Pyroptosis modulation therapy represents a promising disease-modifying approach for neurodegenerative diseases by targeting the inflammatory cell death pathway known as pyroptosis. This therapeutic strategy aims to interrupt the neurotoxic inflammatory cascade driven by gasdermin proteins and inflammatory caspases. 1
Pyroptosis Modulation Therapy is a therapeutic approach or intervention being investigated for neurodegenerative diseases. This page reviews the scientific rationale, preclinical and clinical evidence, dosing considerations, and current status of research. [1]
Pyroptosis is a highly inflammatory form of programmed cell death mediated by gasdermin family proteins. In the context of neurodegenerative diseases, excessive pyroptotic signaling contributes to chronic neuroinflammation and neuronal loss. 2 [2]
Gasdermin D (GSDMD) serves as the primary executor of pyroptosis. Upon activation by inflammatory caspases, GSDMD is cleaved to generate the N-terminal fragment (GSDMD-NT), which forms pores in the plasma membrane. 3 These pores cause cell swelling, membrane rupture, and release of inflammatory intracellular contents including IL-1β and IL-18. 4 [3]
Gasdermin E (GSDME, also known as DFNA5) provides an alternative pathway for pyroptosis. Caspase-3-mediated cleavage of GSDME converts apoptosis to pyroptosis, linking the apoptotic and pyroptotic pathways. 5 [4]
The inflammatory caspases (caspase-1, caspase-4, caspase-5 in humans, and caspase-11 in mice) initiate pyroptosis by cleaving gasdermin proteins and activating pro-inflammatory cytokines. Caspase-1 also processes pro-IL-1β and pro-IL-18 to their active forms. 6 [5]
In Alzheimer's disease models, pyroptosis inhibition has shown neuroprotective effects: [6]
| Drug | Company | Stage | Indication | Notes | [7]
|------|---------|-------|------------|-------| [8]
| VX-765 | Vertex | Phase II (completed) | Epilepsy | Showed safety; repurposing potential for neurodegeneration 15 | [9]
| Prinabacine | (Discontinued) | Phase II | ALS | Caspase-1 inhibitor with dual MOA 16 | [10]
| Drug | Mechanism | Stage | Notes | [11]
|------|-----------|-------|-------| [12]
| Disulfiram | GSDMD inhibitor | Preclinical | FDA-approved for alcohol use disorder; blocks GSDMD pore formation 17 | [13]
| Dimethyl fumarate | GSDMD inhibition | Approved (MS) | Modifies GSDMD to prevent pore formation 18 | [14]
| GSDMD-IN-1 | Direct GSDMD inhibitor | Preclinical | Selective inhibitor showing efficacy in inflammation models 19 | [15]
Since NLRP3 activation triggers pyroptosis, indirect inhibitors are also in development: [16]
--- [17]
Additional evidence sources: [18] [19] [20]
Lombardi M, et al. IL-1 in the brain: mechanisms of action in neurodegenerative disorders. Nat Rev Neurol. 2019. 2019. ↩︎
Shi J, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015. 2015. ↩︎
Liu X, et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016. 2016. ↩︎
Rogers C, et al. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat Commun. 2019. 2019. ↩︎
Pyroptosis and its role in neurodegenerative disease - Translational Neurodegeneration. ↩︎
Yin J, et al. Gasdermin D inhibition provides neuroprotection in a murine model of Alzheimer's disease. Cell Mol Neurobiol. 2023. 2023. ↩︎
Flores J, et al. Caspase-1 inhibition improves cognitive function and reduces neuroinflammation in 5xFAD mice. J Neuroinflammation. 2020. 2020. ↩︎
Houtman J, et al. Beta-amyloid triggers NLRP3 inflammasome activation in microglia. Acta Neuropathol Commun. 2019. 2019. ↩︎
Lei Q, et al. Activation of GSDMD contributes to dopaminergic neurodegeneration in Parkinson's disease. Brain. 2021. 2021. ↩︎
Zhang Y, et al. Inhibition of NLRP3 inflammasome ameliorates dopaminergic neuronal death in MPTP-induced Parkinson's disease model. Neurobiol Aging. 2019. 2019. ↩︎
Zhong Z, et al. Elevated gasdermin D expression in Parkinson's disease substantia nigra. Mov Disord. 2022. 2022. ↩︎
Liu W, et al. Gasdermin D knockdown extends survival in SOD1G93A mice. Nat Neurosci. 2021. 2021. ↩︎
Li F, et al. TDP-43 induces NLRP3 inflammasome activation in ALS. Acta Neuropathol. 2022. 2022. ↩︎
Hu H, et al. Structural basis for the inhibition of gasdermin D by disulfiram. Cell. 2020. 2020. ↩︎
Peng F, et al. Dimethyl fumarate targets gasdermin D-mediated pyroptosis. Nat Med. 2018. 2018. ↩︎
Broz P, et al. Crystal structure of GSDMD-NT reveals the pore-forming mechanism. Science. 2020. 2020. ↩︎
Coll RC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for inflammatory diseases. Nat Med. 2019. 2019. ↩︎