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.
Zhou et al. (Wed,) studied this question.