The ast-120 recovers uremic toxin-induced cognitive deficit via nlrp3 inflammasome pathway in astrocytes and microglia

Abstract

Chronic kidney disease (CKD) is characterized by the progressive loss of renal function; moreover, CKD progression commonly leads to multiple comorbidities, including neurological dysfunction and immune disorders. CKD-triggered neuroinflammation significantly contributes to cognitive impairment. This study aimed to investigate the contribution of uremic toxins to cognitive impairment. Serum creatinine, blood urea nitrogen (BUN), indoxyl sulfate (IS), and p-cresol sulfate (PCS) levels were measured using an enzyme-linked immunosorbent assay and high-performance liquid chromatography. The creatinine, BUN, IS, and PCS levels were increased from 4 weeks after 5/6-nephrectomy in mice, which suggested that 5/6-nephrectomy could yield a CKD animal model. Further, CKD mice showed significantly increased brain and serum indoxyl sulfate levels. Immuno-histochemistry analysis revealed hippocampal inflammation and NLRP3-inflammasomes in astro-cytes. Further, the Y-maze and Morris water maze tests revealed learning and memory defects in CKD mice. AST-120, which is also an IS absorbent, effectively reduced serum and hippocampal IS levels as well as reversed the cognitive impairment in CKD mice. Additionally, NLRP3-knockout mice that underwent 5/6-nephrectomy showed no change in cognitive function. These findings suggested that IS is an important uremic toxin that induces NLRP3 inflammasome-mediated not only in microglia, but it also occurred in astrocytic inflammation, which subsequently causes cognitive impairment.