J147 is Effective in Prevention of Postoperative Cognitive Dysfunction in a Rat Model

Abstract

Postoperative Cognitive Dysfunction (POCD) is a major complication after surgery. Although a dysregulated inflammatory response is indicated to play a key role in POCD, efficacy of anti-inflammatory treatment remains poor. J147 is a newly developed anti-dementia drug that combines neuroprotective, anti-inflammatory and metabolism improving properties. Aim of the present study was to assess the therapeutic potential of J147 in our rat model for POCD. After major abdominal surgery, male (12 weeks old) Wistar rats were divided into: control surgery; surgery treated with acute J147 (gavage before surgery) and surgery treated with chronic J147 (J147 in food). Non-surgery rats served as controls. Timed blood samples were collected to measure peripheral inflammation. Behavioral testing was performed to obtain effects on mood and cognition. At sacrifice, 14 days after surgery, brain tissue was collected to measure neuroinflammation, neurogenesis and cell metabolism. Chronically J147 treated rats lost significantly less body weight after surgery. Moreover, these rats showed preserved shortterm (novel location recognition test) as well as long-term spatial memory (Morris Water Maze). However, chronic J147 did not affect peripheral inflammation, indicated by plasma IL-1beta and neutrophil gelatinase-associated lipocalin levels; nor neuroinflammation, indicated by microglial activity; nor neurogenesis or metabolic parameters (AMPK and rpS6 ratio's). Acute J147 did not affect behavioral parameters, neuroinflammation or metabolic parameters.In conclusion, data show that chronic, but not acute, treatment with J147 can prevent cognitive impairment following abdominal surgery in our POCD rat model, potentially providing a promising new therapeutic avenue for POCD. The lack of impact on markers of (neuro)inflammation, cell metabolism and neurogenesis indicated that J147 may have acted through different, yet to investigate, neuroprotective mechanisms.