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 DOI: 10.1038/s41380-026-03527-1 via PubMed
Summary
AI-generated from the abstractA novel compound, K-4, which positively modulates AMPA receptors, produced longer-lasting antidepressant-like effects in a rat model of treatment-resistant depression than ketamine alone. K-4 reduced expression of the enzyme NOX-1 in the medial prefrontal cortex. Blocking NOX-1, either with an inhibitor or by genetic knockdown, prolonged ketamine's antidepressant-like effects and reduced abnormal bursting in the lateral habenula, a brain region linked to depression. Suppressing NOX-1 may be a promising strategy for extending the benefits of ketamine in treatment-resistant depression.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Wistar Kyoto rats |
| Interventions | ketamine NOX-1 inhibitor short hairpin RNA knockdown of NOX-1 |
| Citations | 1 |
| Key finding | Suppression of NOX-1 prolongs the antidepressant-like effect of ketamine in a rat model of treatment-resistant depression. |
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.