Association between endogenous lactate accumulation and dysregulated activation of the NLRP3 inflammasome pathway in schizophrenia

In this study, we retrospectively analyzed whether serum lactate levels were elevated in patients with schizophrenia (SCZ) and explored cognitive deficits, abnormalities in lactate metabolism, and neuroinflammation in an dizocilpine (MK-801)-induced N-methyl-d-aspartate (NMDA) receptor (NMDAR) inhibition model using the Morris water maze (MWM) test, biochemical assays, immunofluorescence (IF), Western blot (WB), and enzyme-linked immunosorbent assay (ELISA). We found that serum lactate levels were significantly higher than the normal range in patients with schizophrenia, and they were significantly and positively correlated with both length of hospitalization and serum triglyceride levels. In addition, we found that MK-801 induced cognitive deficits in Sprague-Dawley (SD) rats, accompanied by markedly elevated levels of lactate, pyruvate, glutamate and lactate dehydrogenase (LDH) activity in serum and frontal cortex (FCX). MK-801 caused a significant increase in the expression of NOD-, LRR-, and pyrin-containing protein 3 (NLRP3) and Caspase-1 proteins in FCX of rats; and elevated the levels of interleukin (IL)-1β and IL-18 in serum and FCX (P<0.05). We also found that serum lactate was significantly and positively correlated with serum pyruvate and glutamate levels, LDH activity, and IL-1β and IL-18 levels in SD rats. These data suggest that serum lactate is abnormally elevated in both SCZ patients and NMDA receptor inhibition models. Furthermore, there may be a link between MK-801-induced cognitive impairment, elevated serum lactate, and aberrant activation of the NLRP3/Caspase-1/IL-1βinflammatory pathway in rats. Modulation of serum/brain lactate levels and the NLRP3/Caspase-1/IL-1β pathway in SCZ patients may serve as potential targets for improving cognitive impairment in SCZ. Clinical trial registration number: ChiCTR2400091186.