Neuroprotective Role of Ketamine in Reducing Neuroinflammation and Enhancing Neuroplasticity Against a Cortisol-Induced In Vitro Stress Model.
Lucas C. Santos, Fernanda Dos Santos Petry, Carolina Saibro-Girardi, Júlia Hansen, Danielle Martins, Nicole Fröhlich, Luana Possa, Luiz Filipe Bastos Mendes, Hémelin Resende Farias, Alberto Martins Silva, Izabbela Giacon Deitos, Reykla Ramon Bittencourt, Jade de Oliveira, Daniel Pens Gelain, Roberto F Almeida, José Cláudio Fonseca Moreira
Molecular Neurobiology June 5, 2025 DOI: 10.1007/s12035-025-05114-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | Neural-like cells |
| Intervention | Ketamine |
| Topics | Ketamine Esketamine Neuroplasticity |
| Keywords | Bdnf Cortisol Nf-κb Nlrp3 Mental health Psychopharmacology Stress biology Drug mechanisms |
| Citations | 4 |
| Key points | Ketamine prevents, attenuates, and reverses cortisol-induced inflammation and impaired neuroplasticity in neural-like cells, indicating its mechanism extends beyond NMDA receptor antagonism. |
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.
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cites 3
- Management of Treatment-Resistant Depression: Challenges and Strategies Neuropsychiatric Disease and Treatment 2020
- Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine. Pharmacology, Biochemistry, and Behavior December 9, 2019
- Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression. Pharmaceuticals November 7, 2023