Ketamine Affects the Neurogenesis of the Hippocampal Dentate Gyrus in 7-Day-Old Rats

Abstract

Ketamine has been reported to cause neonatal neurotoxicity via a neuronal apoptosis mechanism; however, no in vivo research has reported whether ketamine could affect postnatal neurogenesis in the hippocampal dentate gyrus (DG). A growing number of experiments suggest that postnatal hippocampal neurogenesis is the foundation of maintaining normal hippocampus function into adulthood. Therefore, this study investigated the effect of ketamine on hippocampal neurogenesis. Male Sprague-Dawley rats were divided into two groups: the control group (equal volume of normal saline), and the ketamine-anesthesia group (40 mg/kg ketamine in four injections at 1 h intervals). The S-phase marker 5-bromodeoxyuridine (BrdU) was administered after ketamine exposure to postnatal day 7 (PND-7) rats, and the neurogenesis in the hippocampal DG was assessed using single- or double-immunofluorescence staining. The expression of GFAP in the hippocampal DG was measured by western blot analysis. Spatial reference memory was tested by Morris water maze at 2 months after PND-7 rats exposed to ketamine treatment. The present results showed that neonatal ketamine exposure significantly inhibited neural stem cell (NSC) proliferation, decreased astrocytic differentiation, and markedly enhanced neuronal differentiation. The disruptive effect of ketamine on the proliferation and differentiation of NSCs lasted at least 1 week and disappeared by 2 weeks after ketamine exposure. Moreover, the migration of newborn neurons in the granule cell layer and the growth of astrocytes in the hippocampal DG were inhibited by ketamine on PND-37 and PND-44. Finally, ketamine caused a deficit in hippocampal-dependent spatial reference memory tasks at 2 months old. Our results suggested that ketamine may interfere with hippocampal neurogenesis and long-term neurocognitive function in PND-7 rats. These findings may provide a new perspective to explain the adult neurocognitive dysfunction induced by neonatal ketamine exposure.

The novel antidepressant ketamine enhances dentate gyrus proliferation with no effects on synaptic plasticity or hippocampal function in depressive‐like rats

“…In line with our results, ketamine as well as other classical antidepressants such as imipramine and fluoxetine or agomelatine increase or normalize dentate gyrus proliferation and neurogenesis, which could be essential for the therapeutic effects. Interestingly, both NMDAR activation as well as blockade has been associated with an increase proliferation and differentiation in the dentate gyrus.…”

“…Changes in this process have been implicated in the development of depression and are thus a possible target for the actions of ketamine. Although the nature of the proliferating cells is unknown, there are previously reported effects of ketamine and pre‐natal stress on dentate gyrus neurogenesis. Pre‐natal stress inhibits dentate gyrus but not olfactory bulb neurogenesis and chronic mild stress impacts survival but not proliferation .…”

Effects of Ketamine on Levels of Inflammatory Cytokines IL-6, IL-1β, and TNF-α in the Hippocampus of Mice Following Acute or Chronic Administration

“…injection of ketamine or multiple (six times) consecutive i.p. injections of ketamine at 1-h intervals, based on the methods described in previous studies (Huang et al, 2015, 2016), with modifications. For both single and multiple administrations, mice were randomly assigned to five groups, with 12 mice per group: saline-treated group, 10 mg/kg ketamine group, 20 mg/kg ketamine group, 40 mg/kg ketamine group, and 80 mg/kg ketamine group.…”

Ketamine induces apoptosis in lung adenocarcinoma cells by regulating the expression of CD69

“…Approximately 70% of patients with lung cancer present with locally advanced or metastatic disease at the time of diagnosis, and there terminal stage of cancer [5,6]. In a series of animal experiments, ketamine has been shown to promote neuronal apoptosis and induce cell death in neurons and neural stem progenitor cells [7][8][9]. Moreover, our previous study also revealed that repeated administration of ketamine can induce hippocampal neurodegeneration [10].…”