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.

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.