Esketamine, a drug that blocks NMDA receptors, improved neurological function and promoted nerve repair in mice with intracerebral hemorrhage. RNA sequencing and network pharmacology identified neurotrophin-3 and the PI3K/AKT signaling pathway as key targets. Experiments confirmed that esketamine increased NTF3 protein levels, and blocking the PI3K/AKT pathway with a specific inhibitor reduced the drug's therapeutic effects. The findings suggest esketamine activates the NTF3/PI3K/AKT pathway to aid recovery after brain hemorrhage.
Ketamine improves depressive symptoms in major depressive disorder by altering energy metabolism, including changes in adenosine triphosphate, adenosine diphosphate (ADP), and pyruvate. The shift in ADP levels strongly correlated with reductions in depression severity scores. Lower baseline levels of free triiodothyronine (FT3) predicted a better response to ketamine, suggesting FT3 may serve as a biological marker for treatment efficacy. These findings come from a study of 40 patients in a discovery cohort and 24 in a validation cohort, using metabolomic analysis of serum samples.
Ketamine, a dissociative anesthetic and PCP analog, produces rapid loss of consciousness at anesthetic doses and rapid, lasting antidepressant effects at subanesthetic doses. This review describes ketamine's metabolism and recent advances in understanding how NMDAR inhibition mediates both effects. The roles of NMDARs in anesthesia are well studied, but their involvement in antidepressant actions is complex and debated. The authors also explore possible functions of NMDAR subunits and discuss future directions for ketamine-based drugs.