Microglia dependent BDNF and proBDNF can impair spatial memory performance during persistent inflammatory pain.

Abstract Inflammatory pain is commonly associated with cognitive impairment. However, its molecular mechanisms are poorly understood. Thus, this study was conducted to investigate the molecular mechanisms of behavioral changes associated with inflammatory pain. Briefly, 36 Wistar rats were randomly divided into two main groups: CFA group treated with 100 μL of Complete Freundsʼ Adjuvant (CFA) and CFA + Minocycline group treated with 100 μL of CFA+40 mg/kg/day of minocycline). After that, each group was divided into three subgroups based on different time points of the study. The pain was induced using CFA and subsequent behavioral changes (i.e., hyperalgesia and learning and spatial memory) were analyzed by the Morris Water Maze (MWM) task and Radiant Heat. Then, the cellular and molecular changes were assessed using Western Blotting, Immunohistochemistry, and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) techniques. Results of the study indicated that CFA-induced pain impaired spatial learning and memory functions. Studying the cellular changes showed that persistent inflammatory pain increased the microglial activity in CA1 and Dentate Gyrus (DG) regions. Furthermore, an increase was observed in the percentage of TUNEL-positive cells. Also, pro-Brain-Derived Neurotrophic Factor (BDNF)/BDNF ratio, Caspase3, and Receptor-Interacting Protein kinase 3 (RIP3) levels increased in the rats' hippocampus following induction of persistent inflammatory pain. These changes were reversed following the cessation of pain as well as the injection of minocycline. Taking together, the results of the current study for the first time revealed that an increase in the microglia dependent proBDNF/BDNF ratio following persistent inflammatory pain leads to cell death of the CA1 and DG neurons that subsequently causes a cognitive deficit in the learning and spatial memory functions.