Association between endogenous lactate accumulation and dysregulated activation of the NLRP3 inflammasome pathway in schizophrenia
Abstract 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 (NMD...
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Nature Portfolio
2025-06-01
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| Online Access: | https://doi.org/10.1038/s41598-025-04823-6 |
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| author | Yingying Zhang Yanjun Wang Haoran Xing Yuncheng Bai Mier Li Haiqiang Zhao Luanmei Ding Weiwei Wang Tianhao Bao |
| author_facet | Yingying Zhang Yanjun Wang Haoran Xing Yuncheng Bai Mier Li Haiqiang Zhao Luanmei Ding Weiwei Wang Tianhao Bao |
| author_sort | Yingying Zhang |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-a2df34401df544d0aa0c8c4cc7ff0dff |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-a2df34401df544d0aa0c8c4cc7ff0dff2025-08-20T03:10:35ZengNature PortfolioScientific Reports2045-23222025-06-0115111910.1038/s41598-025-04823-6Association between endogenous lactate accumulation and dysregulated activation of the NLRP3 inflammasome pathway in schizophreniaYingying Zhang0Yanjun Wang1Haoran Xing2Yuncheng Bai3Mier Li4Haiqiang Zhao5Luanmei Ding6Weiwei Wang7Tianhao Bao8Psychiatric Hospital of Yunnan Province, The Affiliated Mental Health Center of Kunming Medical UniversityPsychiatric Hospital of Yunnan Province, The Affiliated Mental Health Center of Kunming Medical UniversityPsychiatric Hospital of Yunnan Province, The Affiliated Mental Health Center of Kunming Medical UniversityThe First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and TechnologyPsychiatric Hospital of Yunnan Province, The Affiliated Mental Health Center of Kunming Medical UniversityPsychiatric Hospital of Yunnan Province, The Affiliated Mental Health Center of Kunming Medical UniversityPsychiatric Hospital of Yunnan Province, The Affiliated Mental Health Center of Kunming Medical UniversityDepartment of Geriatrics, The Second Affiliated Hospital of Kunming Medical UniversityPsychiatric Hospital of Yunnan Province, The Affiliated Mental Health Center of Kunming Medical UniversityAbstract 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.https://doi.org/10.1038/s41598-025-04823-6SchizophreniaLactateMK-801NLRP3Caspase-1 |
| spellingShingle | Yingying Zhang Yanjun Wang Haoran Xing Yuncheng Bai Mier Li Haiqiang Zhao Luanmei Ding Weiwei Wang Tianhao Bao Association between endogenous lactate accumulation and dysregulated activation of the NLRP3 inflammasome pathway in schizophrenia Scientific Reports Schizophrenia Lactate MK-801 NLRP3 Caspase-1 |
| title | Association between endogenous lactate accumulation and dysregulated activation of the NLRP3 inflammasome pathway in schizophrenia |
| title_full | Association between endogenous lactate accumulation and dysregulated activation of the NLRP3 inflammasome pathway in schizophrenia |
| title_fullStr | Association between endogenous lactate accumulation and dysregulated activation of the NLRP3 inflammasome pathway in schizophrenia |
| title_full_unstemmed | Association between endogenous lactate accumulation and dysregulated activation of the NLRP3 inflammasome pathway in schizophrenia |
| title_short | Association between endogenous lactate accumulation and dysregulated activation of the NLRP3 inflammasome pathway in schizophrenia |
| title_sort | association between endogenous lactate accumulation and dysregulated activation of the nlrp3 inflammasome pathway in schizophrenia |
| topic | Schizophrenia Lactate MK-801 NLRP3 Caspase-1 |
| url | https://doi.org/10.1038/s41598-025-04823-6 |
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