Mol Neurobiol. 2025 Jun 5. doi: 10.1007/s12035-025-05114-x. Online ahead of print.
ABSTRACT
Stress is widely recognized as a major environmental factor contributing to the development of mood disorders. In patients with Major Depressive Disorder (MDD) and suicidal behavior, significant hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is observed, characterized by excessive cortisol release, which in turn stimulates the production of pro-inflammatory mediators. Inflammation affects approximately one in four patients with MDD and is associated with treatment resistance. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist used in patients with severe and treatment-resistant MDD, has emerged as a relevant target for investigation. However, the precise mechanism of action of this drug remains unclear. In this study, we investigated the neuroprotective effects of ketamine in response to cortisol using in vitro stress models with neural-like cells. We observed that cortisol reduced cell viability, increased the expression of inflammatory genes such as NF-κB and NLRP3, and enhanced the production of reactive oxygen species. Additionally, cortisol impaired neuroplasticity by reducing BDNF expression and diminishing the number and length of primary and secondary neurites, as well as overall neural connectivity. Ketamine was found to prevent, attenuate, and even reverse cortisol-induced expression of inflammatory genes and reactive species production. Moreover, ketamine significantly increased BDNF expression and promoted the growth and elongation of primary neurites and neural connections. For the first time, using an in vitro model of cortisol-induced stress in neural-like cells, we demonstrated that ketamine’s mechanism of action extends beyond NMDA receptor antagonism to include the reduction of neuroinflammation and the enhancement of neuroplasticity.
PMID:40474026 | DOI:10.1007/s12035-025-05114-x
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