Biomedical subjects

Valerio Magnaghi

Publications and source records attributed to Valerio Magnaghi.

10 recordsLinked to original sources

PubMed2006

Sex-dimorphic effects of progesterone and its reduced metabolites on gene expression of myelin proteins by rat Schwann cells.

Data obtained in our and other laboratories have indicated that progesterone (P) and its derivatives, dihydroprogesterone (DHP) and tetrahydroprogesterone (THP), stimulate the expression of two myelin proteins of the peripheral nervous system (PNS) [i.e., glycoprotein zero (P0) and peripheral myelin protein 22 (PMP22)]. We have now considered the effects of P and its derivatives on these and other myelin proteins [i.e., myelin-associated glycoprotein (MAG) and myelin and lymphocyte protein (MAL)] in sex-specific cultures of rat Schwann cells. Gene expression of myelin proteins was assessed by RNase protection assay. Treatment with P or DHP induced a stimulatory effect on P0 mRNA levels in male but not in female Schwann cells. In contrast, treatment with THP increased gene expression of P0 exclusively in female Schwann cells. A similar sex-difference was also evident for other myelin proteins. Indeed, PMP22 expression was stimulated by treatment with P in male cultures, whereas THP induced an increase of mRNA levels in female cultures. Moreover, MAG was stimulated by THP treatment in male cultures only, whereas MAL expression was unaffected by neuroactive steroid treatment in both male and female cultures. In conclusion, the present observations indicate that the effects of neuroactive steroids on myelin proteins are sexually dimorphic. This finding might represent an important background for sex-specific therapies of acquired and inherited peripheral neuropathies.

20-alpha-Dihydroprogesterone↗

PubMed2006

Neuroactive steroids: A therapeutic approach to maintain peripheral nerve integrity during neurodegenerative events.

It is now well known that peripheral nerves are a target for the action of neuroactive steroids. This review summarizes observations obtained so far, indicating that through the interaction with classical and nonclassical steroid receptors, neuroactive steroids (e.g., progesterone, testosterone and their derivatives, estrogens, etc.) are able to influence several parameters of the peripheral nervous system, particularly its glial compartment (i.e., Schwann cells). Interestingly, some of these neuroactive steroids might be considered as promising neuroprotective agents. They are able to counteract neurodegenerative events of rat peripheral nerves occurring after experimental physical trauma, during the aging process, or in hereditary demyelinating diseases. On this basis, the hypothesis that neuroactive steroids might represent a new therapeutic strategy for peripheral neuropathy is proposed.

Animals↗

PubMed2006

GABA receptor-mediated effects in the peripheral nervous system: A cross-interaction with neuroactive steroids.

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the adult mammalian central nervous system (CNS), exerts its action via an interaction with specific receptors (e.g., GABAA and GABAB). These receptors are expressed not only in neurons but also on glial cells of the CNS, which might represent a target for the allosteric action of neuroactive steroids. Herein, we have demonstrated first that in the peripheral nervous system (PNS), the sciatic nerve and myelin-producing Schwann cells express both GABAA and GABAB receptors. Specific ligands, muscimol and baclofen, respectively, control Schwann-cell proliferation and expression of some specific myelin proteins (i.e., glycoprotein P0 and peripheral myelin protein 22 [PMP22]). Moreover, the progesterone (P) metabolite allopregnanolone, acting via the GABAA receptor, can influence PMP22 synthesis. In addition, we demonstrate that P, dihydroprogesterone, and allopregnanolone influence the expression of GABAB subunits in Schwann cells. The results suggest, at least in the myelinating cells of the PNS, a cross-interaction within the GABAergic receptor system, via GABAA and GABAB receptors and neuroactive steroids.

Animals↗

PubMed2005

Peripheral nerves: a target for the action of neuroactive steroids.

Peripheral nervous system possesses both classical and non-classical steroid receptors and consequently may represent a target for the action of neuroactive steroids. The present review summarizes the state of art of this intriguing field of research reporting data which indicate that neuroactive steroids, like for instance progesterone, dihydroprogesterone, tetrahydroprogesterone, dihydrotestosterone and 3alpha-diol, stimulate the expression of two important proteins of the myelin of peripheral nerves, the glycoprotein P0 (P0) and the peripheral myelin protein 22 (PMP22). Interestingly, the mechanisms by which neuroactive steroids exert their effects involve classical steroid receptors, like for instance progesterone and androgen receptors, in case of P0 and non-classical steroid receptors, like GABA(A) receptor, in case of PMP22. Moreover, neuroactive steroids not only control the expression of these specific myelin proteins, but also influence the morphology of myelin sheaths and axons suggesting that these molecules may represent an interesting new therapeutic approach to maintain peripheral nerve integrity during neurodegenerative events.

Animals↗

PubMed2005

Ro5-4864, a synthetic ligand of peripheral benzodiazepine receptor, reduces aging-associated myelin degeneration in the sciatic nerve of male rats.

The peripheral-type benzodiazepine receptor (PBR) is a protein predominantly located in the mitochondrial outer membrane that plays an important role in the regulation of cell survival and proliferation. Previous studies have shown an enhanced expression of PBR in the regenerating sciatic nerve, suggesting that this protein may be involved in the regenerative response. The rat sciatic nerve suffers important structural alterations with aging, including alterations in the morphology of myelin sheaths and a decrease in the number of myelinated fibers. In this study, we have assessed the effect of two PBR ligands, Ro5-4864 and PK-11195, to determine whether PBR may influence aging-associated morphological changes in the sciatic nerve. The treatment of 23-month-old, Sprague-Dawley male rats for 1 month with Ro5-4864 significantly reduced the percentage of fibers with myelin decompaction and increased the total number of myelinated fibers. In contrast, PK-11195, a PBR ligand that binds to a different site than Ro5-4864 in the PBR molecule, did not significantly affect any of the parameters analyzed. These findings support the potential role of PBR ligands to prevent aging-associated peripheral nerve degeneration.

Aging↗

PubMed2004

The synthesis of glycoprotein Po and peripheral myelin protein 22 in sciatic nerve of male rats is modulated by testosterone metabolites.

Glycoprotein Po (Po) and peripheral myelin protein 22 (PMP22) are two proteins playing a crucial physiological role in the maintenance of the multilamellar structure of peripheral myelin. We here demonstrate that the removal of circulating androgens by orchidectomy induces a significant decrease of the synthesis of Po and PMP22 in the rat sciatic nerve. In case of Po, this effect may be counteracted by the subsequent treatment with testosterone metabolites, dihydrotestosterone or 5alpha-androstan-3alpha,17beta-diol (3alpha-diol). Experiments have been consequently performed in order to evaluate the role of androgen receptor (AR) in the control of Po synthesis. In vivo treatment with flutamide (i.e., an antagonist of AR) induces a decrease of the synthesis of this myelin protein in the sciatic nerve of intact male rats confirming a role for this steroid receptor. On the contrary, PMP22 seems not to be under the control of AR, but a role for GABAA receptor may be proposed. This concept is based on the findings that: (a) only 3alpha-diol, which is able to interact with GABAA receptor, is effective in stimulating the synthesis of PMP22 in the sciatic nerve of castrated male rats, and (b) flutamide treatment is ineffective in decreasing the protein levels in intact male rats. The observations here reported clearly show similarities and dissimilarities with the effects exerted by other members of neuroactive steroid family, like for instance progesterone derivatives, which will be discussed in text.

Aging↗

PubMed2004

GABAB receptors in Schwann cells influence proliferation and myelin protein expression.

The location and the role of gamma-aminobutyric acid type B (GABA(B)) receptors in the central nervous system have recently received considerable attention, whilst relatively little is known regarding the peripheral nervous system. In this regard, here we demonstrate for the first time that GABA(B) receptor isoforms [i.e. GABA(B(1)) and GABA(B(2))] are specifically localized in the rat Schwann cell population of the sciatic nerve. Using the selective GABA(B) agonist [i.e. (-)-baclofen] and the antagonists (i.e. CGP 62349, CGP 56999 A, CGP 55845 A), such receptors are shown to be functionally active and negatively coupled to the adenylate cyclase system. Furthermore, exposure of cultured Schwann cells to (-)-baclofen inhibits their proliferation and reduces the synthesis of specific myelin proteins (i.e. glycoprotein Po, peripheral myelin protein 22, myelin-associated glycoprotein, connexin 32), providing evidence for a physiological role of GABA(B) receptors in the glial cells of the peripheral nervous system.

Animals↗

PubMed2003

Actions of progesterone and its 5alpha-reduced metabolites on the major proteins of the myelin of the peripheral nervous system.

The sciatic nerve, and the Schwann cells in particular, are able to synthesize progesterone and possess the enzymes forming the 5alpha-reduced and the 3alpha-5alpha-reduced derivatives of progesterone: dihydroprogesterone and tetrahydroprogesterone. Moreover, the progesterone receptor (PR) is present in the sciatic nerve and in Schwann cell cultures. These facts suggest that progesterone and its derivatives might play a role in the control of the synthesis of the two major proteins of the peripheral nervous system (PNS): the glycoprotein Po (Po) and peripheral myelin protein 22 (PMP22). We have shown that: (a) dihydroprogesterone enhances the low mRNA levels of Po in the sciatic nerve of aged male rats; (b) progesterone and its derivatives stimulate the gene expression of Po in the sciatic nerve of adult rats and in Schwann cell cultures; (c) tetrahydroprogesterone increases PMP22 gene expression in the sciatic nerve of adult rats and in Schwann cell cultures. In additional experiments, utilizing agonists and antagonists of PR and GABAA receptor, we have observed that progesterone and its derivatives control Po gene expression via the PR, while tetrahydroprogesterone modulates the expression of PMP22 through the GABAA receptor.

Animals↗

PubMed2003

Progesterone and its derivatives dihydroprogesterone and tetrahydroprogesterone reduce myelin fiber morphological abnormalities and myelin fiber loss in the sciatic nerve of aged rats.

Previous studies indicate that steroid hormones may be protective for Schwann cells and promote the expression of myelin proteins in the sciatic nerve of adult rats. In this study, we have evaluated the effect of progesterone (P), dihydroprogesterone (DHP), tetrahydroprogesterone (THP), testosterone (T), dihydrotestosterone (DHT) and 5alpha-androstan-3alpha, 17beta-diol (3alpha-diol) on the morphological alterations of myelinated fibers in the sciatic nerve of 22-24-month-old male rats. The sciatic nerves of untreated old male rats, showed a general disorganization and a significant reduction in the density of myelinated fibers, compared to nerves from 3-month-old male rats. The effect of aging was particularly evident in myelinated fibers of small caliber (<5 microm in diameter). In addition, the sciatic nerves of old rats showed a significant increase in the number of fibers with myelin infoldings in the axoplasm and in the number of fibers with irregular shapes. Treatments of old rats with P, DHP and THP resulted in a significant increase in the number of myelinated fibers of small caliber, a significant reduction in the frequency of myelin abnormalities and a significant increase in the g ratio of small myelinated fibers. Furthermore, P treatment significantly reduced the frequency of myelinated fibers with irregular shapes. In contrast, treatments with T, DHT or 3alpha-diol did not significantly affect any of the morphological parameters examined. In conclusion, our data indicate that P, and its derivatives DHP and THP, are able to reduce aging-associated morphological abnormalities of myelin and aging-associated myelin fiber loss in the sciatic nerve. These data suggest that P, DHP and THP may represent useful therapeutic alternatives to maintain peripheral nerve integrity in aged animals.

20-alpha-Dihydroprogesterone↗

PubMed2002

Decreased GFAP-mRNA expression in spinal cord of cobalamin-deficient rats.

We have demonstrated previously that chronic vitamin B12 [cobalamin (Cbl)] deficiency preferentially affects glial cells in the rat central nervous system (CNS) and severely affects peripheral glial cells independently of and concomitantly with the central neuropathy. In this study, we determined the mRNA levels for myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) in different CNS areas of rats made Cbl-deficient by total gastrectomy, as well as the mRNA levels for glycoprotein Po and peripheral myelin protein (PMP)22 in the sciatic nerve. GFAP-mRNA levels were significantly decreased in the spinal cord (SC) and hypothalamus, but not in the cortex, hippocampus, or striatum of totally gastrectomized (TGX) rats. No differences in GFAP protein levels were found in the SC and hypothalamus of the TGX rats treated or not with Cbl. MBP-mRNA levels were significantly decreased only in the hypothalamus, and the levels of mRNA for both glial markers returned to normal with Cbl replacement therapy. The levels of mRNA for the various myelin proteins in the sciatic nerve were not modified by Cbl deficiency. These results demonstrate that: a) the neurotrophic action of Cbl in rat CNS occurs in a zonal manner; and b) Cbl deficiency does not affect myelin synthesis (with the sole exception of the hypothalamus).

Animals↗