Hypidone Hydrochloride (YL-0919), a Sigma-1 Receptor Agonist, Improves Attention by Increasing BDNF in mPFC

  • Pharmaceuticals (Basel). 2025 Mar 24;18(4):455. doi: 10.3390/ph18040455.
Yixin Yang  1 ,  Yue Zhang  2 ,  Xiaojuan Hou  3 ,  Hailong Li  4 ,  Hui Ma  1 ,  Yunfeng Li  1  5
Affiliations
  • 1. Beijing Institute of Basic Medical Sciences, Beijing 100000, China.
  • 2. Department of Anesthesiology, Capital Medical University, Beijing 100000, China.
  • 3. Department of postgraduate, Hebei North University, Zhangjiakou 075000, China.
  • 4. Department of Clinical Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510000, China.
  • 5. Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100000, China.
PMID: 40283892 DOI: 10.3390/ph18040455
Abstract

Background/Objectives: The available treatment for attention deficit is drug therapy, but the drugs show poor adverse effect profiles and individual variability in response, especially in adults. Hypidone hydrochloride (YL-0919) is a selective sigma-1 receptor agonist that demonstrated a faster onset antidepressant effect in our previous studies. Current studies aim to study the attention-enhancing effect and mechanism of YL-0919. Methods: We used the five-choice serial reaction time task (5-CSRTT) to measure the attention-improving effect of YL-0919 in SD rats under a physiological state and exogenous corticosterone (CORT)-exposed state. The depression/anxiety-like behavioral experiments were used in the CORT-exposed rats. Immunofluorescence staining, western blotting, and Golgi-Cox staining were used to investigate the attention-improving mechanism of YL-0919. Results: The studies found that intragastric administration of 2.5 and 5 mg/kg YL-0919 for 6 days significantly improved the attention of SD rats under a physiological state. CORT exposure caused depression/anxiety-like behaviors and attention deficit in the rats. Intragastric administration of 3 mg/kg SA4503 or 2.5 and 5 mg/kg YL-0919 for 6 days significantly alleviated attention deficit in SD rats under an exogenous CORT-exposed state. In addition, YL-0919 administration obviously increased the expression of BDNF, PSD95, and synapsin1 and improved the dendritic complexity and the dendritic spine density in the medial prefrontal cortex (mPFC). Conclusions: These results reveal that YL-0919 as a selective sigma-1 receptor agonist can significantly improve the attention of SD rats under a physiological state and exogenous CORT-exposed state. Improving the level of BDNF and dendritic complexity in the mPFC may be the important mechanisms of YL-0919 to improve attention. The study also provides a potential novel target for the drug therapy of attention deficit.

Keywords
BDNF; YL-0919; attention deficit; mPFC; sigma-1 receptor.
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