biology in Age-Associated Neurodegenerative Diseases: Therapeutic Potential of Endogenous Gasotransmitters and Synthetic Molecules.
Inflammasomes, particularly the NLRP3 complex, play a central role in coordinating innate immune activation and neuroinflammatory responses within the cytosol. Persistent or dysregulated nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) activation promotes caspase-1-dependent maturation of interleukin (IL)-1β and IL-18 and triggers gasdermin D (GSDMD)-mediated pyroptosis, thereby contributing to the pathogenic cascades underlying Alzheimer's disease (AD) and Parkinson's disease (PD). Endogenous gasotransmitters, including hydrogen sulfide (H2S) and nitric oxide (NO), have emerged as critical modulators of redox homeostasis, mitochondrial function, and inflammatory signaling pathways that directly or indirectly regulate NLRP3 inflammasome activity. Accumulating evidence suggests that 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. However, donors or hybrid molecules, such as peptide conjugates, provide a suitable platform for sustained, controlled release of these gaseous molecules, overcoming their dose-dependent toxicity and facilitating protective biological effects. To date, the most advanced therapeutic strategies have focused on pharmacological inhibition of the NLRP3 inflammasome using synthetic compounds. Preclinical and emerging clinical studies demonstrate that such agents significantly modulate inflammasome-associated downstream signaling events through diverse molecular mechanisms. This review integrates current insights into NLRP3 inflammasome-driven pathology in age-associated neurodegenerative disorders, highlights the regulatory roles of endogenous gasotransmitters, and evaluates the therapeutic prospects of synthetic inflammasome-targeting agents for the treatment of neurodegenerative diseases in the aging population.