1 Univ. Ulm, 89079 Ulm
Traumatic childhood experiences in humans may be responsible via epigenetic mechanisms for an impaired reduction of stress resistance, leading to the development of severe adverse reactions in later years. On the basis of which mechanisms are Mg-supplementation able to positively influence such reactions? Since the intracerebral Mg concentration is a highly regulated process, it is relatively stable against any systemic Mg depletion. However, regional perturbations of the ionic environment in the cerebrospinal fluid and the intraneuronal Mgi concentration may influence the function of neuronal networks responsible for regulation and coordination of the stress reactions that are particularly susceptible to Mgi concentration fluctuations. These networks associate the prefrontal cortex (PFC) responsible for cognitive control with limbic brain regions, whose functions are subject to very effective neuroplastic modulation. Subsequently to the failure of incoming signals from the PFC related to chronic stress situations, the activity level of the hypothalamus-pituitary-adrenal (HPA) axis would be controlled by antagonistic inflows from amygdala or hippocampus. The amount of the stress hormone cortisol circulating in the blood depends thus on the ratio of the influences from the amygdala or the hippocampus. Consequently, disturbances from the positive as well as the negative feedback loop could lead to a dysregulation of the HPA axis, namely via: 1. the sustained activation of the amygdala and/or 2. an impaired expression of hippocampal glucocorticoid receptors (GR). Downregulated GR expression might possibly be caused by following intracellular perturbations: on the one hand, via an epigenetic-related silencing of GR receptor genes and on the other hand through decreasing Mgi ion concentration brought about by chelating tryptophan metabolites produced after enzymatic blockade with Vit-B6 antagonists. Further, the maintenance of a physiological intracellular Mgi concentration might be crucial for the dimerization of the hormone receptor complex as a necessary precursor for GR expression. Since Mg deficiency states may not only have a nutritional origin, but also possibly be due to alterated metabolic pathways and considering the high complexity of the cerebral Mgi homeostasis, a hypothetical efficacy of supplemented Mg to improve the resilience to chronic stress would be demonstrated unequivocally merely through an in-depth knowledge of the neuroplastic modulating mechanisms underlying the stress-related networks.