Unveiling the role of single versus repeated low-dose ketamine in attenuating doxorubicin-induced chemobrain and depression in rats: differential modulation of neuroinflammation, phosphorylated GLT-1, SERT, DAT, and BDNF/TrkB signaling.
Nehal G. Fahmy, Nada M. Kamel, Mahmoud M. Khattab, Radwa N. Muhammad
Neuropharmacology June 1, 2026 DOI: 10.1016/j.neuropharm.2026.111055 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Sample size | 48 |
| Population | Adult male Wistar rats |
| Interventions | Doxorubicin Ketamine |
| Dose | Ketamine 15 mg/kg (single dose) or 15 mg/kg/day for 14 days (repeated doses) |
| Duration | 14 days of repeated ketamine dosing |
| Topics | Depression Ketamine Esketamine |
| Keywords | Animals Rats, wistar Doxorubicin Receptor, trkb Brain-derived neurotrophic factor Antidepressive agents Antibiotics, antineoplastic Signal transduction Phosphorylation Male Chemotherapy-related cognitive impairment Neuroinflammatory diseases Bdnf Glt-1 Chemobrain |
| Key findings | Doxorubicin caused motor dysfunction, cognitive impairment, depression-like behavior, neuroinflammation, and disrupted neurotrophic signaling in male rats. Both single and repeated subanaesthetic ketamine (15 mg/kg) improved these outcomes, with repeated dosing (15 mg/kg/day for 14 days) producing superior behavioral and biochemical improvements. The authors propose that ketamine, particularly repeated low doses, could be a promising adjunctive therapy for cancer patients undergoing doxorubicin chemotherapy, though they regard the proposed mechanistic cascade as a hypothetical model requiring further validation. |
Abstract
Doxorubicin (DOX), a widely utilized chemotherapeutic agent, is associated with significant adverse effects, including cognitive dysfunction (chemobrain) and depression. Ketamine (KET), the anesthetic, was off-label used as antidepressant and got FDA approval in 2019 for treatment-resistant depression management. Hence, this study investigated the therapeutic efficacy of single [KET(S)] versus repeated [KET(R)] subanaesthetic ketamine in mitigating DOX-induced neurological alterations in rats. Forty-eight adult male Wistar rats were subdivided into four groups: control, DOX, KET(S) (DOX followed by a single KET dose, 15 mg/kg), and KET(R) (DOX followed by repeated KET doses, 15 mg/kg/day for 14 days). Results showed that DOX administration caused marked motor dysfunction, cognitive impairment and depression-like behavior, along with elevated neuroinflammation and disrupted neurotrophic signaling. Both KET regimens improved behavioral performance, suppressed systemic and local inflammation, evidenced by suppressing tumor necrosis factor-alpha and nicotinamide adenine dinucleotide phosphate oxidase activity. Also, KET(R) suppressed phosphorylation of key neurotransmitter transporters: phospho T53-dopamine transporter, phospho S563-glutamate transporter-1, and phospho T276-serotonin transporter, which led to enhanced hippocampal brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling. Notably, KET(R) produced superior behavioral and biochemical improvements compared to KET(S). Histopathological examinations corroborated these findings. Collectively, these data suggest that KET, particularly when administered repeatedly at low doses, could be a promising adjunctive therapy to enhance quality of life for cancer patients undergoing DOX chemotherapy. However, because key intermediate nodes were not directly measured and KET-only control groups were not included, the proposed mechanistic cascade should be regarded as a hypothetical integrative model that warrants further validation.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cites 15
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Mechanistic Target of Rapamycin-Independent Antidepressant Effects of (R)-Ketamine in a Social Defeat Stress Model. Biological Psychiatry 2018
- Low-dose S-ketamine exerts antidepressant-like effects via enhanced hippocampal synaptic plasticity in postpartum depression rats. Neurobiology of Stress 2022
- The Impact of Esketamine on Depression: Targeting Oxidative Stress and Neuronal Apoptosis Through BDNF/TrkB/PI3K/AKT Pathway Activation Neuropsychiatric Disease and Treatment August 1, 2025
- Chronic oral ketamine prevents anhedonia and alters neuronal activation in the lateral habenula and nucleus accumbens in rats under chronic unpredictable mild stress. Neuropharmacology February 20, 2023
and 10 more in the library