Myelin regeneration is a major therapeutic goal in demyelinating diseases, and the failure to remyelinate rapidly has profound consequences for the health of axons and for brain function. However, ...there is no efficient treatment for stimulating myelin repair, and current therapies are limited to anti-inflammatory agents. Males are less likely to develop multiple sclerosis than females, but often have a more severe disease course and reach disability milestones at an earlier age than females, and these observations have spurred interest in the potential protective effects of androgens. Here, we demonstrate that testosterone treatment efficiently stimulates the formation of new myelin and reverses myelin damage in chronic demyelinated brain lesions, resulting from the long-term administration of cuprizone, which is toxic for oligodendrocytes. In addition to the strong effect of testosterone on myelin repair, the number of activated astrocytes and microglial cells returned to low control levels, indicating a reduction of neuroinflammatory responses. We also identify the neural androgen receptor as a novel therapeutic target for myelin recovery. After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5α-dihydrotestosterone, a metabolite that is not converted to oestrogens, and blocked by the androgen receptor antagonist flutamide. Testosterone treatment also failed to promote remyelination after chronic cuprizone-induced demyelination in mice with a non-functional androgen receptor. Importantly, testosterone did not stimulate the formation of new myelin sheaths after specific knockout of the androgen receptor in neurons and macroglial cells. Thus, the neural brain androgen receptor is required for the remyelination effect of testosterone, whereas the presence of the receptor in microglia and in peripheral tissues is not sufficient to enhance remyelination. The potent synthetic testosterone analogue 7α-methyl-19-nortestosterone, which has been developed for long-term male contraception and androgen replacement therapy in hypogonadal males and does not stimulate prostate growth, also efficiently promoted myelin repair. These data establish the efficacy of androgens as remyelinating agents and qualify the brain androgen receptor as a promising drug target for remyelination therapy, thus providing the preclinical rationale for a novel therapeutic use of androgens in males with multiple sclerosis.
Hyperpolarized
129Xe was dissolved in a lipid emulsion and administered to anaesthetized rats by manual injections into the carotid (approximately 1–1.5 mL in a maximum time of 30 s). During ...injection,
129Xe NMR brain spectra at 2.35 T were recorded over 51 s, with a repetition time of 253 ms. Two peaks assigned to dissolved
129Xe were observed (the larger at 194 ± 1 ppm assigned to intravascular xenon and the smaller at 199 ± 1 ppm to xenon dissolved in the brain tissue). Their kinetics revealed a rapid intensity increase, followed by a plateau (approximately 15 s duration) and then a decrease over 5 s. This behaviour was attributed to combined influences of the T
1 relaxation of the tracer, of radiofrequency sampling, and of the tracer perfusion rate in rat brain. Similar kinetics were observed in experiments carried out on a simple micro-vessel phantom. An identical experimental set-up was used to acquire a series of 2D projection
129Xe images on the phantom and the rat brain.
Du
129Xe hyperpolarisé a été dissous dans une émulsion lipidique et administré par injection intracarotidienne (1 à 1,5 mL en 30 s) à des rats anesthésiés. Pendant l’injection, des spectres RMN du
129Xe ont été acquis à 2,35 T sur le cerveau toutes les 253 ms, durant 51 s. Deux pics correspondant au
129Xe dissous ont été observés. Le pic de grande amplitude à 194 ± 1 ppm a été attribué au xénon intravasculaire et celui de plus faible amplitude à 199 ± 1 ppm au xénon dissous dans les tissus. La cinétique des amplitudes de ces pics montre une augmentation rapide, puis un plateau (durée approximative: 15 s) suivi d’une décroissance en 5 s. Ce comportement a été attribué aux effets combinés de la relaxation T
1 du traceur, de l’échantillonnage radiofréquence, et du débit associé à la perfusion du traceur. Une évolution temporelle similaire du signal est observée sur un fantôme simulant le réseau vasculaire. Un même protocole expérimental a été utilisé pour acquérir, pendant l’injection, des séries d’images du
129Xe sur le fantôme et sur le cerveau de rat.
Contrast in magnetic resonance imaging depends principally on the longitudinal relaxation (
R
1) and the transverse relaxation rate (
R
2) of the observed nuclei, most often the protons. The ...spin-spin relaxation rate (
R
2) is the result of several mechanisms. The dependence of the interpulse delay of the Carr-Purcell-Meiboom-Gill sequence on the transverse relaxation rate of the water was studied in rat organs in vitro. It gives an insight into the exchange mechanisms involved. The increase of the interpulse delay from 0.2 ms to 5 ms gives an
R
2 increase of 23, 15, 3, and 2 s
−1 for the heart, the liver, the spleen and the brain, respectively. These increases are compared to the
R
2 increases obtained in
17O-enriched water, amino acid and albumin solutions where atomic exchange takes place. The concentration of these materials in organs cannot explain the
R
2 increase of the organs with the interpulse delay. Water exchange between intra and extracellular compartments is proposed to explain the
R
2 increase with interpulse delays in organs like the heart and the liver.
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