Duchenne muscular dystrophy (DMD) is a lethal X-linked disease characterized by progressive muscular wasting due to lack of full-length dystrophin (Dp427), a cytoskeletal protein expressed in muscle and selected brain regions (i.e. hippocampus). Dp427 binds to a large multi-proteic complex (Dystrophin Glycoprotein Complex, DGC), endowed with structural and functional properties, as the modulation of several intracellular signaling pathways. The presence of the dystrophin-DGC in areas involved in cognitive functions suggests that lack of Dp427 may be responsible for the neurological disturbances described in DMD patients. These could be further aggravated by the glucocorticoid (GC) therapeutic treatments of the muscular inflammation in DMD patients. As the hippocampus is one major GC target, in this study I analyzed whether in vitro (acute) and in vivo (acute and sub-chronic) treatments with either corticosterone (CORT) or dexamethasone (DEX) affected the already compromised hippocampal neuron physiology. Under any conditions we analyzed several parameters of the neuronal response to GCs: a) protein levels of the glucocorticoid receptor (GR) and of its phosphorylated (active) form pGR; b) mRNA levels of GR and GILZ; c) changes in the intensity of GR and pGR immunohistochemistry; d) protein levels of GR intracellular signaling effectors (i.e. caveolin 1, ERK 1/2); e) proliferation of hippocampal neural progenitor cells (NPC) (in vivo sub-chronic treatment only). In both in vitro and in vivo studies, mdx mouse hippocampal neurons respond differently than wild type to GC treatments. The general picture emerging is that they could be more sensitive to GCs and, therefore, more predisposed to be damaged. In fact, even acute GC administrations elicit a response similar to the more damaging chronic administration: i.e. reduction in GR levels, increase in the ration pGR/GR, possible reduction in GR gene expression, all aspects that are connotative of a chronic stress response. During high level of stress, which correspond to high and prolonged levels of secreted GCs, several physiological responses are altered, including those typical of hippocampal activity: i.e. synaptic plasticity, cognitive functions. These are accompanied by a reversal of the GC effects on hippocampal neurons: from the promotion of neuronal activity, and hence of its inhibitory control over the HPA axis, to its reduction, with consequent depression of HPA axis activity and increase in GC secretion. These are the basis for psychopathologies, as post-traumatic disorders. Therefore, the already compromised activity of the hippocampus in dystrophic subjects could be further damaged even by mild doses of GC, amplifying the risks for serious neural hilliness. Another crushing data is that sub-chronic treatments with DEX induce an increase in the proliferation of NPC in adult hippocampus, in contrast to what occurs in the wild type. This de-regulation of precursor cell cycle, responsible for of glia and neuronal self-renewal in adult brains, could further compromised hippocampal physiology. In conclusion, in the hope that new therapies could extend the life span of the young DMD patients, it is important to go deeper in the comprehension of how hippocampus and other brain areas affected by DMD, respond to anti-inflammatory (GCs) treatments.
Effects of acute and sub-chronic glucocorticoid treatments on hippocampal neurons of wild type and dystrophin-deficient DMDmdx mice: an in vitro and in vivo study / Cosmi, Francesca. - (2018 Feb 23).
|Titolo:||Effects of acute and sub-chronic glucocorticoid treatments on hippocampal neurons of wild type and dystrophin-deficient DMDmdx mice: an in vitro and in vivo study|
|Data di discussione:||23-feb-2018|
|Appartiene alla tipologia:||07a Tesi di Dottorato|