Novel Caspase-1 inhibitor CZL80 improves neurological function in mice after progressive ischemic stroke within a long therapeutic time-window

Ling Pan1, Wei-dong Tang1, Ke Wang1, Qi-feng Fang1, Meng-ru Liu1, Zhan-xun Wu1, Yi Wang1,2, Sun-liang Cui3, Gang Hu4, Ting-jun Hou3, Wei-wei Hu1, Zhong Chen1,2, Xiang-nan Zhang1
1 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
2 Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
3 Department of Pharmachemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
4 Department of Pharmacology, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing 210029, China
Correspondence to: Zhong Chen:, Xiang-nan Zhang:,
DOI: 10.1038/s41401-022-00913-7
Received: 19 December 2021
Accepted: 16 April 2022
Advance online: 2 May 2022


Progressive ischemic stroke (PIS) is featured by progressive neurological dysfunction after ischemia. Ischemia-evoked neuroinflammation is implicated in the progressive brain injury after cerebral ischemia, while Caspase-1, an active component of inflammasome, exaggerates ischemic brain injury. Current Caspase-1 inhibitors are inadequate in safety and druggability. Here, we investigated the efficacy of CZL80, a novel Caspase-1 inhibitor, in mice with PIS. Mice and Caspase-1−/− mice were subjected to photothrombotic (PT)-induced cerebral ischemia. CZL80 (10, 30 mg·kg−1·d−1, i.p.) was administered for one week after PT onset. The transient and the progressive neurological dysfunction (as foot faults in the grid-walking task and forelimb symmetry in the cylinder task) was assessed on Day1 and Day4-7, respectively, after PT onset. Treatment with CZL80 (30 mg/kg) during Day1-7 significantly reduced the progressive, but not the transient neurological dysfunction. Furthermore, we showed that CZL80 administered on Day4-7, when the progressive neurological dysfunction occurred, produced significant beneficial effects against PIS, suggesting an extended therapeutic time-window. CZL80 administration could improve the neurological function even as late as Day43 after PT. In Caspase-1−/− mice with PIS, the beneficial effects of CZL80 were abolished. We found that Caspase-1 was upregulated during Day4-7 after PT and predominantly located in activated microglia, which was coincided with the progressive neurological deficits, and attenuated by CZL80. We showed that CZL80 administration did not reduce the infarct volume, but significantly suppressed microglia activation in the peri-infarct cortex, suggesting the involvement of microglial inflammasome in the pathology of PIS. Taken together, this study demonstrates that Caspase-1 is required for the progressive neurological dysfunction in PIS. CZL80 is a promising drug to promote the neurological recovery in PIS by inhibiting Caspase-1 within a long therapeutic time-window.

Keywords: progressive ischemic stroke; neuroinflammation; Caspase-1 inhibitor; microglia; neurological dysfunction; therapeutic time-window

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