A single injection of ketamine (5 mg/kg) given to mice one week before exposure to the inflammatory stressors lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-α) prevented depressive-like behaviors measured in the tail suspension test and splash test. A lower dose (1 mg/kg) did not have this effect. LPS increased markers of microglial activation and components of the NLRP3 inflammasome signaling pathway in the ventral hippocampus, while TNF-α only increased two of those components. Ketamine at 5 mg/kg, but not 1 mg/kg, blocked these increases. The findings suggest ketamine can promote resilience against inflammation-induced depressive-like behavior by suppressing NLRP3 inflammasome signaling.
A single injection of ketamine given a week before stress prevented depressive-like behavior in mice, while guanosine did not. The stressor, corticosterone, reduced proteins linked to synapse health in the hippocampus, and ketamine blocked that reduction. Combining low doses of ketamine and guanosine partly prevented one measure of depressive-like behavior. Fluoxetine given for three weeks did not prevent the stress effects. The findings suggest ketamine's lasting protective effect against depression involves pro-synaptogenic signaling in the hippocampus.
In a mouse model of depression induced by corticosterone (CORT), a single combined administration of subthreshold doses of ketamine (0.1 mg/kg) and guanosine (0.01 mg/kg) reversed depressive-like behaviors and hippocampal cell damage. CORT-treated mice showed increased immobility and grooming latency, along with reduced hippocampal viability, elevated inflammatory markers (NF-κB, IDO-1), and decreased glucocorticoid receptor, glutamate transporter, and antioxidant proteins. The combined treatment restored many of these molecular changes and partially reversed oxidative stress markers, suggesting guanosine may enhance ketamine's effects on inflammation and oxidative pathways in depression.
Combining low doses of ketamine and guanosine produces an antidepressant-like effect in mice, likely by activating synaptogenic signaling pathways in the hippocampus and prefrontal cortex. The treatment increased phosphorylation of mTOR and p70S6K in the hippocampus and raised levels of synaptic proteins PSD-95 and GluA1 in the prefrontal cortex. A single co-administration also reversed depressive-like behavior induced by chronic corticosterone exposure. The authors suggest that guanosine could augment ketamine's effects, potentially offering a therapeutic strategy for treatment-resistant depression.