fps-zm1 and Cognitive-Dysfunction

Pneumococcal meningitis is a life-threatening infection of the central nervous system (CNS), and half of the survivors of meningitis suffer from neurological sequelae. We hypothesized that pneumococcal meningitis causes CNS inflammation via the disruption of the blood-brain barrier (BBB) and by increasing the receptor for advanced glycation end product (RAGE) expression in the brain, which causes glial cell activation, leading to cognitive impairment. To test our hypothesis, 60-day-old Wistar rats were subjected to meningitis by receiving an intracisternal injection of Streptococcus pneumoniae or artificial cerebrospinal fluid as a control group and were treated with a RAGE-specific inhibitor (FPS-ZM1) in saline. The rats also received ceftriaxone 100 mg/kg intraperitoneally, bid, and fluid replacements. Experimental pneumococcal meningitis triggered BBB disruption after meningitis induction, and FPS-ZM1 treatment significantly suppressed BBB disruption. Ten days after meningitis induction, surviving animals were free from infection, but they presented increased levels of TNF-α and IL-1β in the prefrontal cortex (PFC); high expression levels of RAGE, amyloid-β (Aβ

Topics: Animals; Benzamides; Blood-Brain Barrier; Blotting, Western; Cognitive Dysfunction; Disease Models, Animal; Interleukin-1beta; Male; Meningitis, Pneumococcal; Morris Water Maze Test; Neuroprotective Agents; Open Field Test; Prefrontal Cortex; Rats; Rats, Wistar; Receptor for Advanced Glycation End Products; Tumor Necrosis Factor-alpha

Neuroinflammation triggered by surgical trauma contributes to postoperative cognitive dysfunction (POCD). The receptor for advanced glycation end‑products (RAGE), a multiligand inflammatory receptor, is involved in the damaging effects of various cellular processes, contributing to neuroinflammation and neurodegeneration. However, the potential role of RAGE in the acute period of POCD has not been fully investigated. C57BL/6 male mice undergoing surgery of the tibia under isoflurane anesthesia were treated with the RAGE antagonist FPS‑ZM1 or vehicle control intraperitoneally for a period of 7 days. The cognitive function of the animals was tested using trace fear conditioning on the third postoperative day. To determine astrocytic activation, microgliosis, p65 expression, inflammatory factor levels and postsynaptic density protein‑95 (PSD‑95) expression in the hippocampus, the animals were euthanized on either the first, third or seventh postoperative day. Compared with the control group, the cognitive function of the surgical animals was impaired on the third postoperative day. Astrocytic activation, microgliosis and the expression levels of p65, interleukin (IL)‑1β, IL‑6, and PSD‑95 were significantly increased on the first, and third postoperative days. However, tumor necrosis factor‑α expression was significantly increased only on postoperative day 1. All of the surgical effects observed were partially inhibited by treatment with FPS‑ZM1. In summary, the results of the present study suggest that RAGE serves an important role in the acute inflammatory process of POCD, and blocking RAGE can inhibit neuroinflammation and attenuate POCD. Thus, the RAGE signaling pathway may be a novel target in the prevention, and treatment of POCD.

Topics: Animals; Benzamides; Calcium-Binding Proteins; Cognitive Dysfunction; Disks Large Homolog 4 Protein; Down-Regulation; Glial Fibrillary Acidic Protein; Hippocampus; Immunohistochemistry; Interleukin-1beta; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; Postoperative Complications; Receptor for Advanced Glycation End Products; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Up-Regulation