BDNF-TrkB signaling-mediated upregulation of Narp is involved in the antidepressant-like effects of (2R,6R)-hydroxynorketamine in a chronic restraint stress mouse model

• DOI: 10.1186/s12888-022-03838-x
• Publication Date: 2022-03-15T11:03:01Z
• Authors: Lingsha Ju; Jiaojiao Yang; Tingting Zhu; Panmiao Liu; Jianjun Yang
• Keywords: Psychiatry; Male; 0303 health sciences; Depression; Research; Brain-Derived Neurotrophic Factor; RC435-571; (2R,6R)-hydroxynorketamine; Antidepressant; Nerve Tissue Proteins; Narp; Hippocampus; Brain-derived neurotrophic factor; Antidepressive Agents; Up-Regulation; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; C-Reactive Protein; Animals; Receptor, trkB; Female; Ketamine

Abstract Background Preclinical studies have indicated that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) is a rapid-acting antidepressant drug with limited dissociation properties and low abuse potential. However, its effects and molecular mechanisms remain unclear. In this work, we examined the involvement of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and Narp in the antidepressant-like actions of (2R,6R)-HNK in a chronic restraint stress (CRS) mouse model.

Methods C57BL/6 male mice were subjected to CRS for 8 h per day for 14 consecutive days. Open field, forced swimming, novelty suppressed feeding, and tail suspension tests were performed after administering (2R,6R)-HNK (10 mg/kg), a combination of (2R,6R)-HNK and NBQX (an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist; 10 mg/kg), or a combination of (2R,6R)-HNK and ANA-12 (a TrkB receptor antagonist; 0.5 mg/kg). The mRNA levels of Bdnf and Narp in the hippocampus were determined by quantitative reverse transcription-PCR (qRT–PCR). Western blotting was used to determine the hippocampal protein levels of GluA1, GluA2, BDNF, Narp, PSD95, and synaptophysin, as well as the p-TrkB/TrkB protein ratio.

Results (2R,6R)-HNK had rapid antidepressant-like effects in CRS mice. Furthermore, (2R,6R)-HNK significantly ameliorated CRS-induced downregulation of GluA1, GluA2, BDNF, Narp, PSD95, and the p-TrkB/TrkB protein ratio in the hippocampus. The effects of (2R,6R)-HNK were blocked by combinations with NBQX or ANA-12.

Conclusion BDNF-TrkB signaling-mediated upregulation of Narp in the hippocampus may play a key role in the antidepressant-like effect of (2R,6R)-HNK in the CRS model of depression.