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IL-1β and IL-18 are pro-inflammatory cytokines that are linked to inflammation. Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is involved in the maturation and secretion of IL-1β and IL-18 and, thus, plays a key role in the pathogenesis of many inflammatory conditions, including multiple sclerosis (MS). OLT1177™ (Dapansutrile) is a newly developed drug that is safe in humans and inhibits specifically the NLRP3 inflammasome. In the present study, we investigated whether OLT1177 exerts therapeutic effects in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We found that EAE mice fed an OLT1177-enriched diet prophylactically were significantly protected against functional deficits and demyelination in the spinal cord. We also demonstrated that prophylactic oral administration of OLT1177 led to marked reduction (~2- to 3-fold) in the protein levels of IL-1β and IL-18, as well as, IL-6 and TNFα, in the spinal cord of EAE mice. Moreover, prophylactic oral administration of OLT1177 significantly attenuated the infiltration of CD4 T cells and macrophages in the spinal cord. We also demonstrated that oral administration of OLT1177, starting at disease onset, resulted in significant amelioration of the clinical signs of EAE. Overall, these first data suggest that OLT1177 could have clinical benefit for the treatment of MS in humans.

Background Parkinson’s disease (PD) is characterized by a progressive degeneration of dopaminergic neurons, which leads to irreversible loss of peripheral motor functions. Death of dopaminergic neurons induces an inflammatory response in microglial cells, which further exacerbates neuronal loss. Reducing inflammation is expected to ameliorate neuronal loss and arrest motor dysfunctions. Because of the contribution of the NLRP3 inflammasome to the inflammatory response in PD, we targeted NLRP3 using the specific inhibitor OLT1177 ® . Methods We evaluated the effectiveness of OLT1177 ® in reducing the inflammatory response in an MPTP neurotoxic model of PD. Using a combination of in vitro and in vivo studies, we analyzed the effects of NLRP3 inhibition on pro-inflammatory markers in the brain, α-synuclein aggregation, and dopaminergic neuron survival. We also determined the effects of OLT1177 ® on locomotor deficits associated with MPTP and brain penetrance. Results Treatment with OLT1177 ® prevented the loss of motor function, reduced the levels of α-synuclein, modulated pro-inflammatory markers in the nigrostriatal areas of the brain, and protected dopaminergic neurons from degeneration in the MPTP model of PD. We also demonstrated that OLT1177 ® crosses the blood–brain barrier and reaches therapeutic concentrations in the brain. Conclusions These data suggest that targeting the NLRP3 inflammasome by OLT1177 ® may be a safe and novel therapeutic approach to arrest neuroinflammation and protect against neurological deficits of Parkinson’s disease in humans.

Dapansutrile, an orally active and selective NLRP3 inflammasome inhibitor, exerts its effects by directly binding to the NLRP3 NACHT domain. This action disrupts inflammasome assembly and caspase-1 activation, thereby inhibiting the maturation and release of the pro-inflammatory cytokines IL-1β and IL-18. Beyond this core inhibition, dapansutrile modulates immune cell chemotaxis and inhibits pyroptosis. Preclinical and clinical studies demonstrate its efficacy in mitigating pathology in diverse conditions, including gouty arthritis, cardiovascular diseases, neurodegenerative disorders, inflammatory bowel disease, and periodontitis. A favorable safety profile distinguishes it from other NLRP3 inhibitors like MCC950, with no significant hepatotoxicity reported in trials. Furthermore, dapansutrile exhibits synergistic effects when combined with agents such as lonafarnib or immune checkpoint inhibitors, enhancing anti-inflammatory and anti-tumor responses. This review consolidates evidence on dapansutrile's molecular mechanisms, therapeutic applications, and biosafety, highlighting its potential as a novel, well-tolerated, and versatile anti-inflammatory agent. Future research should focus on optimizing its delivery, particularly to the central nervous system, and leveraging artificial intelligence to predict effective drug combinations.

Intracerebral haemorrhage (ICH) is a severe stroke subtype with high mortality and poor functional recovery. Neuroinflammation, mediated by NLRP3 inflammasome and caspase-1 (Casp1) activation, drives secondary brain injury, including oedema and cell death after ICH. We hypothesize that combining NLRP3 inhibitor OLT1177 and Casp1 inhibitor VX765 will provide enhanced neuroprotection against brain oedema and injury in experimental ICH. ICH was induced by injecting autologous blood into the basal ganglia in mouse models. Sixty-three C57Bl/6 male mice were randomly assigned to five groups: sham, vehicle, OLT1177 (dapansutrile, 200 mg/kg intraperitoneally), VX765 (75 mg/kg intraperitoneally) and combination of OLT1177 and VX765. Mice were treated for three consecutive days, starting 1 hour after ICH surgery. Behavioural tests, brain oedema, brain water content, blood-brain barrier integrity, vascular permeability, cell apoptosis, and levels of NLRP3 and its downstream proteins were measured. OLT1177 significantly reduced cerebral oedema after ICH and improved neurological function. It preserved blood-brain barrier integrity and reduced vascular leakage. Furthermore, OLT1177 prevented micro­glial morphological changes and significantly inhibited activation of Casp1 and release of IL-1β. OLT1177 also protected against neuronal loss in the affected hemisphere. Notably, the combination of OLT1177 and VX765 further attenuated brain injury after ICH by inhibiting inflammasome activation. The combination of OLT1177 and VX765 thus provided enhanced protection against brain injury by inhibiting inflammasome activation, suggesting that OLT1177 in combination with VX765 might serve as a promising therapeutic strategy for the treatment of ICH.