2. Academic Validation
  3. Small molecule compound K-7174 attenuates neuropsychiatric manifestations in lupus-prone mice

Small molecule compound K-7174 attenuates neuropsychiatric manifestations in lupus-prone mice

  • Brain Res. 2023 Feb 15:1801:148203. doi: 10.1016/j.brainres.2022.148203.
Yu Fan 1,  Xuan Liu 1,  Jinjin Wu 1,  Jiali Ni 1,  Jun Liang 2,  Yayi Hou 3,  Huan Dou 4
Affiliations

Affiliations

  • 1 The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China.
  • 2 Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.
  • 3 The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China. Electronic address: [email protected].
  • 4 The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China. Electronic address: [email protected].
PMID: 36521514 DOI: 10.1016/j.brainres.2022.148203
Abstract

The neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) present significant morbidity and mortality due to frequent non-response or adverse effects of the current clinical drugs. The disruption of the blood-brain barrier (BBB) contributes to inflammatory NPSLE disease progression. K-7174, a highly piperazine-derived compound, inhibits leukocyte adhesion and inflammatory factor expression. The present study aimed to comprehensively assess the treatment effect of neurobehavioral deficits in MRL/lpr mice, a validated neuropsychiatric lupus model. The intraperitoneal injection of K-7174 alleviated lupus-like symptoms and improved cognitive dysfunction in MRL/lpr mice. Also, it significantly attenuated neuronal degeneration and decreased serum albumin deposition in the hippocampus. Furthermore, K-7174 acted directly on the brain microvascular endothelial bEnd.3 cells and reduced the BBB permeability, manifested by inhibiting the activation of brain microvascular endothelial cells and increasing the expression of tight junctions (TJs). Notably, in vitro experiments showed that K-7174 alleviates the decreased ZO1 and Occludin expression in bEnd.3 cells caused by lactate increase, improving cell permeability via the MCT4/NKAP/CREB signaling pathway. These findings suggested that K-7174 mediates the attenuation of NPSLE in MRL/lpr mice, indicating a promising therapeutic strategy for NPSLE.

Keywords

Blood–brain barrier; Cerebral microvascular endothelial cells; K-7174; Neuropsychiatric systemic lupus erythematosus.

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