Downregulation of hippocampal NR2A/2B subunits related to cognitive impairment in a pristane-induced lupus BALB/c mice

Abstract

Neuropsychiatric systemic lupus erythematosus (NPSLE) is associated with learning and memory deficit. Murine model of lupus induced by pristane in BALB/c mice is an experimental model that resembles some clinical and immunological SLE pathogenesis. Nevertheless, there is no experimental evidence that relates this model to cognitive dysfunction associated with NR2A/2B relative expression. To evaluate cognitive impairment related to memory deficits in a murine model of lupus induced by pristane in BALB/c mice related to mRNA relative expression levels of NR2A/2B hippocampal subunits in short and long-term memory task at 7 and 12 weeks after LPS exposition in a behavioral test with the use of Barnes maze. A total of 54 female BALB/c mice 8–12 weeks old were included into 3 groups: 7 and 12 weeks using pristane alone (0.5 mL of pristane) by a single intraperitoneal (i.p.) injection. A control group (single i.p. injection of 0.5 mL NaCl 0.9%) and pristane plus LPS exposure using single i.p. pristane injection and LPS of E. coli O55:B5, in a dose of 3mg/kg diluted in NaCl 0.9% 16 weeks post-pristane administration. To determine cognitive dysfunction, mice were tested in a Barnes maze. Serum anti-Sm antibodies and relative expression of hippocampal NR2A/2B subunits (GAPDH as housekeeping gene) with SYBR green quantitative reverse transcription polymerase chain reaction and 2-ΔΔCT method were determined in the groups. Downregulation of hippocampal NR2A subunit was more evident than NR2B in pristane and pristane+LPS at 7 and 12 weeks of treatment and it is related to learning and memory disturbance assayed by Barnes maze. This is the first report using the murine model of lupus induced by pristane that analyzes the NMDA subunit receptors, finding a downregulation of NR2A subunit related to learning and memory disturbance being more evident when they were exposed to LPS.

Postconditioning with Sevoflurane or Propofol Alleviate Lipopolysaccharide-Induced Neuroinflammation, but Exert Dissimilar Effects on NR2B Subunit and Cognition

“…For instance, iso urane up-regulated extrasynaptic NR2B in the hippocampus in elderly rats and impaired cognitive function [24]; and iso urane or sevo urane upregulated NR2B in the hippocampus, facilitated LTP in CA1 area, and improved cognition in adult mice [14,16]. Sevo urane induced NR1 and NR2B up-regulation, NR2A down-regulation in the PFC, and caused cognitive de cits in adolescent rats [71], while propofol down-regulated NR1, NR2B, NR2A, and PSD-95 in the PFC of developing rat brain, and caused long-term cognitive dysfunction [17,72]. The possible reasons for this discrepancy might be different ages, species of animals, and strategies of drug treatment.…”

Using the Mouse to Model Human Diseases: Cognitive Impairment in Systemic Lupus Erythematosus

“…Intraperitoneal injection of pristane to Balb/c mice develops an SLE-like disease with ANA and immune complex-mediated glomerulonephritis with high levels of IFN. It also results in downregulation of the GluN2A subunit of the NMDA receptor in hippocampal neurons and to disrupted learning and memory deficits 19 . Abnormal levels of IFN-α have been observed in the sera and cerebrospinal fluid (CSF) of patients with mental disorders 20,21 .…”

The GLP-1 receptor agonist Exendin-4 modulates hippocampal NMDA-receptor signalling in aged rats and improves cognitive impairment in diabetic elderly patients

“…Induction of memory long term potentiation (LTP) in the hippocampus requires agonistic activity on NMDA-R, while antagonists impair learning and memory capabilities 10 . Recently, it has been demonstrated that the downregulation of NMDA-R subunits is related to learning and memory disturbance in an animal model of neuropsychiatric systemic lupus erythematosus 11 . On the contrary, extracellular glutamate accumulation leads to an over-stimulation of glutamate receptors, including NMDA, hesitating in neurotoxicity 12 .…”