Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in animal models of post-traumatic stress disorder

Abstract

Recently, the translocator protein (18 kDa) (TSPO), previously called peripheral benzodiazepine receptor (PBR) and both the starting point and an important rate-limiting step in neurosteroidogenesis, has received increased attention in the pathophysiology of post-traumatic stress disorder (PTSD) because it affects the production of neurosteroids, reinforcing the hypothesis that selective TSPO ligands could potentially be used as anti-PTSD drugs. As expected, we showed that chronic treatment with YL-IPA08 [N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-ichlorophenyl)-7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride], a potent and selective TSPO ligand synthesized by our institute, caused significant suppression of enhanced anxiety and contextual fear induced in the inescapable electric foot-shock-induced mouse model of PTSD and the time-dependent sensitization (TDS) procedure. These effects were completely blocked by the TSPO antagonist PK11195. Furthermore, YL-IPA08 could increase the level of allopregnanolone in the prefrontal cortex and serum of post-TDS rats, and these effects were antagonized by PK11195. In summary, the findings from the current study showed that YL-IPA08, a potent and selective TSPO ligand, had a clear anti-PTSD-like effect, which might be partially mediated by binding to TSPO and the subsequent synthesis of allopregnanolone.

The inulin-type oligosaccharides extract from morinda officinalis, a traditional Chinese herb, ameliorated behavioral deficits in an animal model of post-traumatic stress disorder

“…Accumulating evidence demonstrates that serotonin (5-HT) dysfunction plays an important role in the etiology of PTSD, and 5-HT systems are also implicated in the treatment of PTSD (Zhang et al 2014). Decreased 5-HT levels in animal models and human studies have been associated with increased impulsivity, aggression, fear, and sadness/depression (Zhang et al 2012(Zhang et al , 2014.…”

“…Sertraline (Ser), purchased from Sigma-Aldrich (St Louis, MO, U.S.A.), was administered as a positive control in all behavioral tests at a dose (15 mg/kg, i.g.) based on previous PTSD studies (Zhang et al 2012(Zhang et al , 2014. It was prepared in distilled water.…”

“…Based on these evidences, the brain regions were selected in the present study. The experimental procedure was conducted as described previously (Qiu et al 2015;Zhang et al 2014). The rats were decapitated at the conclusion of the behavioral tests in 24 h and there was a last drug treatment 1 h before the rat killing.…”

“…The samples were assayed with ELISA. Based on the studies of allopregnanolone measurement (Zhang et al 2014), level of allopregnanolone was quantified by Enzyme Immunoassay kit (Raybiotech, 3B362, USA) that was specific for allopregnanolone measurement. Six samples in each group were used to determine the optical density (OD) values at 450 nm in ELISA plate reader and used for statistical analyzes.…”

“…The decreased allopregnanolone biosynthesis was implicated as one of possible contributors to aetiology of PTSD (Pinna and Rasmusson 2012). The lowered allopregnanolone levels in patients with PTSD might contribute to an imbalance in inhibitory versus excitatory neurotransmission, leading to re-experiencing symptoms of PTSD (Zhang et al 2014). Based on these evidences above, the present study is to evaluate the role of allopregnanolone biosynthesis in the anti-PTSD-like effects of IOMO.…”