Neuroactive Steroid Levels in a transgenic rat model of CMT1A Neuropathy.
Charcot-Marie-Tooth type 1A (CMT1A) represents 80% of all the demyelinating hereditary motor and sensory neuropathies. As recently suggested, neuroactive steroids may have a role in a therapeutic strategy for peripheral neuropathies, including CMT1A. To this aim, an accurate qualitative and quantitative analysis of neuroactive steroid levels in this disease could be extremely important to define effective pharmacological strategies. We here analyzed by liquid chromatography-tandem mass spectrometry the levels of neuroactive steroids present in the sciatic nerve of male and female peripheral myelin protein 22 transgenic rats (PMP22(tg) rats; i.e., an experimental model of CMT1A) and of the corresponding wild-type littermates. We observed that, both in PMP22(tg) rats and in the wild types, the levels of neuroactive steroids, such as progesterone, tetrahydroprogesterone (THP), isopregnanolone (3beta,5alpha-THP), testosterone, dihydrotestosterone, and 5alpha-androstane-3alpha, 17beta-diol (3alpha-diol) are sexually dimorphic. It is interesting to note that the levels of 3beta,5alpha-THP and of 3alpha-diol, which are exclusively detectable in sciatic nerve of female and male rats, respectively, are strongly decreased in PMP22(tg) rats. 3beta,5alpha-THP and 3alpha-diol are modulators of gamma-amino butyric acid A receptor. Thus, the present findings may be considered an interesting background for experiments aimed to evaluate the possible therapeutic effects of modulators of this neurotransmitter receptor in male and female PMP22(tg) rats.
Caruso
Donatella
D
Department of Pharmacological Sciences and Center for Metrological Traceability in Laboratory Medicine, University of Milan, Milan, Italy.
Scurati
Samuele
S
Roglio
Ilaria
I
Nobbio
Lucilla
L
Schenone
Angelo
A
Melcangi
Roberto C
RC
D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D008297:Male; D013058:Mass Spectrometry; D009154:Mutation / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics; D010525:Peripheral Nerves / Q000378:metabolism* / Q000503:physiopathology; D011280:Pregnanolone / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism / Q000503:physiopathology; D012727:Sex Characteristics; D013256:Steroids / Q000032:analysis / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D009185:Myelin Proteins; C489546:Pmp22 protein, rat; D011963:Receptors, GABA-A; D013256:Steroids; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone