Alpha-7 nicotinic receptor allosteric modulator PNU120596 prevents lipopolysaccharide-induced anxiety, cognitive deficit and depression-like behaviors in mice

Abstract

Neuroinflammation is often associated with the development of major depressive disorder (MDD)-related symptoms. Previous studies have indicated that activation of glial cells, upregulation of proinflammatory cytokines and dysregulation of adrenergic system in the central nervous system (CNS) could be the key mediators to modulate depression-related behaviors after peripheral immune activation. Central α7 nicotinic acetylcholine receptor (α7 nAChR) has a role in the regulation of the cholinergic anti-inflammatory pathway. The present study determined the effects of PNU120596, α7 nAChR positive allosteric modulator (PAM), on lipopolysaccharide (LPS)-induced anxiety, cognitive deficit, and depression-like behaviors in mice. These behaviors were evaluated 24 h after LPS (1 mg/kg) administration using elevated plus-maze, Y-maze, and forced swim test, respectively. The effects of PNU120596 on mRNA of neuroinflammatory markers and norepinephrine (NE) level in behaviorally-relevant brain regions such as the hippocampus and prefrontal cortex were examined. PNU120596 administration (1 or 4 mg/kg) showed anxiolytic, pro-cognitive, and antidepressant-like effects by preventing LPS-induced behavioral abnormalities. Following LPS treatment, PNU120596 hindered activation markers of the microglia and astrocytes (cluster of differentiation molecule 11b and glial fibrillary acidic protein) and upregulation of proinflammatory cytokines such as interleukin 1 beta and tumor necrosis factor-alpha in the hippocampus and prefrontal cortex. NE level that was reduced by peripheral LPS challenge was normalized by PNU120596 effects in both brain regions. Overall, the results in this study indicate that activation of α7 nAChR by PAM effectively prevents LPS-induced anxiety, cognitive deficit, and depression-like behaviors and regulates relevant neuroinflammatory markers in the hippocampus and prefrontal cortex.

Keywords: Major depression; Mice; Microglia; Neuroinflammation; Nicotinic receptor; α7 nicotinic receptor positive allosteric modulator.