Effects of α7 nicotinic receptor positive allosteric modulator, PNU120596, on BDNF, NKCC1, and KCC2 expressions following LPS‐induced depressive‐like behavior in mice

Abstract

Previous evidence indicates that neuroinflammation plays a critical role in the pathophysiology of major depressive disorder (MDD) by inducing neuronal excitability via dysregulation of microglial brain‐derived neurotrophic factor (BDNF), Na‐K‐Cl cotransporter‐1 (NKCC1), and K‐Cl cotransporter‐2 (KCC2). However, the role of microglial α7 nicotinic acetylcholine receptors (nAChRs), exhibiting anti‐inflammatory function during the activation, on these mediators is unknown. The objective of the present study was to determine the effects of PNU120596 on BDNF, NKCC1, and KCC2 expressions in lipopolysaccharide (LPS)‐induced mouse model of MDD using Western blot analysis, immunofluorescence staining, and real‐time polymerase chain reaction. We also examined the pharmacological interaction between PNU120596 and ANA12, an antagonist of TrkB which is the primary receptor for BDNF, on LPS‐induced depressive‐like behavior using forced swim test (FST), tail suspension test (TST), and Y‐maze test. Systemic administration of LPS (1 mg/kg, i.p.) significantly increased BDNF protein expression and mRNA ratio of NKCC1 to KCC2, and decreased KCC2 mRNA expression in the hippocampus and prefrontal cortex, the brain regions implicated in MDD. The PNU120596 (1 or 4 mg/kg, i.p.) dose‐dependently prevented the LPS‐induced dysregulated BDNF, NKCC1, and KCC2 expressions in these brain regions. Combination treatment with PNU120596 (1 mg/kg, i.p.) and ANA12 (0.25 mg/kg, i.p.) prevented LPS‐induced increased immobility time during FST and TST and LPS‐induced decreased spontaneous alternations (%) during Y‐maze test. Overall, our results suggest that PNU120596 prevented LPS‐induced depressive‐like behavior by decreasing neuronal excitability by targeting microglial α7 nAChR in the hippocampus and prefrontal cortex. (Supported in part by grant from Saudi Arabian Cultural Mission, USA).Support or Funding InformationSupported in part by grant from Saudi Arabian Cultural Mission, USA.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.