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Roberto Cosimo Melcangi - One of the best experts on this subject based on the ideXlab platform.
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Exploring the Impact of the Microbiome on Neuroactive Steroid Levels in Germ-Free Animals
'MDPI AG', 2021Co-Authors: Silvia Diviccaro, Silvia Giatti, Donatella Caruso, Valentina Caputi, Lucia Cioffi, Joshua M. Lyte, Siobhain M. O’mahony, Roberto Cosimo MelcangiAbstract:Steroid hormones are essential biomolecules for human physiology as they modulate the endocrine system, nervous function and behaviour. Recent studies have shown that the gut microbiota is directly involved in the production and metabolism of Steroid hormones in the periphery. However, the influence of the gut microbiota on levels of Steroids acting and present in the brain (i.e., Neuroactive Steroids) is not fully understood. Therefore, using liquid chromatography–tandem mass spectrometry, we assessed the levels of several Neuroactive Steroids in various brain areas and the plasma of germ-free (GF) male mice and conventionally colonized controls. The data obtained indicate an increase in allopregnanolone levels associated with a decrease in those of 5α-androstane-3α, 17β-diol (3α-diol) in the plasma of GF mice. Moreover, an increase of dihydroprogesterone and isoallopregnanolone in the hippocampus, cerebellum, and cerebral cortex was also reported. Changes in dihydrotestosterone and 3α-diol levels were also observed in the hippocampus of GF mice. In addition, an increase in dehydroepiandrosterone was associated with a decrease in testosterone levels in the hypothalamus of GF mice. Our findings suggest that the absence of microbes affects the Neuroactive Steroids in the periphery and the brain, supporting the evidence of a microbiota-mediated modulation of neuroendocrine pathways involved in preserving host brain functioning
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Axonal transport in a peripheral diabetic neuropathy model: sex-dimorphic features
Biology of Sex Differences, 2018Co-Authors: Marzia Pesaresi, Silvia Diviccaro, Tiziana Borsello, Silvia Giatti, Roberto Spezzano, Nico Mitro, Simone Romano, Donatella Caruso, Luis Miguel Garcia-segura, Roberto Cosimo MelcangiAbstract:Background Disruption of axonal transport plays a pivotal role in diabetic neuropathy. A sex-dimorphism exists in the incidence and symptomatology of diabetic neuropathy; however, no studies so far have addressed sex differences in axonal motor proteins expression in early diabetes as well as the possible involvement of Neuroactive Steroids. Interestingly, recent data point to a role for mitochondria in the sexual dimorphism of neurodegenerative diseases. Mitochondria have a fundamental role in axonal transport by producing the motors’ energy source, ATP. Moreover, Neuroactive Steroids can also regulate mitochondrial function. Methods Here, we investigated the impact of short-term diabetes in the peripheral nervous system of male and female rats on key motor proteins important for axonal transport, mitochondrial function, and Neuroactive Steroids levels. Results We show that short-term diabetes alters mRNA levels and axoplasm protein contents of kinesin family member KIF1A, KIF5B, KIF5A and Myosin Va in male but not in female rats. Similarly, the expression of peroxisome proliferator-activated receptor γ co-activator-1α, a subunit of the respiratory chain complex IV, ATP levels and the key regulators of mitochondrial dynamics were affected in males but not in females. Concomitant analysis of Neuroactive Steroid levels in sciatic nerve showed an alteration of testosterone, dihydrotestosterone, and allopregnanolone in diabetic males, whereas no changes were observed in female rats. Conclusions These findings suggest that sex-specific decrease in Neuroactive Steroid levels in male diabetic animals may cause an alteration in their mitochondrial function that in turn might impact in axonal transport, contributing to the sex difference observed in diabetic neuropathy.
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Diabetes induces mitochondrial dysfunction and alters cholesterol homeostasis and neuroSteroidogenesis in the rat cerebral cortex
'Elsevier BV', 2018Co-Authors: R. S, Silvia Giatti, Marzia Pesaresi, Roberto Spezzano, Nico Mitro, S. Diviccaro, Matteo Audano, D. Caruso, Roberto Cosimo MelcangiAbstract:The nervous system synthesizes and metabolizes Steroids (i.e., neuroSteroidogenesis). Recent observations indicate that neuroSteroidogenesis is affected by different nervous pathologies. Among these, long-term type 1 diabetes, together with other functional and biochemical changes, has been shown to alter Neuroactive Steroid levels in the nervous system. Using an experimental model of type 1 diabetes (i.e., streptozotocin injection) we here show that the levels of these molecules are already decreased in the rat cerebral cortex after one month of the initiation of the pathology. Moreover, decreased levels of free cholesterol, together with alterations in the expression of molecules involved in cholesterol biosynthesis, bioavailability, trafficking and metabolism were detected in the rat cerebral cortex after one month of diabetes. Furthermore, mitochondrial functionality was also affected in the cerebral cortex and consequently may also contribute to the decrease in Neuroactive Steroid levels. Altogether, these results indicate that neuroSteroidogenesis is an early target for the effect of type 1 diabetes in the cerebral cortex
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patients treated for male pattern hair with finasteride show after discontinuation of the drug altered levels of Neuroactive Steroids in cerebrospinal fluid and plasma
The Journal of Steroid Biochemistry and Molecular Biology, 2015Co-Authors: Donatella Caruso, Silvia Giatti, Simone Romano, Guido Cavaletti, Federico Abbiati, Letizia Fusco, Roberto Cosimo MelcangiAbstract:Abstract Observations performed in a subset of patients treated for male pattern hair loss indicate that persistent sexual side effects as well as anxious/depressive symptomatology have been reported even after discontinuation of finasteride treatment. Due to the capability of finasteride to block the metabolism of progesterone (PROG) and/or testosterone (T) we have evaluated, by liquid chromatography–tandem mass spectrometry, the levels of several Neuroactive Steroids in paired plasma and cerebrospinal fluid (CSF) samples obtained from post-finasteride patients and in healthy controls. At the examination, post-finasteride patients reported muscular stiffness, cramps, tremors and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Although severity of the anxious/depressive symptoms was quite variable in their frequency, overall all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of Neuroactive Steroid levels in CSF showed a decrease of PROG and its metabolites, dihydroprogesterone (DHP) and tetrahydroprogesterone (THP), associated with an increase of its precursor pregnenolone (PREG). Altered levels were also observed for T and its metabolites. Thus, a significant decrease of dihydrotestosterone (DHT) associated with an increase of T as well as of 3α-diol was detected. Changes in Neuroactive Steroid levels also occurred in plasma. An increase of PREG, T, 3α-diol, 3β-diol and 17β-estradiol was associated with decreased levels of DHP and THP. The present observations show that altered levels of Neuroactive Steroids, associated with depression symptoms, are present in androgenic alopecia patients even after discontinuation of the finasteride treatment. This article is part of a Special Issue entitled ‘Sex Steroids and brain disorders’.
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Neuroactive Steroid levels are modified in cerebrospinal fluid and plasma of post finasteride patients showing persistent sexual side effects and anxious depressive symptomatology
The Journal of Sexual Medicine, 2013Co-Authors: Roberto Cosimo Melcangi, Silvia Giatti, Donatella Caruso, Federico Abbiati, Donato Calabrese, Fabrizio Piazza, Guido CavalettiAbstract:Abstract Introduction Observations performed in a subset of subjects treated with finasteride (an inhibitor of the enzyme 5α‐reductase) for male pattern hair loss seem to indicate that sexual dysfunction as well as anxious/depressive symptomatology may occur at the end of the treatment and continue after discontinuation. Aim A possible hypothesis to explain depression symptoms after finasteride treatment might be impairment in the levels of Neuroactive Steroids. Therefore, Neuroactive Steroid levels were evaluated in paired plasma and cerebrospinal fluid samples obtained from male patients who received finasteride for the treatment of androgenic alopecia and who, after drug discontinuation, still show long‐term sexual side effects as well as anxious/depressive symptomatology. Methods The levels of Neuroactive Steroids were evaluated by liquid chromatography–tandem mass spectrometry in three postfinasteride patients and compared to those of five healthy controls. Main Outcome Measures Neuroactive Steroid levels in plasma and cerebrospinal fluid of postfinasteride patients and healthy controls. Results At the examination, the three postfinasteride patients reported muscular stiffness, cramps, tremors, and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Severity and frequency of the anxious/depressive symptoms were quite variable; overall, all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of Neuroactive Steroid levels in patients showed some interindividual differences. However, the most important finding was the comparison of their Neuroactive Steroid levels with those of healthy controls. Indeed, decreased levels of tetrahydroprogesterone, isopregnanolone and dihydrotestosterone and increased levels of testosterone and 17β‐estradiol were reported in cerebrospinal fluid of postfinasteride patients. Moreover, decreased levels of dihydroprogesterone and increased levels of 5α‐androstane‐3α,17β‐diol and 17β‐estradiol were observed in plasma. Conclusion The present observations confirm that an impairment of Neuroactive Steroid levels, associated with depression symptoms, is still present in androgenic alopecia patients treated with finasteride despite the discontinuation of the treatment. Melcangi RC, Caruso D, Abbiati F, Giatti S, Calabrese D, Piazza F, and Cavaletti G. Neuroactive Steroid levels are modified in cerebrospinal fluid and plasma of postfinasteride patients showing persistent sexual side effects and anxious/depressive symptomatology. J Sex Med 2013;10:2598–2603.
Silvia Giatti - One of the best experts on this subject based on the ideXlab platform.
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Exploring the Impact of the Microbiome on Neuroactive Steroid Levels in Germ-Free Animals
'MDPI AG', 2021Co-Authors: Silvia Diviccaro, Silvia Giatti, Donatella Caruso, Valentina Caputi, Lucia Cioffi, Joshua M. Lyte, Siobhain M. O’mahony, Roberto Cosimo MelcangiAbstract:Steroid hormones are essential biomolecules for human physiology as they modulate the endocrine system, nervous function and behaviour. Recent studies have shown that the gut microbiota is directly involved in the production and metabolism of Steroid hormones in the periphery. However, the influence of the gut microbiota on levels of Steroids acting and present in the brain (i.e., Neuroactive Steroids) is not fully understood. Therefore, using liquid chromatography–tandem mass spectrometry, we assessed the levels of several Neuroactive Steroids in various brain areas and the plasma of germ-free (GF) male mice and conventionally colonized controls. The data obtained indicate an increase in allopregnanolone levels associated with a decrease in those of 5α-androstane-3α, 17β-diol (3α-diol) in the plasma of GF mice. Moreover, an increase of dihydroprogesterone and isoallopregnanolone in the hippocampus, cerebellum, and cerebral cortex was also reported. Changes in dihydrotestosterone and 3α-diol levels were also observed in the hippocampus of GF mice. In addition, an increase in dehydroepiandrosterone was associated with a decrease in testosterone levels in the hypothalamus of GF mice. Our findings suggest that the absence of microbes affects the Neuroactive Steroids in the periphery and the brain, supporting the evidence of a microbiota-mediated modulation of neuroendocrine pathways involved in preserving host brain functioning
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Treatment of male rats with finasteride, an inhibitor of 5alpha-reductase enzyme, induces long-lasting effects on depressive-like behavior, hippocampal neurogenesis, neuroinflammation and gut microbiota composition
'Elsevier BV', 2019Co-Authors: Silvia Diviccaro, Silvia Giatti, Luis Miguel Garcia-segura, F. Borgo, M. Barcella, E. Borghi, J.l. Trejo, C. MelcangiAbstract:Persistent alteration of plasma Neuroactive Steroid levels associated with major depression has been recently reported in men after the suspension of the treatment for androgenetic alopecia with finasteride, an inhibitor of the enzyme 5alpha-reductase. Observations in male rats confirmed persistent alterations in Neuroactive Steroid levels also in the brain. In the present study, we have ascertained possible effects on depressive-like behavior, neurogenesis, gliosis, neuroinflammation and gut microbiota in male rats after subchronic treatment for 20 days with finasteride and after one month of its withdrawal. At the end of treatment there was an increase in the number of pH3 immunoreactive cells in the subgranular zone of the dentate gyrus together with an increase in the mRNA levels of TNF-α in the hippocampus. By one month after the end of finasteride treatment, rats showed depressive-like behavior coupled with a decrease in the number of pH3 immunoreactive cells in the subgranular zone of the dentate gyrus, a decrease in granule cell density in the granule cell layer and an increase in the number of GFAP immunoreactive astrocytes in the dentate gyrus. Finally, alteration of gut microbiota (i.e., an increase in Bacteroidetes phylum and in Prevotellaceae family at the end of the treatment and a decrease in Ruminococcaceae family, Oscillospira and Lachnospira genus at the end of the withdrawal period) was detected. In conclusion, finasteride treatment in male rats has long term effects on depressive-like behavior, hippocampal neurogenesis and neuroinflammation and gut microbiota composition
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Axonal transport in a peripheral diabetic neuropathy model: sex-dimorphic features
Biology of Sex Differences, 2018Co-Authors: Marzia Pesaresi, Silvia Diviccaro, Tiziana Borsello, Silvia Giatti, Roberto Spezzano, Nico Mitro, Simone Romano, Donatella Caruso, Luis Miguel Garcia-segura, Roberto Cosimo MelcangiAbstract:Background Disruption of axonal transport plays a pivotal role in diabetic neuropathy. A sex-dimorphism exists in the incidence and symptomatology of diabetic neuropathy; however, no studies so far have addressed sex differences in axonal motor proteins expression in early diabetes as well as the possible involvement of Neuroactive Steroids. Interestingly, recent data point to a role for mitochondria in the sexual dimorphism of neurodegenerative diseases. Mitochondria have a fundamental role in axonal transport by producing the motors’ energy source, ATP. Moreover, Neuroactive Steroids can also regulate mitochondrial function. Methods Here, we investigated the impact of short-term diabetes in the peripheral nervous system of male and female rats on key motor proteins important for axonal transport, mitochondrial function, and Neuroactive Steroids levels. Results We show that short-term diabetes alters mRNA levels and axoplasm protein contents of kinesin family member KIF1A, KIF5B, KIF5A and Myosin Va in male but not in female rats. Similarly, the expression of peroxisome proliferator-activated receptor γ co-activator-1α, a subunit of the respiratory chain complex IV, ATP levels and the key regulators of mitochondrial dynamics were affected in males but not in females. Concomitant analysis of Neuroactive Steroid levels in sciatic nerve showed an alteration of testosterone, dihydrotestosterone, and allopregnanolone in diabetic males, whereas no changes were observed in female rats. Conclusions These findings suggest that sex-specific decrease in Neuroactive Steroid levels in male diabetic animals may cause an alteration in their mitochondrial function that in turn might impact in axonal transport, contributing to the sex difference observed in diabetic neuropathy.
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Diabetes induces mitochondrial dysfunction and alters cholesterol homeostasis and neuroSteroidogenesis in the rat cerebral cortex
'Elsevier BV', 2018Co-Authors: R. S, Silvia Giatti, Marzia Pesaresi, Roberto Spezzano, Nico Mitro, S. Diviccaro, Matteo Audano, D. Caruso, Roberto Cosimo MelcangiAbstract:The nervous system synthesizes and metabolizes Steroids (i.e., neuroSteroidogenesis). Recent observations indicate that neuroSteroidogenesis is affected by different nervous pathologies. Among these, long-term type 1 diabetes, together with other functional and biochemical changes, has been shown to alter Neuroactive Steroid levels in the nervous system. Using an experimental model of type 1 diabetes (i.e., streptozotocin injection) we here show that the levels of these molecules are already decreased in the rat cerebral cortex after one month of the initiation of the pathology. Moreover, decreased levels of free cholesterol, together with alterations in the expression of molecules involved in cholesterol biosynthesis, bioavailability, trafficking and metabolism were detected in the rat cerebral cortex after one month of diabetes. Furthermore, mitochondrial functionality was also affected in the cerebral cortex and consequently may also contribute to the decrease in Neuroactive Steroid levels. Altogether, these results indicate that neuroSteroidogenesis is an early target for the effect of type 1 diabetes in the cerebral cortex
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sterol regulatory element binding protein 1c knockout mice show altered Neuroactive Steroid levels in sciatic nerve
Journal of Neurochemistry, 2017Co-Authors: Nico Mitro, Silvia Giatti, Marzia Pesaresi, Roberto Spezzano, Donatella Caruso, Gaia Cermenati, Matteo Audano, Silvia Pedretti, R C MelcangiAbstract:Neuroactive Steroid levels are altered in several experimental models of peripheral neuropathy, and on this basis, they have been proposed as protective agents. For the first time, the levels of these molecules were here assessed in sterol regulatory-binding protein-1c (SREBP-1c) knock-out (KO) male mice (i.e., an experimental model of peripheral neuropathy) and compared with observations in wild type animals. The levels of Neuroactive Steroids have been evaluated by liquid chromatography tandem mass spectrometry in plasma and sciatic nerve at two and ten months of age and these analyses were implemented analyzing the gene expression of crucial Steroidogenic enzymes in sciatic nerve. Data obtained at two months of age showed high levels of pregnenolone in sciatic nerve, associated with low levels of its first metabolite, progesterone, and further metabolites (i.e., 5α-pregnane-3,20-dione and 5α-pregnan-3β-ol-20-one). High levels of testosterone and 17β-estradiol were also observed. At ten months of age, the Neuroactive Steroid profile showed some differences. Indeed, low levels of pregnenolone and high levels of 5α-pregnan-3α-ol-20-one and 5α-pregnan-3β-ol-20-one were observed. The analysis of the gene expression of Steroidogenic enzymes here considered generally followed these changes. Interestingly, the levels of pregnenolone and progesterone were unmodified in plasma suggesting a specific effect of SREBP-1c on neuroSteroidogenesis. Because this peripheral neuropathy is due to altered fatty acid biosynthesis, data here reported support the belief that the cross-talk between this biosynthetic pathway and Neuroactive Steroids may represent a possible therapeutic strategy for peripheral neuropathy. This article is protected by copyright. All rights reserved.
Donatella Caruso - One of the best experts on this subject based on the ideXlab platform.
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Exploring the Impact of the Microbiome on Neuroactive Steroid Levels in Germ-Free Animals
'MDPI AG', 2021Co-Authors: Silvia Diviccaro, Silvia Giatti, Donatella Caruso, Valentina Caputi, Lucia Cioffi, Joshua M. Lyte, Siobhain M. O’mahony, Roberto Cosimo MelcangiAbstract:Steroid hormones are essential biomolecules for human physiology as they modulate the endocrine system, nervous function and behaviour. Recent studies have shown that the gut microbiota is directly involved in the production and metabolism of Steroid hormones in the periphery. However, the influence of the gut microbiota on levels of Steroids acting and present in the brain (i.e., Neuroactive Steroids) is not fully understood. Therefore, using liquid chromatography–tandem mass spectrometry, we assessed the levels of several Neuroactive Steroids in various brain areas and the plasma of germ-free (GF) male mice and conventionally colonized controls. The data obtained indicate an increase in allopregnanolone levels associated with a decrease in those of 5α-androstane-3α, 17β-diol (3α-diol) in the plasma of GF mice. Moreover, an increase of dihydroprogesterone and isoallopregnanolone in the hippocampus, cerebellum, and cerebral cortex was also reported. Changes in dihydrotestosterone and 3α-diol levels were also observed in the hippocampus of GF mice. In addition, an increase in dehydroepiandrosterone was associated with a decrease in testosterone levels in the hypothalamus of GF mice. Our findings suggest that the absence of microbes affects the Neuroactive Steroids in the periphery and the brain, supporting the evidence of a microbiota-mediated modulation of neuroendocrine pathways involved in preserving host brain functioning
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Axonal transport in a peripheral diabetic neuropathy model: sex-dimorphic features
Biology of Sex Differences, 2018Co-Authors: Marzia Pesaresi, Silvia Diviccaro, Tiziana Borsello, Silvia Giatti, Roberto Spezzano, Nico Mitro, Simone Romano, Donatella Caruso, Luis Miguel Garcia-segura, Roberto Cosimo MelcangiAbstract:Background Disruption of axonal transport plays a pivotal role in diabetic neuropathy. A sex-dimorphism exists in the incidence and symptomatology of diabetic neuropathy; however, no studies so far have addressed sex differences in axonal motor proteins expression in early diabetes as well as the possible involvement of Neuroactive Steroids. Interestingly, recent data point to a role for mitochondria in the sexual dimorphism of neurodegenerative diseases. Mitochondria have a fundamental role in axonal transport by producing the motors’ energy source, ATP. Moreover, Neuroactive Steroids can also regulate mitochondrial function. Methods Here, we investigated the impact of short-term diabetes in the peripheral nervous system of male and female rats on key motor proteins important for axonal transport, mitochondrial function, and Neuroactive Steroids levels. Results We show that short-term diabetes alters mRNA levels and axoplasm protein contents of kinesin family member KIF1A, KIF5B, KIF5A and Myosin Va in male but not in female rats. Similarly, the expression of peroxisome proliferator-activated receptor γ co-activator-1α, a subunit of the respiratory chain complex IV, ATP levels and the key regulators of mitochondrial dynamics were affected in males but not in females. Concomitant analysis of Neuroactive Steroid levels in sciatic nerve showed an alteration of testosterone, dihydrotestosterone, and allopregnanolone in diabetic males, whereas no changes were observed in female rats. Conclusions These findings suggest that sex-specific decrease in Neuroactive Steroid levels in male diabetic animals may cause an alteration in their mitochondrial function that in turn might impact in axonal transport, contributing to the sex difference observed in diabetic neuropathy.
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sterol regulatory element binding protein 1c knockout mice show altered Neuroactive Steroid levels in sciatic nerve
Journal of Neurochemistry, 2017Co-Authors: Nico Mitro, Silvia Giatti, Marzia Pesaresi, Roberto Spezzano, Donatella Caruso, Gaia Cermenati, Matteo Audano, Silvia Pedretti, R C MelcangiAbstract:Neuroactive Steroid levels are altered in several experimental models of peripheral neuropathy, and on this basis, they have been proposed as protective agents. For the first time, the levels of these molecules were here assessed in sterol regulatory-binding protein-1c (SREBP-1c) knock-out (KO) male mice (i.e., an experimental model of peripheral neuropathy) and compared with observations in wild type animals. The levels of Neuroactive Steroids have been evaluated by liquid chromatography tandem mass spectrometry in plasma and sciatic nerve at two and ten months of age and these analyses were implemented analyzing the gene expression of crucial Steroidogenic enzymes in sciatic nerve. Data obtained at two months of age showed high levels of pregnenolone in sciatic nerve, associated with low levels of its first metabolite, progesterone, and further metabolites (i.e., 5α-pregnane-3,20-dione and 5α-pregnan-3β-ol-20-one). High levels of testosterone and 17β-estradiol were also observed. At ten months of age, the Neuroactive Steroid profile showed some differences. Indeed, low levels of pregnenolone and high levels of 5α-pregnan-3α-ol-20-one and 5α-pregnan-3β-ol-20-one were observed. The analysis of the gene expression of Steroidogenic enzymes here considered generally followed these changes. Interestingly, the levels of pregnenolone and progesterone were unmodified in plasma suggesting a specific effect of SREBP-1c on neuroSteroidogenesis. Because this peripheral neuropathy is due to altered fatty acid biosynthesis, data here reported support the belief that the cross-talk between this biosynthetic pathway and Neuroactive Steroids may represent a possible therapeutic strategy for peripheral neuropathy. This article is protected by copyright. All rights reserved.
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patients treated for male pattern hair with finasteride show after discontinuation of the drug altered levels of Neuroactive Steroids in cerebrospinal fluid and plasma
The Journal of Steroid Biochemistry and Molecular Biology, 2015Co-Authors: Donatella Caruso, Silvia Giatti, Simone Romano, Guido Cavaletti, Federico Abbiati, Letizia Fusco, Roberto Cosimo MelcangiAbstract:Abstract Observations performed in a subset of patients treated for male pattern hair loss indicate that persistent sexual side effects as well as anxious/depressive symptomatology have been reported even after discontinuation of finasteride treatment. Due to the capability of finasteride to block the metabolism of progesterone (PROG) and/or testosterone (T) we have evaluated, by liquid chromatography–tandem mass spectrometry, the levels of several Neuroactive Steroids in paired plasma and cerebrospinal fluid (CSF) samples obtained from post-finasteride patients and in healthy controls. At the examination, post-finasteride patients reported muscular stiffness, cramps, tremors and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Although severity of the anxious/depressive symptoms was quite variable in their frequency, overall all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of Neuroactive Steroid levels in CSF showed a decrease of PROG and its metabolites, dihydroprogesterone (DHP) and tetrahydroprogesterone (THP), associated with an increase of its precursor pregnenolone (PREG). Altered levels were also observed for T and its metabolites. Thus, a significant decrease of dihydrotestosterone (DHT) associated with an increase of T as well as of 3α-diol was detected. Changes in Neuroactive Steroid levels also occurred in plasma. An increase of PREG, T, 3α-diol, 3β-diol and 17β-estradiol was associated with decreased levels of DHP and THP. The present observations show that altered levels of Neuroactive Steroids, associated with depression symptoms, are present in androgenic alopecia patients even after discontinuation of the finasteride treatment. This article is part of a Special Issue entitled ‘Sex Steroids and brain disorders’.
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Neuroactive Steroid levels are modified in cerebrospinal fluid and plasma of post finasteride patients showing persistent sexual side effects and anxious depressive symptomatology
The Journal of Sexual Medicine, 2013Co-Authors: Roberto Cosimo Melcangi, Silvia Giatti, Donatella Caruso, Federico Abbiati, Donato Calabrese, Fabrizio Piazza, Guido CavalettiAbstract:Abstract Introduction Observations performed in a subset of subjects treated with finasteride (an inhibitor of the enzyme 5α‐reductase) for male pattern hair loss seem to indicate that sexual dysfunction as well as anxious/depressive symptomatology may occur at the end of the treatment and continue after discontinuation. Aim A possible hypothesis to explain depression symptoms after finasteride treatment might be impairment in the levels of Neuroactive Steroids. Therefore, Neuroactive Steroid levels were evaluated in paired plasma and cerebrospinal fluid samples obtained from male patients who received finasteride for the treatment of androgenic alopecia and who, after drug discontinuation, still show long‐term sexual side effects as well as anxious/depressive symptomatology. Methods The levels of Neuroactive Steroids were evaluated by liquid chromatography–tandem mass spectrometry in three postfinasteride patients and compared to those of five healthy controls. Main Outcome Measures Neuroactive Steroid levels in plasma and cerebrospinal fluid of postfinasteride patients and healthy controls. Results At the examination, the three postfinasteride patients reported muscular stiffness, cramps, tremors, and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Severity and frequency of the anxious/depressive symptoms were quite variable; overall, all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of Neuroactive Steroid levels in patients showed some interindividual differences. However, the most important finding was the comparison of their Neuroactive Steroid levels with those of healthy controls. Indeed, decreased levels of tetrahydroprogesterone, isopregnanolone and dihydrotestosterone and increased levels of testosterone and 17β‐estradiol were reported in cerebrospinal fluid of postfinasteride patients. Moreover, decreased levels of dihydroprogesterone and increased levels of 5α‐androstane‐3α,17β‐diol and 17β‐estradiol were observed in plasma. Conclusion The present observations confirm that an impairment of Neuroactive Steroid levels, associated with depression symptoms, is still present in androgenic alopecia patients treated with finasteride despite the discontinuation of the treatment. Melcangi RC, Caruso D, Abbiati F, Giatti S, Calabrese D, Piazza F, and Cavaletti G. Neuroactive Steroid levels are modified in cerebrospinal fluid and plasma of postfinasteride patients showing persistent sexual side effects and anxious/depressive symptomatology. J Sex Med 2013;10:2598–2603.
Guido Cavaletti - One of the best experts on this subject based on the ideXlab platform.
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patients treated for male pattern hair with finasteride show after discontinuation of the drug altered levels of Neuroactive Steroids in cerebrospinal fluid and plasma
The Journal of Steroid Biochemistry and Molecular Biology, 2015Co-Authors: Donatella Caruso, Silvia Giatti, Simone Romano, Guido Cavaletti, Federico Abbiati, Letizia Fusco, Roberto Cosimo MelcangiAbstract:Abstract Observations performed in a subset of patients treated for male pattern hair loss indicate that persistent sexual side effects as well as anxious/depressive symptomatology have been reported even after discontinuation of finasteride treatment. Due to the capability of finasteride to block the metabolism of progesterone (PROG) and/or testosterone (T) we have evaluated, by liquid chromatography–tandem mass spectrometry, the levels of several Neuroactive Steroids in paired plasma and cerebrospinal fluid (CSF) samples obtained from post-finasteride patients and in healthy controls. At the examination, post-finasteride patients reported muscular stiffness, cramps, tremors and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Although severity of the anxious/depressive symptoms was quite variable in their frequency, overall all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of Neuroactive Steroid levels in CSF showed a decrease of PROG and its metabolites, dihydroprogesterone (DHP) and tetrahydroprogesterone (THP), associated with an increase of its precursor pregnenolone (PREG). Altered levels were also observed for T and its metabolites. Thus, a significant decrease of dihydrotestosterone (DHT) associated with an increase of T as well as of 3α-diol was detected. Changes in Neuroactive Steroid levels also occurred in plasma. An increase of PREG, T, 3α-diol, 3β-diol and 17β-estradiol was associated with decreased levels of DHP and THP. The present observations show that altered levels of Neuroactive Steroids, associated with depression symptoms, are present in androgenic alopecia patients even after discontinuation of the finasteride treatment. This article is part of a Special Issue entitled ‘Sex Steroids and brain disorders’.
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Neuroactive Steroid levels in plasma and cerebrospinal fluid of male multiple sclerosis patients
'Wiley', 2014Co-Authors: D. Caruso, Silvia Giatti, Guido Cavaletti, M. Melis, G. Fenu, S. Romano, M. Grimoldi, D. Crippa, M.g. Marrosu, R C MelcangiAbstract:Neuroactive Steroid family includes molecules synthesized in peripheral glands (i.e., hormonal Steroids) and directly in the nervous system (i.e., neuroSteroids) which are key regulators of the nervous function. As already reported in clinical and experimental studies, neurodegenerative diseases affect the levels of Neuroactive Steroids. However, a careful analysis comparing the levels of these molecules in cerebrospinal fluid (CSF) and in plasma of multiple sclerosis (MS) patients is still missing. To this aim, the levels of Neuroactive Steroids were evaluated by liquid chromatography-tandem mass spectrometry in CSF and plasma of male adults affected by Relapsing-Remitting MS and compared with those collected in control patients. An increase in pregnenolone and isopregnanolone levels associated with a decrease in progesterone metabolites, dihydroprogesterone, and tetrahydroprogesterone was observed in CSF of MS patients. Moreover, an increase of 5\u3b1-androstane- 3\u3b1,17\u3b2-diol and of 17\u3b2-estradiol levels associated with a decrease of dihydrotestosterone also occurred. In plasma, an increase in pregnenolone, progesterone, and dihydrotestosterone and a decrease in dihydroprogesterone and tetrahydroprogesterone levels were reported. This study shows for the first time that the levels of several Neuroactive Steroids, and particularly those of progesterone and testosterone metabolites, are deeply affected in CSF of relapsing-remitting MS male patients. We here demonstrated that, the cerebrospinal fluid and plasma levels of several Neuroactive Steroids are modified in relapsing remitting multiple sclerosis male patients. Interestingly, we reported for the first time that, the levels of progesterone and testosterone metabolites are deeply affected in cerebrospinal fluid. These findings may have an important relevance in therapeutic and/or diagnostic field of multiple sclerosis. We here demonstrated that, the cerebrospinal fluid and plasma levels of several Neuroactive Steroids are modified in relapsing remitting multiple sclerosis male patients. Interestingly, we reported for the first time that, the levels of progesterone and testosterone metabolites are deeply affected in cerebrospinal fluid. These findings may have an important relevance in therapeutic and/or diagnostic field of multiple sclerosis
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Neuroactive Steroid levels are modified in cerebrospinal fluid and plasma of post finasteride patients showing persistent sexual side effects and anxious depressive symptomatology
The Journal of Sexual Medicine, 2013Co-Authors: Roberto Cosimo Melcangi, Silvia Giatti, Donatella Caruso, Federico Abbiati, Donato Calabrese, Fabrizio Piazza, Guido CavalettiAbstract:Abstract Introduction Observations performed in a subset of subjects treated with finasteride (an inhibitor of the enzyme 5α‐reductase) for male pattern hair loss seem to indicate that sexual dysfunction as well as anxious/depressive symptomatology may occur at the end of the treatment and continue after discontinuation. Aim A possible hypothesis to explain depression symptoms after finasteride treatment might be impairment in the levels of Neuroactive Steroids. Therefore, Neuroactive Steroid levels were evaluated in paired plasma and cerebrospinal fluid samples obtained from male patients who received finasteride for the treatment of androgenic alopecia and who, after drug discontinuation, still show long‐term sexual side effects as well as anxious/depressive symptomatology. Methods The levels of Neuroactive Steroids were evaluated by liquid chromatography–tandem mass spectrometry in three postfinasteride patients and compared to those of five healthy controls. Main Outcome Measures Neuroactive Steroid levels in plasma and cerebrospinal fluid of postfinasteride patients and healthy controls. Results At the examination, the three postfinasteride patients reported muscular stiffness, cramps, tremors, and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Severity and frequency of the anxious/depressive symptoms were quite variable; overall, all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of Neuroactive Steroid levels in patients showed some interindividual differences. However, the most important finding was the comparison of their Neuroactive Steroid levels with those of healthy controls. Indeed, decreased levels of tetrahydroprogesterone, isopregnanolone and dihydrotestosterone and increased levels of testosterone and 17β‐estradiol were reported in cerebrospinal fluid of postfinasteride patients. Moreover, decreased levels of dihydroprogesterone and increased levels of 5α‐androstane‐3α,17β‐diol and 17β‐estradiol were observed in plasma. Conclusion The present observations confirm that an impairment of Neuroactive Steroid levels, associated with depression symptoms, is still present in androgenic alopecia patients treated with finasteride despite the discontinuation of the treatment. Melcangi RC, Caruso D, Abbiati F, Giatti S, Calabrese D, Piazza F, and Cavaletti G. Neuroactive Steroid levels are modified in cerebrospinal fluid and plasma of postfinasteride patients showing persistent sexual side effects and anxious/depressive symptomatology. J Sex Med 2013;10:2598–2603.
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Neuroactive Steroid Levels are Modified in Cerebrospinal Fluid and Plasma of Post-Finasteride Patients Showing Persistent Sexual Side Effects and Anxious/Depressive Symptomatology
'Wiley', 2013Co-Authors: R C Melcangi, Silvia Giatti, Federico Abbiati, Donato Calabrese, Fabrizio Piazza, D. Caruso, Guido CavalettiAbstract:Introduction: Observations performed in a subset of subjects treated with finasteride (an inhibitor of the enzyme 5\u3b1-reductase) for male pattern hair loss seem to indicate that sexual dysfunction as well as anxious/depressive symptomatology may occur at the end of the treatment and continue after discontinuation. Aim: A possible hypothesis to explain depression symptoms after finasteride treatment might be impairment in the levels of Neuroactive Steroids. Therefore, Neuroactive Steroid levels were evaluated in paired plasma and cerebrospinal fluid samples obtained from male patients who received finasteride for the treatment of androgenic alopecia and who, after drug discontinuation, still show long-term sexual side effects as well as anxious/depressive symptomatology. Methods: The levels of Neuroactive Steroids were evaluated by liquid chromatography-tandem mass spectrometry in three postfinasteride patients and compared to those of five healthy controls. Main Outcome Measures: Neuroactive Steroid levels in plasma and cerebrospinal fluid of postfinasteride patients and healthy controls. Results: At the examination, the three postfinasteride patients reported muscular stiffness, cramps, tremors, and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Severity and frequency of the anxious/depressive symptoms were quite variable; overall, all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of Neuroactive Steroid levels in patients showed some interindividual differences. However, the most important finding was the comparison of their Neuroactive Steroid levels with those of healthy controls. Indeed, decreased levels of tetrahydroprogesterone, isopregnanolone and dihydrotestosterone and increased levels of testosterone and 17\u3b2-estradiol were reported in cerebrospinal fluid of postfinasteride patients. Moreover, decreased levels of dihydroprogesterone and increased levels of 5\u3b1-androstane-3\u3b1,17\u3b2-diol and 17\u3b2-estradiol were observed in plasma. Conclusion: The present observations confirm that an impairment of Neuroactive Steroid levels, associated with depression symptoms, is still present in androgenic alopecia patients treated with finasteride despite the discontinuation of the treatment
R C Melcangi - One of the best experts on this subject based on the ideXlab platform.
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sterol regulatory element binding protein 1c knockout mice show altered Neuroactive Steroid levels in sciatic nerve
Journal of Neurochemistry, 2017Co-Authors: Nico Mitro, Silvia Giatti, Marzia Pesaresi, Roberto Spezzano, Donatella Caruso, Gaia Cermenati, Matteo Audano, Silvia Pedretti, R C MelcangiAbstract:Neuroactive Steroid levels are altered in several experimental models of peripheral neuropathy, and on this basis, they have been proposed as protective agents. For the first time, the levels of these molecules were here assessed in sterol regulatory-binding protein-1c (SREBP-1c) knock-out (KO) male mice (i.e., an experimental model of peripheral neuropathy) and compared with observations in wild type animals. The levels of Neuroactive Steroids have been evaluated by liquid chromatography tandem mass spectrometry in plasma and sciatic nerve at two and ten months of age and these analyses were implemented analyzing the gene expression of crucial Steroidogenic enzymes in sciatic nerve. Data obtained at two months of age showed high levels of pregnenolone in sciatic nerve, associated with low levels of its first metabolite, progesterone, and further metabolites (i.e., 5α-pregnane-3,20-dione and 5α-pregnan-3β-ol-20-one). High levels of testosterone and 17β-estradiol were also observed. At ten months of age, the Neuroactive Steroid profile showed some differences. Indeed, low levels of pregnenolone and high levels of 5α-pregnan-3α-ol-20-one and 5α-pregnan-3β-ol-20-one were observed. The analysis of the gene expression of Steroidogenic enzymes here considered generally followed these changes. Interestingly, the levels of pregnenolone and progesterone were unmodified in plasma suggesting a specific effect of SREBP-1c on neuroSteroidogenesis. Because this peripheral neuropathy is due to altered fatty acid biosynthesis, data here reported support the belief that the cross-talk between this biosynthetic pathway and Neuroactive Steroids may represent a possible therapeutic strategy for peripheral neuropathy. This article is protected by copyright. All rights reserved.
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Neuroactive Steroid levels and psychiatric and andrological features in post-finasteride patients
'Elsevier BV', 2017Co-Authors: R C Melcangi, Silvia Giatti, Roberto Spezzano, S. Diviccaro, M. Grimoldi, D. Santi, T. Tabacchi, M.l. Fusco, G. Carrà, D. CarusoAbstract:Recent reports show that, in patients treated with finasteride for male pattern hair loss, persistent side effects including sexual side effects, depression, anxiety and cognitive complaints may occur. We here explored the psychiatric and andrological features of patients affected by post-finasteride syndrome (PFS) and verified whether the cerebrospinal fluid (CSF) and plasma levels of Neuroactive Steroids (i.e., important regulators of nervous function) are modified. We found that eight out of sixteen PFS male patients considered suffered from a DSM-IV major depressive disorder (MDD). In addition, all PFS patients showed erectile dysfunction (ED); in particular, ten patients showed a severe and six a mild-moderate ED. We also reported abnormal somatosensory evoked potentials of the pudendal nerve in PFS patients with severe ED, the first objective evidence of a neuropathy involving peripheral neurogenic control of erection. Testicular volume by ultrasonography was normal in PFS patients. Data obtained on Neuroactive Steroid levels also indicate interesting features. Indeed, decreased levels of pregnenolone, progesterone and its metabolite (i.e., dihydroprogesterone), dihydrotestosterone and 17beta-estradiol and increased levels of dehydroepiandrosterone, testosterone and 5alpha-androstane-3alpha,17beta-diol were observed in CSF of PFS patients. Neuroactive Steroid levels were also altered in plasma of PFS patients, however these changes did not reflect exactly what occurs in CSF. Finally, finasteride did not only affect, as expected, the levels of 5alpha-reduced metabolites of progesterone and testosterone, but also the further metabolites and precursors suggesting that this drug has broad consequence on Neuroactive Steroid levels of PFS patients
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NeuroSteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research
'Wiley', 2016Co-Authors: P. Porcu, Giancarlo Panzica, A.m. Barron, C.a. Frye, A.a. Walf, S.-. Yang, A.l. Morrow, R C MelcangiAbstract:Neuroactive Steroids are endogenous neuromodulators synthesised in the brain that rapidly alter neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular Steroid receptors. Neuroactive Steroids induce potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the GABAA receptor. They also exert neuroprotective, neurotrophic and antiapoptotic effects in several animal models of neurodegenerative diseases. Neuroactive Steroids regulate many physiological functions, such as the stress response, puberty, the ovarian cycle, pregnancy and reward. Their levels are altered in several neuropsychiatric and neurological diseases and both preclinical and clinical studies emphasise a therapeutic potential of Neuroactive Steroids for these diseases, whereby symptomatology ameliorates upon restoration of Neuroactive Steroid concentrations. However, direct administration of Neuroactive Steroids has several challenges, including pharmacokinetics, low bioavailability, addiction potential, safety and tolerability, which limit its therapeutic use. Therefore, modulation of neuroSteroidogenesis to restore the altered endogenous Neuroactive Steroid tone may represent a better therapeutic approach. This review summarises recent approaches that target the Neuroactive Steroid biosynthetic pathway at different levels aiming to promote neuroSteroidogenesis. These include modulation of neuroSteroidogenesis through ligands of the translocator protein 18 kDa and the pregnane xenobiotic receptor, as well as targeting of specific neuroSteroidogenic enzymes such as 17\u3b2-hydroxySteroid dehydrogenase type 10 or P450 side chain cleavage. Enhanced neuroSteroidogenesis through these targets may be beneficial not only for neurodegenerative diseases, such as Alzheimer's disease and age-related dementia, but also for neuropsychiatric diseases, including alcohol use disorders
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allopregnanolone state of the art
Progress in Neurobiology, 2014Co-Authors: R C Melcangi, Giancarlo PanzicaAbstract:Allopregnanolone, a Neuroactive Steroid derived from progesterone, is synthesized within the nervous tissue, by means of specific enzymes. Contrary to progesterone and its first metabolite dihydroprogesterone, allopregnanolone is able to interact with GABA-A receptor and not with the classical progesterone receptor. This suggests that the effect of progesterone administration may be due to activation of progesterone receptor, or of GABA-A receptor, or both. However, this is rarely considered in the experimental studies. Here we summarize and discuss the hot topics involving the actions of allopregnanolone within the nervous tissue. One major role of this Neuroactive Steroid is neuroprotection in case of lesion, ischemia or peripheral neuropathies (i.e., diabetes). In addition, allopregnanolone may reduce the symptoms of neurodegenerative diseases (e.g., Alzheimer, Parkinson, Niemann-Pick type C, multiple sclerosis) in animal models and now translational studies are developed for its therapeutic use. Allopregnanolone may exert a beneficial effect also in case of neuropathic pain and it is also a potential candidate for the treatment of mood and anxiety disorders. Finally, this Neuroactive Steroid seems to have important physiological roles in the early differentiation of some neural circuits (in particular at hippocampal level), and to reduce stress during pregnancy. In conclusion, it appears that allopregnanolone is a key regulator of physiological functions and may have interesting therapeutic perspectives for neurodegenerative and psychiatric disorders.
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Neuroactive Steroid levels in plasma and cerebrospinal fluid of male multiple sclerosis patients
'Wiley', 2014Co-Authors: D. Caruso, Silvia Giatti, Guido Cavaletti, M. Melis, G. Fenu, S. Romano, M. Grimoldi, D. Crippa, M.g. Marrosu, R C MelcangiAbstract:Neuroactive Steroid family includes molecules synthesized in peripheral glands (i.e., hormonal Steroids) and directly in the nervous system (i.e., neuroSteroids) which are key regulators of the nervous function. As already reported in clinical and experimental studies, neurodegenerative diseases affect the levels of Neuroactive Steroids. However, a careful analysis comparing the levels of these molecules in cerebrospinal fluid (CSF) and in plasma of multiple sclerosis (MS) patients is still missing. To this aim, the levels of Neuroactive Steroids were evaluated by liquid chromatography-tandem mass spectrometry in CSF and plasma of male adults affected by Relapsing-Remitting MS and compared with those collected in control patients. An increase in pregnenolone and isopregnanolone levels associated with a decrease in progesterone metabolites, dihydroprogesterone, and tetrahydroprogesterone was observed in CSF of MS patients. Moreover, an increase of 5\u3b1-androstane- 3\u3b1,17\u3b2-diol and of 17\u3b2-estradiol levels associated with a decrease of dihydrotestosterone also occurred. In plasma, an increase in pregnenolone, progesterone, and dihydrotestosterone and a decrease in dihydroprogesterone and tetrahydroprogesterone levels were reported. This study shows for the first time that the levels of several Neuroactive Steroids, and particularly those of progesterone and testosterone metabolites, are deeply affected in CSF of relapsing-remitting MS male patients. We here demonstrated that, the cerebrospinal fluid and plasma levels of several Neuroactive Steroids are modified in relapsing remitting multiple sclerosis male patients. Interestingly, we reported for the first time that, the levels of progesterone and testosterone metabolites are deeply affected in cerebrospinal fluid. These findings may have an important relevance in therapeutic and/or diagnostic field of multiple sclerosis. We here demonstrated that, the cerebrospinal fluid and plasma levels of several Neuroactive Steroids are modified in relapsing remitting multiple sclerosis male patients. Interestingly, we reported for the first time that, the levels of progesterone and testosterone metabolites are deeply affected in cerebrospinal fluid. These findings may have an important relevance in therapeutic and/or diagnostic field of multiple sclerosis