Neuroprotective effects of dihydroprogesterone and progesterone in an experimental model of nerve crush injury.
A satisfactory management to ensure a full restoration of peripheral nerve after trauma is not yet available. Using an experimental protocol, in which crush injury was applied 1 cm above the bifurcation of the rat sciatic nerve for 20 s, we here demonstrate that the levels of neuroactive steroids, such as pregnenolone and progesterone (P) metabolites (i.e. dihydroprogesterone, DHP, and tetrahydroprogesterone, THP) present in injured sciatic nerve were significantly decreased. On this basis, we have focused our attention on DHP and its direct precursor, P, analyzing whether these two neuroactive steroids may have neuroprotective effects on biochemical, functional and morphological alterations occurring during crush-induced degeneration-regeneration. We demonstrate that DHP and/or P counteract biochemical alterations (i.e. myelin proteins and Na(+),K(+)-ATPase pump) and stimulate reelin gene expression. These two neuroactive steroids also counteract nociception impairment, and DHP treatment significantly decreases the up-regulation of myelinated fibers' density occurring in crushed animals. Altogether, these observations suggest that DHP and P (i.e. two neuroactive steroids interacting with progesterone receptor) may be considered protective agents in case of nerve crush injury.
Roglio
I
I
Department of Endocrinology and Center of Excellence on Neurodegenerative Diseases, University of Milano, Via Balzaretti 9, 20133 Milano, Italy.
Bianchi
R
R
Gotti
S
S
Scurati
S
S
Giatti
S
S
Pesaresi
M
M
Caruso
D
D
Panzica
G C
GC
Melcangi
R C
RC
D004092:20-alpha-Dihydroprogesterone / Q000627:therapeutic use*; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008970:Molecular Weight; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017288:Pain Threshold / Q000187:drug effects; D011374:Progesterone / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000091042:Reelin Protein; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013373:Substance P / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D000091042:Reelin Protein; C000717129:Reln protein, rat; D004092:20-alpha-Dihydroprogesterone; D013373:Substance P; D011374:Progesterone; D012697:Serine Endopeptidases; D000254:Sodium-Potassium-Exchanging ATPase