Brief Treatment With the Glucocorticoid Receptor Antagonist Mifepristone Normalises the Corticosterone‐Induced Reduction of Adult Hippocampal Neurogenesis

Abstract

The glucocorticoid receptor antagonist mifepristone has been shown to rapidly and effectively ameliorate symptoms of psychotic major depression. To better understand its mechanism, we investigated mifepristone's cellular effects, and found that it rapidly reversed a chronic corticosterone-induced reduction of adult neurogenesis in rats. Unlike other antidepressants, mifepristone is particularly potent in a high corticosterone environment. These data indicate that similarly to its clinical efficacy, mifepristone's effects on adult neurogenesis are rapid and positive, and may therefore be important for its mechanism of action.

Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis

“…A large body of evidence has demonstrated that chronically high concentrations of glucocorticoids impair hippocampal neurogenesis, that is, the development of new neurons from stem cells in the dentate gyrus, by activating the glucocorticoid receptor (GR) (1)(2)(3)(4)(5)(6). However, the mechanisms by which GR activation reduces neurogenesis are not fully understood.…”

Regulation of Structural Plasticity and Neurogenesis during Stress and Diabetes; Protective Effects of Glucocorticoid Receptor Antagonists

“…The antagonist prevented astrogliosis and excessive neuronal activation and reversed the suppressed markers for neurogenesis in the hippocampus induced by the diabetic state and associated high corticosterone [66,75]. Cognitive deficits observed at day 11 of diabetes were also ameliorated resulting in a performance even better than the untreated controls [75].…”

“…This ends with a fully functional neuron that is integrated into the preexisting hippocampal network [38]. The existence and number of true multipotent neural stem• cells and DCX-positive cell numbers after chronic stress or corticosterone treatment is normalized by four days of high dose treatment with the GR antagonist mifepristone, whereas application of the drug alone to control animals has no effect (see Mayer et al [66] and Oomen et al…”

“…In a series of recent experimental studies [45, [63][64][65][66], mifepristone was also effective in rats that were exposed to 21 days of chronic multiple unpredictable stressors, a paradigm that altered many structural and functional parameters in the hippocampus (Figure 6.3•) [5,8]. Interestingly, treatment with a high dose of Q6 mifepristone during the final 4 days of this 21 day paradigm rapidly normalized the stress-induced reduction in adult generated cell numbers and neurogenesis in the hippocampal DG [45,66]. In similar studies with the same design, the increased amplitude of high-voltage activated Ca-currents in CA1 neurons [63,64] as well as the impaired induction of LTP in the CA1 region that occurred after 21 days of chronic stress [65] were all normalized already after 4 days of high dose mifepristone application.…”

“…Even higher doses are One concern is mifepristone's clinical efficacy, as highlighted by studies comparing treatment with mifepristone to placebo or other antidepressive and antipsychotic treatments (for a review see [62]). In a series of recent experimental studies [45,[63][64][65][66], mifepristone was also effective in rats that were exposed to 21 days of chronic multiple unpredictable stressors, a paradigm that altered many structural and functional parameters in the hippocampus (Figure 6.3•) [5,8]. Interestingly, treatment with a high dose of Q6 mifepristone during the final 4 days of this 21 day paradigm rapidly normalized the stress-induced reduction in adult generated cell numbers and neurogenesis in the hippocampal DG [45,66].…”