Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in animal models of post-traumatic stress disorder.
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.
Department of New Drug Evaluation,Beijing Institute of Pharmacology and Toxicology,Haidian, Beijing,China.
Li-Ming
LM
Zhang
Department of New Drug Evaluation,Beijing Institute of Pharmacology and Toxicology,Haidian, Beijing,China.
Zhi-Kun
ZK
Qiu
Department of New Drug Evaluation,Beijing Institute of Pharmacology and Toxicology,Haidian, Beijing,China.
Nan
N
Zhao
Department of New Drug Evaluation,Beijing Institute of Pharmacology and Toxicology,Haidian, Beijing,China.
Hong-Xia
HX
Chen
Department of New Drug Evaluation,Beijing Institute of Pharmacology and Toxicology,Haidian, Beijing,China.
Yan-Qin
YQ
Liu
Department of Pharmacology, School of Pharmaceutical Sciences,Southern Medical University,Guangzhou,China.
Jiang-Ping
JP
Xu
Department of New Drug Evaluation,Beijing Institute of Pharmacology and Toxicology,Haidian, Beijing,China.
You-Zhi
YZ
Zhang
Department of Medicinal Chemistry,Beijing Institute of Pharmacology and Toxicology,Haidian, Beijing,China.
Ri-Fang
RF
Yang
Department of New Drug Evaluation,Beijing Institute of Pharmacology and Toxicology,Haidian, Beijing,China.
Yun-Feng
YF
Li
D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism; D020280:Sertraline / Q000494:pharmacology / Q000627:therapeutic use; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy* / Q000209:etiology
D014151:Anti-Anxiety Agents; C463819:Bzrp protein, mouse; D007093:Imidazoles; D007546:Isoquinolines; C000598174:N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-chlorophenyl)-7-methylimidazo(1,2-a)pyridine-3-acetamide; D011725:Pyridines; D018079:Receptors, GABA; D020280:Sertraline; C037850:PK 11195