Dexpramipexole ameliorates cognitive deficits in sepsis-associated encephalopathy through suppressing mitochondria-mediated pyroptosis and apoptosis

Abstract

ObjectivesThis study was aimed at evaluating the effects of dexpramipexole (DPX) -a mitochondrial protectant that sustains mitochondrial function and energy production -on cognitive function in a mouse model of sepsis-associated encephalopathy (SAE) induced by peripheral administration of lipopolysaccharide (LPS) and examining the potential mechanisms. Methods C57BL/6 male mice were randomized into one of four treatment protocols: Con+Sal, Con+DPX, LPS+Sal or LPS+DPX. The mice were intraperitoneally (i.p.) injected with LPS or equivalent volumes of normal saline once daily for 3 consecutive days. To evaluate the protective effects of DPX, we administered DPX or normal saline i.p. to the mice once daily for 6 consecutive days. Six mice in each group were decapitated on day 7, and each brain was rapidly removed and separated into two halves for biochemical and histochemical analysis. The remaining surviving mice in each group were subjected to behavioral tests from days 7 to 10. ResultsPeripheral administration of LPS to mice led to learning and memory deficits in behavioral tests, which were associated with mitochondrial impairment and ATP depletion in the hippocampus. Repeated DPX treatment protected the mitochondria against LPSinduced morphological and functional impairment; inhibited the activation of the Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-caspase-1-dependent pyroptosis pathway and cytochrome c (Cyt-c)-caspase-3-dependent apoptosis pathway; and attenuated LPS-induced neuroinflammation and cell death in the hippocampus in SAE mice.Conclusions Mitochondria-mediated pyroptosis and apoptosis are involved in the pathogenesis of cognitive deficits in a mouse model of SAE and DPX protects mitochondria and suppresses the mitochondria-medicated pyroptosis and apoptosis pathways, and ameliorates LPSinduced neuroinflammation and cognitive deficits. This study provides theoretical evidence supporting DPX for the treatment of SAE.

The role of pyroptosis in cognitive impairment

“…Mitochondria-mediated pyroptosis was reported in SAE, mitochondria impairment was associated with cognitive dysfunction. The mitochondrial protectant dexpramipexole (DPX) could sustain mitochondrial function and inhibit NLRP3/caspase-1 pyroptosis pathway, thus ameliorating neuroinflammation and cognitive impairment in SAE (Zhang et al, 2023). Sevoflurane was reported to activate HMGB1-induced NLRP3/ASC inflammasome, induce pyroptosis, and impair cognitive function in PND (Shan et al, 2023), however, in SAE, sevoflurane could act as protective role.…”