NADPH oxidase-1 suppression prolongs the antidepressant-like effect of ketamine.
Waki Nakajima, Tetsu Arisawa, Susumu Jitsuki, Tomomi Yamanoue, Kaoru Fujikawa, Megumi Hara, Akane Sano, Yuuki Takada, Ryunosuke Iai, Kimito Kimura, Masataka Suzuki, Mai Hatano, Shariful A Syed, Ayano Yajima, Minami Nagata, Taisuke Yatomi, Hiroki Abe, Takuya Takahashi
Molecular psychiatry July 1, 2026 Peer reviewed DOI: 10.1038/s41380-026-03527-1 via PubMed
Summary
K-4, a novel positive allosteric modulator of AMPAR, produced a more sustained antidepressant-like effect than ketamine in Wistar Kyoto rats, a model for treatment-resistant depression (TRD). The study found that K-4 led to lower expression of NADPH-oxidase-1 (NOX-1) in the medial prefrontal cortex compared to ketamine. Additionally, inhibiting NOX-1 alongside ketamine extended its antidepressant effects and reduced abnormal firing in the lateral habenula, suggesting NOX-1 suppression could be key for maintaining treatment efficacy.
Study at a glance
| Population | Wistar Kyoto rats |
|---|---|
| Key finding | K-4 produced a more sustained antidepressant-like effect than ketamine in Wistar Kyoto rats. |
Abstract
Subanesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, produce rapid and robust antidepressant effects in patients with treatment-resistant depression (TRD). However, after a single administration, the therapeutic benefit is short-lived, and strategies to maintain its efficacy remain unclear. This study focused on the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), whose activation is known to be a key effector for the action of ketamine. Thus, we developed a novel positive allosteric modulator of AMPAR (K-4) with potential antidepressant-like effects. In Wistar Kyoto rats, a model of TRD, K-4 produced a more sustained antidepressant-like effect than ketamine. Bulk RNA sequencing analysis revealed that K-4-treated rats showed lower expression of NADPH-oxidase-1 (NOX-1) in the medial prefrontal cortex (mPFC) than in ketamine-treated rats. Furthermore, simultaneous administration of a NOX-1 inhibitor with ketamine prolonged the antidepressant-like effect and reduced burst firing in the lateral habenula (LHb). Similarly, short hairpin RNA knockdown of NOX-1 in the mPFC sustained the antidepressant-like effects of ketamine and suppressed LHb bursting activity. These results indicate that NOX-1 suppression prolongs the antidepressant-like effect of ketamine and represents a promising target for maintenance strategies in TRD.