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1.
Eur J Pharmacol ; 933: 175256, 2022 Oct 15.
Article in English | MEDLINE | ID: mdl-36088983

ABSTRACT

Many studies have indicated that the risk of cognitive impairment is higher in patients with rheumatoid arthritis (RA). Additionally, patients with RA may have a lower incidence of cognitive impairment with long-term use of ibuprofen. This study was aimed at investigating the impacts of RA on memory function and the mechanisms that ibuprofen may exhibit to improve memory function in rats with collagen-induced arthritis (CIA). Ibuprofen (30 mg/kg) was given twice daily to CIA rats for two weeks starting from Day 18 following the first immunization. Memory function was measured by the Morris water maze (MWM) test and long-term potentiation (LTP). The proinflammatory cytokine levels and downstream signaling pathways, including mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB), were examined. Furthermore, the glutamatergic system, including glutamate transporters/receptors and brain extracellular levels of glutamate, was investigated. The results showed that the impaired learning memory in CIA rats, examined by the MWM test and LTP, can be ameliorated by ibuprofen treatment. Along with the improvement in memory deficits, ibuprofen attenuated both neuroinflammation and the associated elevated levels of phosphorylated p38, JNK, and p65 in the hippocampus of CIA rats. In addition, the decreased excitatory amino acid transporter 2 level, the increased extracellular glutamate, and the upregulated hippocampal NMDA receptor 2B of CIA rats were all normalized by ibuprofen treatment. These findings suggest that the effect of ibuprofen on the memory improvement in CIA rats is associated with the normalization of the activated MAPK and NF-κB pathways and the aberrant glutamatergic system.


Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/complications , Arthritis, Experimental/drug therapy , Cytokines/metabolism , Excitatory Amino Acid Transporter 2 , Glutamates , Ibuprofen/pharmacology , Ibuprofen/therapeutic use , Memory Disorders/drug therapy , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Rats
2.
J Neuroinflammation ; 18(1): 35, 2021 Jan 30.
Article in English | MEDLINE | ID: mdl-33516259

ABSTRACT

BACKGROUND: Rheumatoid arthritis (RA) is characterized by synovial inflammation, cartilage damage, and systemic inflammation. RA is also associated with the occurrence of neuroinflammation and neurodegenerative diseases. In this study, the impacts of RA on the function of the blood-brain barrier (BBB) and the disposition of amyloid beta (Aß), including BBB transport and peripheral clearance of Aß, were investigated in rats with collagen-induced arthritis (CIA), an animal model with similarity to clinical and pathological features of human RA. METHODS: CIA was induced in female Lewis rats. In addition to neuroinflammation, the integrity and function of the BBB were examined. The expression of Aß-transporting proteins at brain blood vessels was measured. Blood-to-brain influx and plasma clearance of Aß were determined. RESULTS: Both microgliosis and astrogliosis were significantly increased in the brain of CIA rats, compared with controls. In terms of BBB function, the BBB permeability of sodium fluorescein, a marker compound for BBB integrity, was significantly increased in CIA rats. Moreover, increased expression of matrix metalloproteinase-3 (MMP-3) and MMP-9 and decreased expression of tight junction proteins, zonula occludens-1 (ZO-1) and occludin, were observed in brain microvessels of CIA rats. In related to BBB transport of Aß, protein expression of the receptor of advanced glycation end product (RAGE) and P-glycoprotein (P-gp) was significantly increased in brain microvessels of CIA rats. Notably, much higher expression of RAGE was identified at the arterioles of the hippocampus of CIA rats. Following an intravenous injection of human Aß, significant higher brain influx of Aß was observed in the hippocampus of CIA rats. CONCLUSIONS: Neuroinflammation and the changes of BBB function were observed in CIA rats. The increased RAGE expression at cerebral blood vessels and enhanced blood-to-brain influx of Aß indicate the imbalanced BBB clearance of Aß in RA.


Subject(s)
Amyloid beta-Peptides/metabolism , Arthritis, Experimental/metabolism , Blood-Brain Barrier/metabolism , Brain/metabolism , Peptide Fragments/metabolism , Animals , Arthritis, Experimental/complications , Arthritis, Experimental/pathology , Blood-Brain Barrier/pathology , Brain/blood supply , Brain/pathology , Female , Metabolic Clearance Rate/physiology , Microvessels/metabolism , Microvessels/pathology , Rats , Rats, Inbred Lew , Receptor for Advanced Glycation End Products/metabolism
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