219 results on '"Roberto Cosimo Melcangi"'
Search Results
2. Neuroactive Steroid–Gut Microbiota Interaction in T2DM Diabetic Encephalopathy
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Silvia Diviccaro, Lucia Cioffi, Rocco Piazza, Donatella Caruso, Roberto Cosimo Melcangi, and Silvia Giatti
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memory ,hippocampus ,allopregnanolone ,corticosterone ,ZDF ,Collinsella ,Microbiology ,QR1-502 - Abstract
The pathological consequences of type 2 diabetes mellitus (T2DM) also involve the central nervous system; indeed, T2DM patients suffer from learning and memory disabilities with a higher risk of developing dementia. Although several factors have been proposed as possible contributors, how neuroactive steroids and the gut microbiome impact brain pathophysiology in T2DM remain unexplored. On this basis, in male Zucker diabetic fatty (ZDF) rats, we studied whether T2DM alters memory abilities using the novel object recognition test, neuroactive steroid levels by liquid chromatography–tandem mass spectrometry, hippocampal parameters using molecular assessments, and gut microbiome composition using 16S next-generation sequencing. Results obtained reveal that T2DM worsens memory abilities and that these are correlated with increased levels of corticosterone in plasma and with a decrease in allopregnanolone in the hippocampus, where neuroinflammation, oxidative stress, and mitochondrial dysfunction were reported. Interestingly, our analysis highlighted a small group of taxa strictly related to both memory impairment and neuroactive steroid levels. Overall, the data underline an interesting role for allopregnanolone and microbiota that may represent candidates for the development of therapeutic strategies.
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- 2023
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3. Diabetic Encephalopathy in a Preclinical Experimental Model of Type 1 Diabetes Mellitus: Observations in Adult Female Rat
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Eva Falvo, Silvia Giatti, Silvia Diviccaro, Lucia Cioffi, Monika Herian, Paola Brivio, Francesca Calabrese, Donatella Caruso, and Roberto Cosimo Melcangi
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cognition ,brain ,sex-dimorphism ,dihydroprogesterone ,allopregnanolone ,neuroinflammation ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Patients affected by diabetes mellitus (DM) show diabetic encephalopathy with an increased risk of cognitive deficits, dementia and Alzheimer’s disease, but the mechanisms are not fully explored. In the male animal models of DM, the development of cognitive impairment seems to be the result of the concomitance of different processes such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and aberrant synaptogenesis. However, even if diabetic encephalopathy shows some sex-dimorphic features, no observations in female rats have been so far reported on these aspects. Therefore, in an experimental model of type 1 DM (T1DM), we explored the impact of one month of pathology on memory abilities by the novel object recognition test and on neuroinflammation, synaptogenesis and mitochondrial functionality. Moreover, given that steroids are involved in memory and learning, we also analysed their levels and receptors. We reported that memory dysfunction can be associated with different features in the female hippocampus and cerebral cortex. Indeed, in the hippocampus, we observed aberrant synaptogenesis and neuroinflammation but not mitochondrial dysfunction and oxidative stress, possibly due to the results of locally increased levels of progesterone metabolites (i.e., dihydroprogesterone and allopregnanolone). These observations suggest specific brain-area effects of T1DM since different alterations are observed in the cerebral cortex.
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- 2023
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4. Multimodal Comparison of Diabetic Neuropathy in Aged Streptozotocin-Treated Sprague–Dawley and Zucker Diabetic Fatty Rats
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Annalisa Canta, Valentina A. Carozzi, Alessia Chiorazzi, Cristina Meregalli, Norberto Oggioni, Virginia Rodriguez-Menendez, Barbara Sala, Roberto Cosimo Melcangi, Silvia Giatti, Raffaella Lombardi, Roberto Bianchi, Paola Marmiroli, and Guido Cavaletti
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experimental diabetes ,peripheral neuropathy ,streptozotocin ,Zucker rats ,Biology (General) ,QH301-705.5 - Abstract
The development and progression of diabetic polyneuropathy (DPN) are due to multiple mechanisms. The creation of reliable animal models of DPN has been challenging and this issue has not yet been solved. However, despite some recognized differences from humans, most of the current knowledge on the pathogenesis of DPN relies on results achieved using rodent animal models. The simplest experimental DPN model reproduces type 1 diabetes, induced by massive chemical destruction of pancreatic beta cells with streptozotocin (STZ). Spontaneous/transgenic models of diabetes are less frequently used, mostly because they are less predictable in clinical course, more expensive, and require a variable time to achieve homogeneous metabolic conditions. Among them, Zucker diabetic fatty (ZDF) rats represent a typical type 2 diabetes model. Both STZ-induced and ZDF rats have been extensively used, but only very few studies have compared the long-term similarities and differences existing between these two models. Moreover, inconsistencies have been reported regarding several aspects of short-term in vivo studies using these models. In this study, we compared the long-term course of DPN in STZ-treated Sprague–Dawley and ZDF rats with a multimodal set of readout measures.
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- 2022
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5. Gut Inflammation Induced by Finasteride Withdrawal: Therapeutic Effect of Allopregnanolone in Adult Male Rats
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Silvia Diviccaro, Silvia Giatti, Lucia Cioffi, Eva Falvo, Monika Herian, Donatella Caruso, and Roberto Cosimo Melcangi
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pro-inflammatory cytokines ,serotonin ,dopamine ,gut steroids ,pregnenolone ,GABA-A receptor ,Microbiology ,QR1-502 - Abstract
The treatment with finasteride (i.e., an inhibitor of 5α-reductase) may be associated with different side effects (i.e., depression, anxiety, cognitive impairment and sexual dysfunction) inducing the so-called post finasteride syndrome (PFS). Moreover, previous observations in PFS patients and an experimental model showed alterations in gut microbiota populations, suggesting an inflammatory environment. To confirm this hypothesis, we have explored the effect of chronic treatment with finasteride (i.e., for 20 days) and its withdrawal (i.e., for 1 month) on the levels of steroids, neurotransmitters, pro-inflammatory cytokines and gut permeability markers in the colon of adult male rat. The obtained data demonstrate that the levels of allopregnanolone (ALLO) decreased after finasteride treatment and after its withdrawal. Following the drug suspension, the decrease in ALLO levels correlates with an increase in IL-1β and TNF-α, serotonin and a decrease in dopamine. Importantly, ALLO treatment is able to counteract some of these alterations. The relation between ALLO and GABA-A receptors and/or pregnenolone (ALLO precursor) could be crucial in their mode of action. These observations provide an important background to explore further the protective effect of ALLO in the PFS experimental model and the possibility of its translation into clinical therapy.
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- 2022
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6. Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: a pilot study
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Roberto Cosimo Melcangi, Livio Casarini, Marco Marino, Daniele Santi, Samantha Sperduti, Silvia Giatti, Silvia Diviccaro, Maria Grimoldi, Donatella Caruso, Guido Cavaletti, and Manuela Simoni
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5 alpha-reductase ,neuroactive steroids ,finasteride ,side effects ,epigenetic changes ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Context: Post-finasteride syndrome (PFS) occurs in patients with androgenic alopecia after suspension of the finasteride treatment, leading to a large variety of persistent side effects. Despite the severity of the clinical picture, the mechanism underlying the PFS symptoms onset and persistence is still unclear. Objective: To study whether epigenetic modifications occur in PFS patients. Methods: Retrospective analysis of a multicentric, prospective, longitudinal, case–control clinical trial, enrolling 16 PFS patients, compared to 20 age-matched healthy men. Main outcomes were methylation pattern of SRD5A1 and SRD5A2 promoters and concentration of 11 neuroactive steroids, measured by liquid chromatography-tandem mass spectrometry, in blood and cerebrospinal fluid (CSF) samples. Results: SRD5A1 and SRD5A2 methylation analysis was performed in all blood samples (n = 16 PFS patients and n = 20 controls), in 16 CSF samples from PFS patients and in 13 CSF samples from controls. The SRD5A2 promoter was more frequently methylated in CSF of PFS patients compared to controls (56.3 vs 7.7%). No promoter methylation was detected in blood samples in both groups. No methylation occurred in the SRD5A1 promoter of both groups. Unmethylated controls compared to unmethylated SRD5A2 patients showed higher pregnenolone, dihydrotestosterone and dihydroprogesterone, together with lower testosterone CSF levels. Andrological and neurological assessments did not differ between methylated and unmethylated subjects. Conclusions: For the first time, we demonstrate a tissue-specific methylation pattern of SRD5A2 promoter in PFS patients. Although we cannot conclude whether this pattern is prenatally established or induced by finasteride treatment, it could represent an important mechanism of neuroactive steroid levels and behavioural disturbances previously described in PFS.
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- 2019
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7. Gut Steroids and Microbiota: Effect of Gonadectomy and Sex
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Silvia Diviccaro, Jamie A. FitzGerald, Lucia Cioffi, Eva Falvo, Fiona Crispie, Paul D. Cotter, Siobhain M. O’Mahony, Silvia Giatti, Donatella Caruso, and Roberto Cosimo Melcangi
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pregnenolone ,sex steroids ,gut microbiota ,branched- and short-chain fatty acids ,sex dimorphism ,gastrointestinal tract ,Microbiology ,QR1-502 - Abstract
Sex steroids, derived mainly from gonads, can shape microbiota composition; however, the impact of gonadectomy and sex on steroid production in the gut (i.e., gut steroids), and its interaction with microbiota composition, needs to be clarified. In this study, steroid environment and gut steroidogenesis were analysed by liquid chromatography tandem mass spectrometry and expression analyses. Gut microbiota composition as branched- and short-chain fatty acids were determined by 16S rRNA gene sequence analysis and gas chromatography flame ionisation detection, respectively. Here, we first demonstrated that levels of pregnenolone (PREG), progesterone (PROG), and isoallopregnanolone (ISOALLO) were higher in the female rat colon, whereas the level of testosterone (T) was higher in males. Sexual dimorphism on gut steroidogenesis is also reported after gonadectomy. Sex, and more significantly, gonadectomy, affects microbiota composition. We noted that a number of taxa and inferred metabolic pathways were associated with gut steroids, such as positive associations between Blautia with T, dihydroprogesterone (DHP), and allopregnanolone (ALLO), whereas negative associations were noted between Roseburia and T, ALLO, PREG, ISOALLO, DHP, and PROG. In conclusion, this study highlights the novel sex-specific association between microbiota and gut steroids with possible relevance for the gut-brain axis.
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- 2022
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8. Post-finasteride syndrome: An emerging clinical problem
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Silvia Diviccaro, Roberto Cosimo Melcangi, and Silvia Giatti
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Finasteride ,5alpha-reductase ,Neuroactive steroids ,Sexual dysfunction ,Depression ,Androgenetic alopecia ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 ,Neurophysiology and neuropsychology ,QP351-495 - Abstract
The presence of side effects during pharmacological treatment is unfortunately a quite common problem. In this review, we focused our attention on adverse events related to 5 alpha-reductase (5α-R) inhibitors (i.e., finasteride and dutasteride), approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia (AGA).Although these drugs are generally well tolerated, many reports described adverse effects in men during treatment, such as sexual dysfunction and mood alteration. In addition, it has been also reported that persistent side effects may occur in some AGA patients. This condition, termed post-finasteride syndrome (PFS) is characterized by sexual side effects (i.e., low libido, erectile dysfunction, decreased arousal and difficulty in achieving orgasm), depression, anxiety and cognitive complaints that are still present despite drug withdrawal. Indeed, some national agencies (e.g., Swedish Medical Products Agency, the Medicines and Healthcare Products Regulatory Agency of UK and the U.S. Food and Drug Administration) required to include multiple persistent side effects within the finasteride labels.As here reported, these observations are mainly based on self-reporting of the symptomatology by the patients and few clinical studies have been performed so far. In addition, molecular mechanisms and/or genetic determinants behind such adverse effects have been poorly explored both in patients and animal models. Therefore, results here discussed indicate that PFS is an emerging clinical problem that needs to be further elucidated.
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- 2020
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9. Axonal transport in a peripheral diabetic neuropathy model: sex-dimorphic features
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Marzia Pesaresi, Silvia Giatti, Roberto Spezzano, Simone Romano, Silvia Diviccaro, Tiziana Borsello, Nico Mitro, Donatella Caruso, Luis Miguel Garcia-Segura, and Roberto Cosimo Melcangi
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Streptozotocin ,Sciatic nerve ,Dorsal root ganglia ,Mitochondria ,Neuroactive steroids ,Male ,Medicine ,Physiology ,QP1-981 - Abstract
Abstract 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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- 2018
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10. Exploring the Impact of the Microbiome on Neuroactive Steroid Levels in Germ-Free Animals
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Silvia Diviccaro, Valentina Caputi, Lucia Cioffi, Silvia Giatti, Joshua M. Lyte, Donatella Caruso, Siobhain M. O’Mahony, and Roberto Cosimo Melcangi
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liquid chromatography–tandem mass spectrometry ,hippocampus ,cerebellum ,cerebral cortex ,hypothalamus ,plasma ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
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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- 2021
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11. Physiopathological Role of Neuroactive Steroids in the Peripheral Nervous System
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Eva Falvo, Silvia Diviccaro, Roberto Cosimo Melcangi, and Silvia Giatti
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peripheral neuropathy ,pain ,diabetes mellitus ,physical injury ,chemotherapy-induced peripheral neuropathy ,steroidogenesis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Peripheral neuropathy (PN) refers to many conditions involving damage to the peripheral nervous system (PNS). Usually, PN causes weakness, numbness and pain and is the result of traumatic injuries, infections, metabolic problems, inherited causes, or exposure to chemicals. Despite the high prevalence of PN, available treatments are still unsatisfactory. Neuroactive steroids (i.e., steroid hormones synthesized by peripheral glands as well as steroids directly synthesized in the nervous system) represent important physiological regulators of PNS functionality. Data obtained so far and here discussed, indeed show that in several experimental models of PN the levels of neuroactive steroids are affected by the pathology and that treatment with these molecules is able to exert protective effects on several PN features, including neuropathic pain. Of note, the observations that neuroactive steroid levels are sexually dimorphic not only in physiological status but also in PN, associated with the finding that PN show sex dimorphic manifestations, may suggest the possibility of a sex specific therapy based on neuroactive steroids.
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- 2020
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12. Interactions between neuroactive steroids and reelin haploinsufficiency in Purkinje cell survival
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Filippo Biamonte, Giovanni Assenza, Ramona Marino, Marcello D'Amelio, Roger Panteri, Donatella Caruso, Samuele Scurati, Josue Garcia Yague, Luis Miguel Garcia-Segura, Roberta Cesa, Piergiorgio Strata, Roberto Cosimo Melcangi, and Flavio Keller
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Reelin ,Neuroactive steroids ,Epigenetic regulation ,Brain sexual dimorphisms ,Stereology ,Mass spectrometry ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
We determined total Purkinje cell (PC) numbers in cerebella of wild-type (+/+) and heterozygous (rl/+) reeler mice of either sex during early postnatal development; in parallel, we quantified levels of neuroactive steroids in the cerebellum with mass spectrometry. We also quantified reelin mRNA and protein expression with RT-PCR and Western blotting. PC numbers are selectively reduced at postnatal day 15 (P15) in rl/+ males in comparison to +/+ males, +/+ females, and rl/+ females. Administration of 17β-estradiol (17β-E) into the cisterna magna at P5 increases PC numbers in rl/+ males, but not in the other groups; conversely, estrogen antagonists 4-OH-tamoxifen or ICI 182,780 reduce PC numbers in +/+ and rl/+ females, but have no effect in males. Testosterone (T) levels at P5 are much higher in males than in females, reflecting the perinatal testosterone surge in males. In addition, rl/+ male cerebella at P5 show a peculiar hormonal profile in comparison with the other groups, consisting of increased levels of T and 17β-E, and decreased levels of dihydrotestosterone. RT-PCR analysis indicated that heterozygosity leads to a 50% reduction of reelin mRNA in the cerebellum in both sexes, as expected, and that 17β-E upregulates reelin mRNA, particularly in rl/+ males; reelin mRNA upregulation is associated with an increase of all major reelin isoforms. These effects may represent a novel model of how reelin deficiency interacts with variable perinatal levels of neuroactive steroids, leading to gender-dependent differences in genetic vulnerability.
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- 2009
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13. Experimental epothilone B neurotoxicity: Results of in vitro and in vivo studies
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Alessia Chiorazzi, Gabriella Nicolini, Annalisa Canta, Norberto Oggioni, Roberta Rigolio, Giacomo Cossa, Raffaella Lombardi, Ilaria Roglio, Ilaria Cervellini, Giuseppe Lauria, Roberto Cosimo Melcangi, Roberto Bianchi, Donatella Crippa, and Guido Cavaletti
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Epothilone B ,In vivo ,In vitro ,Toxicity ,Peripheral neuropathy ,Tubulin ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Epothilones are a novel class of microtubule-targeting anticancer agents that are neurotoxic. In this study, we investigated the epothilone B toxic effect in vitro and we characterized in vivo the general and neurological side effects of epothilone B administration in Wistar and Fischer rats.The in vitro experiments made it possible to explore a wide concentration range (0.1 nM–1 μM) and evidenced a dose-dependent effect of epothilone B exposure on neuron neurite elongation. This dose-dependent neurotoxic effect was confirmed in both in vivo studies performed on two different rat strains at the neurophysiological, behavioral and pathological levels in the dose range 0.25–1.5 mg/kg iv weekly×4 weeks and tubulin hyper-polymerization was demonstrated in sciatic nerve specimens.These are the first studies of the neurological effects of epothilone B and they can provide a basis for extending pre-clinical investigation to other members of the epothilone family.
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- 2009
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14. Gut microbiota composition is altered in a preclinical model of type 1 diabetes mellitus: Influence on gut steroids, permeability, and cognitive abilities
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Silvia Diviccaro, Eva Falvo, Rocco Piazza, Lucia Cioffi, Monika Herian, Paola Brivio, Francesca Calabrese, Silvia Giatti, Donatella Caruso, Roberto Cosimo Melcangi, Diviccaro, S, Falvo, E, Piazza, R, Cioffi, L, Herian, M, Brivio, P, Calabrese, F, Giatti, S, Caruso, D, and Melcangi, R
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Pharmacology ,Akkermansia ,Allopregnanolone ,Blautia ,Claudin-1 ,NOR test ,Pregnenolone ,Cellular and Molecular Neuroscience ,Settore BIO/10 - Biochimica ,Settore BIO/14 - Farmacologia ,Settore MED/13 - Endocrinologia - Abstract
Sex steroid hormones are not only synthesized from the gonads but also by other tissues, such as the brain (i.e., neurosteroids) and colon (i.e., gut steroids). Gut microbiota can be shaped from sex steroid hormones synthesized from the gonads and locally interacts with gut steroids as in turn modulates neurosteroids. Type 1 diabetes mellitus (T1DM) is characterized by dysbiosis and also by diabetic encephalopathy. However, the interactions of players of gut-brain axis, such as gut steroids, gut permeability markers and microbiota, have been poorly explored in this pathology and, particularly in females. On this basis, we have explored, in streptozotocin (STZ)induced adult female rats, whether one month of T1DM may alter (I) gut microbiome composition and diversity by 16S next-generation sequencing, (II) gut steroid levels by liquid chromatography-tandem mass spectrometry, (III) gut permeability markers by gene expression analysis, (IV) cognitive behavior by the novel object recognition (NOR) test and whether correlations among these aspects may occur. Results obtained reveal that T1DM alters gut beta-, but not alpha-diversity. The pathology is also associated with a decrease and an increase in colonic pregnenolone and allopregnanolone levels, respectively. Additionally, diabetes alters gut permeability and worsens cognitive behavior. Finally, we reported a significant correlation of pregnenolone with Blautia, claudin-1 and the NOR index and of allopregnanolone with Parasutterella, Gammaproteobacteria and claudin-1. Altogether, these results suggest new putative roles of these two gut steroids related to cognitive deficit and dysbiosis in T1DM female experimental model.
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- 2023
15. Development of Adverse Outcome Pathways relevant for the identification of substances having endocrine disruptors properties
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Barbara Viviani, Elena Bernardini, Valentina Galbiati, Ambra Maddalon, Gloria Melzi, Miriam Midali, Melania Serafini, Emanuela Corsini, Roberto Cosimo Melcangi, and Eugenio Scanziani
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General Engineering - Published
- 2023
16. Diagnostic criteria for enduring sexual dysfunction after treatment with antidepressants, finasteride and isotretinoin
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Irwin Goldstein, Silvia Diviccaro, Silvia Giatti, Audrey S. Bahrick, Barbara D'Avanzo, Caroline F. Pukall, David Healy, Heiko Graf, Angelo Barbato, David Edmund Johannes Linden, Amy M. Pearlman, Barbara M. Chubak, Michał Lew-Starowicz, Mohit Khera, Stuart Shipko, Fiammetta Cosci, Omar Walid Muquebil Ali Al Shaban Rodríguez, Joanna Le Noury, Michael S. Irwig, Arianna Patacchini, Paddy K.C. Janssen, Rudy Schreiber, Celine Lüning, Maarten Bak, Jalesh N. Panicker, Dee Mangin, Ahad Waraich, Manoj Therayil Kumar, Barbora Vašečková, Rachel Rubin, Yacov Reisman, Emmanuele A. Jannini, Wayne J.G. Hellstrom, Roberto Cosimo Melcangi, Sanjana Raj, Rocco Salvatore Calabrò, Antonei B. Csoka, RS: MHeNs - R3 - Neuroscience, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: DA KFT Medische Staf (9), Clinical Pharmacy, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Section Psychopharmacology, and RS: FPN NPPP II
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Male ,Adolescent ,Serotonin reuptake inhibitor ,Irritability ,Asexuality ,Arousal ,Persistent genital arousal disorder ,DOUBLE-BLIND ,PERSISTENT ,selective serotonin reuptake inhibitors ,medicine ,Humans ,Child ,business.industry ,Health Policy ,Public Health, Environmental and Occupational Health ,isotretinoin ,General Medicine ,GENITAL AROUSAL DISORDER ,medicine.disease ,EFFICACY ,Antidepressive Agents ,finasteride ,Sexual Dysfunction, Physiological ,Sexual desire ,Post-SSRI sexual dysfunction ,Sexual dysfunction ,Erectile dysfunction ,PREMATURE EJACULATION ,CITALOPRAM ,antidepressants ,SAFETY ,medicine.symptom ,business ,Clinical psychology - Abstract
BACKGROUND: A set of enduring conditions have been reported in the literature involving persistent sexual dysfunction after discontinuation of serotonin reuptake inhibiting antidepressants, 5 alpha-reductase inhibitors and isotretinoin.OBJECTIVE: To develop diagnostic criteria for post-SSRI sexual dysfunction (PSSD), persistent genital arousal disorder (PGAD) following serotonin reuptake inhibitors, post-finasteride syndrome (PFS) and post-retinoid sexual dysfunction (PRSD).METHODS: The original draft was designed using data from two published case series (Hogan et al., 2014 and Healy et al., 2018), which represent the largest public collections of data on these enduring conditions. It was further developed with the involvement of a multidisciplinary panel of experts.RESULTS: A set of criteria were agreed upon for each of the above conditions. Features of PSSD, PFS and PRSD commonly include decreased genital and orgasmic sensation, decreased sexual desire and erectile dysfunction. Ancillary non-sexual symptoms vary depending on the specific condition but can include emotional blunting and cognitive impairment. PGAD presents with an almost mirror image of unwanted sensations of genital arousal or irritability in the absence of sexual desire. A new term, post-SSRI asexuality, is introduced to describe a dampening of sexual interest and pleasure resulting from a pre-natal or pre-teen exposure to a serotonin reuptake inhibitor.CONCLUSIONS: These criteria will help in both clinical and research settings. As with all criteria, they will likely need modification in the light of developments.
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- 2022
17. Synthesis and Actions of 5α-Reduced Metabolites of Testosterone in the Nervous System
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Roberto Cosimo Melcangi, Lucia Cioffi, Silvia Diviccaro, and Abdulmaged M. Traish
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Endocrinology ,Reproductive Medicine ,Urology - Published
- 2021
18. Pregnenolone for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease
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Sara Corsi, Simona Scheggi, Alessandra Pardu, Giulia Braccagni, Donatella Caruso, Lucia Cioffi, Silvia Diviccaro, Mauro Gentile, Silvia Fanni, Roberto Stancampiano, Carla Gambarana, Roberto Cosimo Melcangi, Roberto Frau, and Manolo Carta
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Developmental Neuroscience ,Neurology - Published
- 2023
19. Three-Dimensional Proteome-Wide Scale Screening for the 5-Alpha Reductase Inhibitor Finasteride: Identification of a Novel Off-Target
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Silvia Diviccaro, Alessandro Di Domizio, Silvia Giatti, Donatella Caruso, Eva Falvo, Alessandro Contini, and Roberto Cosimo Melcangi
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Male ,endocrine system ,Epinephrine ,Reductase ,Pharmacology ,Molecular Dynamics Simulation ,01 natural sciences ,Binding, Competitive ,Article ,Rats, Sprague-Dawley ,03 medical and health sciences ,5 Alpha-Reductase Inhibitor ,chemistry.chemical_compound ,5-alpha Reductase Inhibitors ,Catecholamines ,In vivo ,Tandem Mass Spectrometry ,Drug Discovery ,Animals ,Humans ,Databases, Protein ,Chromatography, High Pressure Liquid ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Binding Sites ,Phenylethanolamine N-Methyltransferase ,Finasteride ,In vitro ,0104 chemical sciences ,Rats ,Phenylethanolamine ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Enzyme ,chemistry ,Docking (molecular) ,Molecular Medicine ,Thermodynamics ,Protein Binding - Abstract
Finasteride, a 5-alpha reductase (5α-R) inhibitor, is a widely used drug for treating androgen-dependent conditions. However, its use is associated with sexual, psychological, and physical complaints, suggesting that other mechanisms, in addition to 5α-R inhibition, may be involved. Here, a multidisciplinary approach has been used to identify potential finasteride off-target proteins. SPILLO-PBSS software suggests an additional inhibitory activity of finasteride on phenylethanolamine N-methyltransferase (PNMT), the limiting enzyme in formation of the stress hormone epinephrine. The interaction of finasteride with PNMT was supported by docking and molecular dynamics analysis and by in vitro assay, confirming the inhibitory nature of the binding. Finally, this inhibition was also confirmed in an in vivo rat model. Literature data indicate that PNMT activity perturbation may be correlated with sexual and psychological side effects. Therefore, results here obtained suggest that the binding of finasteride to PNMT might have a role in producing the side effects exerted by finasteride treatment.
- Published
- 2021
20. Exploring the Impact of the Microbiome on Neuroactive Steroid Levels in Germ-Free Animals
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Siobhain M. O'Mahony, Valentina Caputi, Silvia Diviccaro, Joshua M. Lyte, Roberto Cosimo Melcangi, Lucia Cioffi, Silvia Giatti, and Donatella Caruso
- Subjects
Male ,hippocampus ,Pregnanolone ,Mice ,Tandem Mass Spectrometry ,liquid chromatography–tandem mass spectrometry ,cerebellum ,cerebral cortex ,hypothalamus ,plasma ,androgens ,allopregnanolone ,Testosterone ,Biology (General) ,Gonadal Steroid Hormones ,Spectroscopy ,Chromatography ,Microbiota ,Brain ,Dihydrotestosterone ,General Medicine ,Computer Science Applications ,Chemistry ,Dihydroprogesterone ,Hypothalamus ,Neurosteroids ,medicine.drug ,medicine.medical_specialty ,Neuroactive steroid ,QH301-705.5 ,Dehydroepiandrosterone ,Biology ,Article ,Catalysis ,Inorganic Chemistry ,Internal medicine ,medicine ,Animals ,Endocrine system ,Physical and Theoretical Chemistry ,Molecular Biology ,QD1-999 ,Organic Chemistry ,Androstane-3,17-diol ,Gastrointestinal Microbiome ,Germ Cells ,Endocrinology ,Hormone - Abstract
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.
- Published
- 2021
21. Identification of a novel off-target of paroxetine: Possible role in sexual dysfunction induced by this SSRI antidepressant drug
- Author
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Silvia Giatti, Alessandro Di Domizio, Silvia Diviccaro, Lucia Cioffi, Iacopo Marmorini, Eva Falvo, Donatella Caruso, Alessandro Contini, and Roberto Cosimo Melcangi
- Subjects
Inorganic Chemistry ,Organic Chemistry ,Spectroscopy ,Analytical Chemistry - Published
- 2022
22. Allopregnanolone: An overview on its synthesis and effects
- Author
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Lucia Cioffi, Silvia Giatti, Silvia Diviccaro, Eva Falvo, and Roberto Cosimo Melcangi
- Subjects
Drug ,medicine.medical_specialty ,Neuroactive steroid ,Allosteric modulator ,Endocrine and Autonomic Systems ,Chemistry ,Endocrinology, Diabetes and Metabolism ,media_common.quotation_subject ,Metabolite ,Allopregnanolone ,Pregnanolone ,Neuroprotection ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,medicine ,Receptor ,Neurosteroids ,Progesterone ,Drug metabolism ,media_common - Abstract
Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the synthesis of this neuroactive steroid occurring in the nervous system is discussed with respect to physiological and pathological conditions. In addition, its physiological and neuroprotective effects are also reported. Interestingly, the levels of this neuroactive steroid, as well as its effects, are sex-dimorphic, suggesting a possible gender medicine based on this neuroactive steroid for neurological disorders. However, allopregnanolone presents low bioavailability and extensive hepatic metabolism, limiting its use as a drug. Therefore, synthetic analogues or a different therapeutic strategy able to increase allopregnanolone levels have been proposed to overcome any pharmacokinetic issues.
- Published
- 2021
23. Author response for 'Allopregnanolone: An overview on its synthesis and effects'
- Author
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Eva Falvo, Lucia Cioffi, Silvia Giatti, Roberto Cosimo Melcangi, and Silvia Diviccaro
- Subjects
chemistry.chemical_compound ,chemistry ,Allopregnanolone ,Psychology ,Neuroscience - Published
- 2021
24. Neuroactive steroids, neurosteroidogenesis and sex
- Author
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Luis M. Garcia-Segura, George E. Barreto, Roberto Cosimo Melcangi, Silvia Giatti, Ministero dell'Istruzione, dell'Università e della Ricerca, Colciencias (Colombia), Ministerio de Economía, Industria y Competitividad (España), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (España), Instituto de Salud Carlos III, and European Commission
- Subjects
Male ,0301 basic medicine ,Nervous system ,medicine.medical_specialty ,Neuroactive steroid ,Biology ,Neuroprotection ,Synaptic plasticity ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Humans ,Testosterone ,Nervous System Physiological Phenomena ,Epigenetics ,Progesterone ,Neurons ,Sex Characteristics ,Estradiol ,General Neuroscience ,microRNAs ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Steroidogenesis ,Pregnenolone ,Steroid receptors ,Female ,Neurosteroids ,Neuroscience ,030217 neurology & neurosurgery ,Hormone ,medicine.drug - Abstract
The nervous system is a target and a source of steroids. Neuroactive steroids are steroids that target neurons and glial cells. They include hormonal steroids originated in the peripheral glands, steroids locally synthesized by the neurons and glial cells (neurosteroids) and synthetic steroids, some of them used in clinical practice. Here we review the mechanisms of synthesis, metabolism and action of neuroactive steroids, including the role of epigenetic modifications and the mitochondria in their sex specific actions. We examine sex differences in neuroactive steroid levels under physiological conditions and their role in the establishment of sex dimorphic structures in the nervous system and sex differences in its function. In addition, particular attention is paid to neuroactive steroids under pathological conditions, analyzing how pathology alters their levels and their role as neuroprotective factors, considering the influence of sex in both cases., This research was supported by grants from MIUR Progetto Eccellenza. We also acknowledge support from Fondazione CARIPLO (Rif.2012-0547), Colciencias (Convocatoria 777-2017, Contract #120377757021), Ministerio de Economía, Industria y Competitividad (MINECO), Spain (grant numbers BFU2014–51836-C2-1-R and BFU2017-82754-R), CIBER de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain and Fondos Feder.
- Published
- 2019
25. Contributors
- Author
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Mareike Albert, C. Álvarez-Zaragoza, Brenda Angulo, Pauline Maciel August, Eva Ausó, André Rocha Barbosa, Renata Bartesaghi, Soledad Bárez-López, Dafna Ben Bashat, Liat Ben-Sira, Johanna Bendas, Christine Bibby, John W. Bigbee, Byron K.Y. Bitanihirwe, James A. Bourne, Antoine Bouyeure, Helena Brentani, J. Peter H. Burbach, Joshua A. Burk, F.J. Calabro, Victor Hugo Calegari de Toledo, Rita M. Cantor, Brian Chiou, Clodagh Cogley, Ilona Croy, Jorge Davila, Cheryl L. Dickter, Silvia Diviccaro, Stephanie D’Souza, Jeroen Dudink, Claire Enea-Drapeau, Carmen Espinós, Sade J. Faneyte, Arthur Sant’Anna Feltrin, Hilde Feys, Gianluca Gallo, A.A. García-Contreras, Laura Gaspari, Silvia Giatti, Courtney Gilchrist, Juan Antonio González-Barrios, Marisel González-Maya, Mihaela Grigore, Ana-Maria Grigore, Carmen Grijota-Martínez, Carlos M. Gómez, Ana Guadaño-Ferraz, Sandra Guidi, Loredana-Maria Himiniuc, Freek E. Hoebeek, Janine Hoffmann, Kurt L. Hoffman, Jihane Homman-Ludiye, Kiho Im, Iris Žunić Išasegi, Keiichi Ishihara, Ismael Jiménez-Estrada, Vijaya Kancherla, Tomohisa Katada, Ana Katušić, Sahar Kiani, Jeongtae Kim, Gregory W. Kirschen, Masaaki Kitada, Caroline Peres Klein, Katrijn Klingels, Shiori Kobayashi, Yoshinori Kosaka, Ivica Kostović, Mirna Kostović Srzentić, Željka Krsnik, Jennifer K. Lowe, Daniela López-Espíndola, B. Luna, Vincenzo Lupo, Zilu Ma, Lisa Mailleux, Louis N. Manganas, Vladimir Martínez-Álvarez, Mariana Maschietto, Cristiane Matté, Nadia McMillan, Roberto Cosimo Melcangi, Angel I. Melo, Elka Miller, Sara Mirsadeghi, A.J. Mitchell, Edwin A. Mitchell, Esraa Mohamed, Ruth Monaghan, Ana Montero-Pedrazuela, C.W. Musket, Marion Noulhiane, Tadahiro Numakawa, Haruki Odaka, Akihito Okabe, Fiadhnait O’Keeffe, Els Ortibus, Xianhua Piao, Hector Ramiro Quintá, A. Rea-Rosas, Aiguo Ren, Elena I. Rodríguez-Martínez, Liangyou Rui, Francisco J. Ruíz-Martínez, Hiroyuki Sakurai, Paula Sancho, Carmen Sato-Bigbee, Matthew Selby, Himanshu Sharma, Chigusa Shimizu-Okabe, Cristina Simon-Martinez, M.-O. Soyer-Gobillard, Fiorenza Stagni, Elinor L. Sullivan, Charles Sultan, Masanobu Sunagawa, Ana Carolina Tahira, Chitoshi Takayama, Akihito Takeuchi, Abhijeet Taori, Margot J. Taylor, B. Tervo-Clemmens, Verena Theis, Carsten Theiss, Deanne Kim Thompson, John M.D. Thompson, Bogdan Florin Toma, Raphaele Tsao, Charline Urbain, Verônica Luiza Vale Euclydes Colovati, E.M. Vásquez-Garibay, Karen E. Waldie, Linlin Wang, Tsung-Ung Wilson Woo, Paul Yao, René Zempoalteca, and Nanyin Zhang
- Published
- 2021
26. Neuroactive steroids and neurodevelopment
- Author
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Silvia Diviccaro, Silvia Giatti, and Roberto Cosimo Melcangi
- Subjects
Neuroactive steroid ,Brain development ,medicine.medical_treatment ,Neurogenesis ,Brain maturation ,medicine ,Biology ,Receptor ,Neuroscience ,Perinatal period ,Settore MED/13 - Endocrinologia ,Hormone ,Steroid - Abstract
Steroid hormones are key players in the development of vertebrate brain. Through the interaction with specific receptors, they regulate myelination, neurogenesis, and brain maturation, as well as sex-specific features in developing brain, which will be present in adult subjects. The correct levels of such molecules and the timing when they exert their action are crucial for a proper brain development. In this chapter, the physiological actions of steroid hormones able to modulate brain functions (i.e., neuroactive steroids) have been described. Moreover, neuroactive steroid-level perturbations in the perinatal period able to produce behavioral alterations during adulthood in animal models as well as in human subjects have been here discussed.
- Published
- 2021
27. Alterations of gut microbiota composition in post-finasteride patients: a pilot study
- Author
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Silvia Diviccaro, A D Macandog, Eva Falvo, Silvia Giatti, Francesca Borgo, Roberto Cosimo Melcangi, Guido Cavaletti, Borgo, F, Macandog, A, Diviccaro, S, Falvo, E, Giatti, S, Cavaletti, G, and Melcangi, R
- Subjects
0301 basic medicine ,Male ,Endocrinology, Diabetes and Metabolism ,Physiology ,Disease ,Gut flora ,Gut microbiota-brain axi ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,5-alpha Reductase Inhibitors ,RNA, Ribosomal, 16S ,Correlation of Data ,education.field_of_study ,biology ,Depression ,Finasteride ,Biodiversity ,Middle Aged ,Physical Functional Performance ,Major depressive disorder ,Original Article ,Sample collection ,medicine.symptom ,Androgenic alopecia ,Drug-Related Side Effects and Adverse Reactions ,Fecal microbiota ,Population ,Sexual dysfunction ,digestive system ,03 medical and health sciences ,medicine ,Humans ,Cognitive Dysfunction ,education ,Feces ,business.industry ,Alopecia ,Sequence Analysis, DNA ,medicine.disease ,biology.organism_classification ,Gastrointestinal Microbiome ,Sexual Dysfunction, Physiological ,030104 developmental biology ,chemistry ,Gut microbiota-brain axis ,5alpha-reductase ,business ,030217 neurology & neurosurgery - Abstract
Purpose Post-finasteride syndrome (PFS) has been reported in a subset of patients treated with finasteride (an inhibitor of the enzyme 5alpha-reductase) for androgenetic alopecia. These patients showed, despite the suspension of the treatment, a variety of persistent symptoms, like sexual dysfunction and cognitive and psychological disorders, including depression. A growing body of literature highlights the relevance of the gut microbiota-brain axis in human health and disease. For instance, alterations in gut microbiota composition have been reported in patients with major depressive disorder. Therefore, we have here analyzed the gut microbiota composition in PFS patients in comparison with a healthy cohort. Methods Fecal microbiota of 23 PFS patients was analyzed by 16S rRNA gene sequencing and compared with that reported in ten healthy male subjects. Results Sexual dysfunction, psychological and cognitive complaints, muscular problems, and physical alterations symptoms were reported in more than half of the PFS patients at the moment of sample collection. The quality sequence check revealed a low library depth for two fecal samples. Therefore, the gut microbiota analyses were conducted on 21 patients. The α-diversity was significantly lower in PFS group, showing a reduction of richness and diversity of gut microbiota structure. Moreover, when visualizing β-diversity, a clustering effect was found in the gut microbiota of a subset of PFS subjects, which was also characterized by a reduction in Faecalibacterium spp. and Ruminococcaceae UCG-005, while Alloprevotella and Odoribacter spp were increased compared to healthy control. Conclusion Gut microbiota population is altered in PFS patients, suggesting that it might represent a diagnostic marker and a possible therapeutic target for this syndrome.
- Published
- 2021
28. Steroidogenic machinery in the adult rat colon
- Author
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Silvia Diviccaro, Roberto Cosimo Melcangi, Eva Falvo, Silvia Giatti, Luis M. Garcia-Segura, Donatella Caruso, Francesca Borgo, Ministero dell'Istruzione, dell'Università e della Ricerca, Post-Finasteride Syndrome Foundation, Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (España), Agencia Estatal de Investigación (España), and European Commission
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Neuroactive steroid ,medicine.drug_class ,Colon ,Steroidogenic enzymes ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Clinical Biochemistry ,chromatography-tandem mass spectrometry ,Biochemistry ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Animals ,Gut ,Molecular Biology ,Testosterone ,Cerebral Cortex ,Liquid ,Chemistry ,Neuroactive steroids ,Cell Biology ,Androgen ,Steroid hormone ,030104 developmental biology ,Sex steroids ,030220 oncology & carcinogenesis ,Dihydrotestosterone ,Pregnenolone ,Molecular Medicine ,Steroids ,Gastrointestinal function ,medicine.drug ,Hormone - Abstract
Gastrointestinal function is known to be regulated by steroid molecules produced by the gonads, the adrenal glands and the gut microbiota. However, we have a limited knowledge on the functional significance of local steroid production by gastrointestinal tract tissue. On this basis, we have here evaluated, as a first methodological approach, the expression of steroidogenic molecules and the local levels of key steroids in the male rat colon. Our findings indicate that the colon tissue expresses molecules involved in the early steps of steroidogenesis and in the consecutive synthesis and metabolism of steroid hormones, such as progesterone, testosterone and 17β-estradiol. In addition, the levels of the steroid hormone precursor pregnenolone and the levels of active metabolites of progesterone and testosterone, such as dihydroprogesterone, tetrahydroprogesterone, dihydrotestosterone and 17β-estradiol, were higher in colon than in plasma. Higher levels of the androgen metabolite 3α-diol were detected in the colon in comparison with another non-classical steroidogenic tissue, such as the cerebral cortex. These findings suggest the existence of local steroid synthesis and metabolism in the colon, with the production of active steroid metabolites that may impact on the activity of the enteric nervous system and on the composition of the gut microbiota., This work was supported from MIUR “Progetto Eccellenza” and PON “Ricerca e Innovazione” PerMedNet -project ARS01_01226; Post-Finasteride Foundation; CIBERFES and Agencia Estatal de Investigación, Spain (BFU2017-82754-R), co-funded by Fondo Europeo de Desarrollo Regional (FEDER).
- Published
- 2020
29. ENZIMA 5ALFA-REDUTTASI NEL CERVELLO: UNA STORIA ANCORA COMPLICATA
- Author
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Roberto Cosimo Melcangi
- Subjects
macromolecular substances - Abstract
The enzyme 5alpha-reductase represents an important enzymatic pathway of the sex steroids, such as progesterone and testosterone. Its physiophatological role in the nervous system will be here discussed. Indeed, despite several observations have been obtained so far, several diagnostic and therapeutic aspects need to be clarified.
- Published
- 2020
30. Neuroactive steroids and the new decade
- Author
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Roberto Cosimo Melcangi and Giancarlo Panzica
- Subjects
medicine.medical_specialty ,Neuroactive steroid ,Endocrine and Autonomic Systems ,business.industry ,Endocrinology, Diabetes and Metabolism ,MEDLINE ,Brain ,Bioinformatics ,Cellular and Molecular Neuroscience ,Endocrinology ,Internal medicine ,nerous system ,Animals ,Humans ,Medicine ,neurosteroids ,business ,steroids, nerous system, neurosteroids ,steroids - Published
- 2020
31. Sex dimorphism in an animal model of multiple sclerosis: Focus on pregnenolone synthesis
- Author
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Luis M. Garcia-Segura, Roberta Rigolio, Silvia Giatti, Roberto Cosimo Melcangi, Eva Falvo, Guido Cavaletti, Silvia Diviccaro, Donatella Caruso, Agencia Estatal de Investigación (España), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (España), Instituto de Salud Carlos III, European Commission, Giatti, S, Rigolio, R, Diviccaro, S, Falvo, E, Caruso, D, Garcia-Segura, L, Cavaletti, G, and Melcangi, R
- Subjects
0301 basic medicine ,Nervous system ,Male ,medicine.medical_specialty ,Neuroactive steroid ,Encephalomyelitis, Autoimmune, Experimental ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Biochemistry ,Substrate Specificity ,Multiple sclerosis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Oxysterol ,Internal medicine ,medicine ,Animals ,Humans ,Multiple sclerosi ,Molecular Biology ,Sex Characteristics ,Spinal cord ,business.industry ,Cholesterol ,Experimental autoimmune encephalomyelitis ,Cell Biology ,Oxysterols ,medicine.disease ,Rats ,Sexual dimorphism ,Disease Models, Animal ,Kinetics ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Pregnenolone ,Molecular Medicine ,Female ,business ,Neurosteroids ,medicine.drug - Abstract
Neuroactive steroids, molecules produced from cholesterol in steroidogenic cells (i.e., peripheral glands and nervous system) are physiological modulators and protective agents of nervous function. A possible role for neuroactive steroids in the sex-dimorphic clinical manifestation, onset and progression of Multiple Sclerosis (MS) has been recently suggested. To explore this possibility, we assessed the synthesis of the first steroidogenic product (pregnenolone; PREG) in the spinal cord of experimental autoimmune encephalomyelitis rats, a MS model. Data obtained indicate that the synthesis of PREG in the spinal cord is altered by the pathology in a sex-dimorphic way and depending on the pathological progression. Indeed, in male spinal cord the synthesis was already decreased at the acute phase of the disease (i.e., 14 days post induction - dpi) and maintained low during the chronic phase (i.e., 45 dpi), while in females this effect was observed only at the chronic phase. Substrate availability had also a role in the sex-dimorphic kinetics. Indeed, at the chronic phase, male animals showed a reduction in the levels of free cholesterol coupled to alteration of cholesterol metabolism into oxysterols; these effects were not observed in female animals. These findings suggest that the comprehension of the neurosteroidogenic processes could be relevant to better understand the sexual dimorphism of MS and to possibly design sex-oriented therapeutic strategies based on neuroactive steroids., We also acknowledge support from Agencia Estatal de Investigación, Spain (grant number BFU2017-82754-R), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain and Fondos Feder to LM.G-S.
- Published
- 2020
32. Neuroactive Steroids and Sex-Dimorphic Nervous Damage Induced by Diabetes Mellitus
- Author
-
Silvia Diviccaro, Silvia Giatti, and Roberto Cosimo Melcangi
- Subjects
Male ,0301 basic medicine ,Neuroactive steroid ,Central nervous system ,Type 2 diabetes ,Bioinformatics ,Nervous System ,Neuroprotection ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Myelin ,0302 clinical medicine ,Diabetes mellitus ,Diabetes Mellitus ,Animals ,Humans ,Medicine ,Metabolic disease ,Sex Characteristics ,business.industry ,Cell Biology ,General Medicine ,medicine.disease ,Sexual dimorphism ,030104 developmental biology ,medicine.anatomical_structure ,Female ,Steroids ,business ,030217 neurology & neurosurgery - Abstract
Diabetes mellitus is a metabolic disease where improper glycaemic control may induce severe complications in different organs. In this review, we will discuss alterations occurring in peripheral and central nervous system of patients with type 1 (i.e., insulin dependent diabetes mellitus,) or type 2 diabetes (i.e., non-insulin dependent diabetes mellitus), as well as related experimental models. A particular focus will be on the role exerted by neuroactive steroids (i.e., important regulators of nervous functions) in the nervous damage induced by diabetes. Indeed, the nervous levels of these molecules are affected by the pathology and, in agreement, their neuroprotective effects have been reported. Interestingly, the sex is another important variable. As discussed, nervous diabetic complications show sex dimorphic features in term of incidence, functional outcomes and neuroactive steroid levels. Therefore, these features represent an interesting background for possible sex-oriented therapies with neuroactive steroids aimed to counteract nervous damage observed in diabetic pathology.
- Published
- 2018
33. Post-finasteride syndrome and post-SSRI sexual dysfunction: two sides of the same coin?
- Author
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Silvia Diviccaro, Silvia Giatti, Giancarlo Panzica, and Roberto Cosimo Melcangi
- Subjects
Sexual behavior ,Male ,0301 basic medicine ,Serotonin ,Neuroactive steroid ,Side effect ,Dopamine ,Libido ,Endocrinology, Diabetes and Metabolism ,Iatrogenic Disease ,Bioinformatics ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,medicine ,Humans ,Sex organ ,Depression ,business.industry ,Finasteride ,Neuroactive steroids ,Alopecia ,Syndrome ,Antidepressive Agents ,Diabetes and Metabolism ,Sexual Dysfunction, Physiological ,030104 developmental biology ,Sexual dysfunction ,medicine.anatomical_structure ,chemistry ,Female ,medicine.symptom ,business ,Selective Serotonin Reuptake Inhibitors ,030217 neurology & neurosurgery ,Penis ,medicine.drug - Abstract
Sexual dysfunction is a clinical condition due to different causes including the iatrogenic origin. For instance, it is well known that sexual dysfunction may occur in patients treated with antidepressants like selective serotonin reuptake inhibitors (SSRI). A similar side effect has been also reported during treatment with finasteride, an inhibitor of the enzyme 5alpha-reductase, for androgenetic alopecia. Interestingly, sexual dysfunction persists in both cases after drug discontinuation. These conditions have been named post-SSRI sexual dysfunction (PSSD) and post-finasteride syndrome (PFS). In particular, feeling of a lack of connection between the brain and penis, loss of libido and sex drive, difficulty in achieving an erection and genital paresthesia have been reported by patients of both conditions. It is interesting to note that the incidence of these diseases is probably so far underestimated and their etiopathogenesis is not sufficiently explored. To this aim, the present review will report the state of art of these two different pathologies and discuss, on the basis of the role exerted by three different neuromodulators such as dopamine, serotonin and neuroactive steroids, whether the persistent sexual dysfunction observed could be determined by common mechanisms.
- Published
- 2018
34. Diabetes induces mitochondrial dysfunction and alters cholesterol homeostasis and neurosteroidogenesis in the rat cerebral cortex
- Author
-
Simone Romano, Luis M. Garcia-Segura, Nico Mitro, Donatella Caruso, Matteo Audano, Roberto Cosimo Melcangi, Silvia Diviccaro, Silvia Giatti, Marzia Pesaresi, and Roberto Spezzano
- Subjects
Male ,0301 basic medicine ,Nervous system ,medicine.medical_specialty ,Neuroactive steroid ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Mitochondrion ,Biochemistry ,Diabetes Mellitus, Experimental ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Diabetes mellitus ,Internal medicine ,medicine ,Animals ,Homeostasis ,Molecular Biology ,Cerebral Cortex ,Neurons ,Cholesterol ,business.industry ,Cell Biology ,medicine.disease ,Streptozotocin ,Mitochondria ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Cerebral cortex ,Pregnenolone ,Molecular Medicine ,Steroids ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
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.
- Published
- 2018
35. Axonal transport in a peripheral diabetic neuropathy model: sex-dimorphic features
- Author
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Donatella Caruso, Simone Romano, Silvia Giatti, Nico Mitro, Roberto Spezzano, Roberto Cosimo Melcangi, Silvia Diviccaro, Luis M. Garcia-Segura, Tiziana Borsello, and Marzia Pesaresi
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Neuroactive steroid ,Diabetic neuropathy ,Myosin Type V ,Kinesins ,lcsh:Medicine ,Sciatic nerve ,Biology ,Mitochondrion ,Axonal Transport ,lcsh:Physiology ,Diabetes Mellitus, Experimental ,Rats, Sprague-Dawley ,Gender Studies ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Diabetic Neuropathies ,Ganglia, Spinal ,Internal medicine ,medicine ,Animals ,Gonadal Steroid Hormones ,Dorsal root ganglia ,Testosterone ,KIF1A ,Sex Characteristics ,lcsh:QP1-981 ,Streptozotocin ,Research ,lcsh:R ,Neuroactive steroids ,medicine.disease ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Mitochondria ,030104 developmental biology ,Dihydrotestosterone ,Axoplasmic transport ,Female ,Energy source ,030217 neurology & neurosurgery ,medicine.drug - Abstract
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., The financial support of Fondazione CARIPLO (Rif. 2012-0547) to R. C. Melcangi is gratefully acknowledged.
- Published
- 2018
36. Neuroactive steroids and diabetic complications in the nervous system
- Author
-
Roberto Cosimo Melcangi, Rosa Mastrangelo, Marzia Pesaresi, Maurizio D'Antonio, Silvia Diviccaro, Simone Romano, Nico Mitro, Silvia Giatti, and Donatella Caruso
- Subjects
Male ,0301 basic medicine ,Nervous system ,medicine.medical_specialty ,Neuroactive steroid ,Context (language use) ,Biology ,Diabetes Complications ,03 medical and health sciences ,0302 clinical medicine ,Diabetic Neuropathies ,Diabetes mellitus ,Internal medicine ,medicine ,Animals ,Humans ,Gonadal Steroid Hormones ,Myelin Sheath ,Testosterone ,Brain Diseases ,Sex Characteristics ,Endocrine and Autonomic Systems ,Neuropeptides ,medicine.disease ,Streptozotocin ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Peripheral neuropathy ,Peripheral nervous system ,Female ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Important complications of diabetes mellitus in the nervous system are represented by diabetic peripheral neuropathy and diabetic encephalopathy. In this context, an important link is represented by neuroactive steroids (i.e., steroids coming from peripheral glands and affecting nervous functionality as well as directly synthesized in the nervous system). Indeed, diabetes does not only affect the reproductive axis and consequently the levels of sex steroid hormones, but also those of neuroactive steroids. Indeed, as will be here summarized, the levels of these neuromodulators present in the central and peripheral nervous system are affected by the pathology in a sex-dimorphic way. In addition, some of these neuroactive steroids, such as the metabolites of progesterone or testosterone, as well as pharmacological tools able to increase their levels have been demonstrated, in experimental models, to be promising protective agents against diabetic peripheral neuropathy and diabetic encephalopathy.
- Published
- 2018
37. Effect of the 5α-reductase enzyme inhibitor dutasteride in the brain of intact and parkinsonian mice
- Author
-
Nadhir Litim, Marc Morissette, Donatella Caruso, Thérèse Di Paolo, and Roberto Cosimo Melcangi
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Dopamine ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Vesicular monoamine transporter 2 ,Biochemistry ,Neuroprotection ,03 medical and health sciences ,chemistry.chemical_compound ,5-alpha Reductase Inhibitors ,0302 clinical medicine ,Endocrinology ,Dopamine receptor D1 ,Internal medicine ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,Testosterone Congeners ,Molecular Biology ,Testosterone ,Dopamine Plasma Membrane Transport Proteins ,Behavior, Animal ,biology ,Receptors, Dopamine D2 ,Receptors, Dopamine D1 ,MPTP ,Brain ,MPTP Poisoning ,Isopregnanolone ,Cell Biology ,Dutasteride ,3. Good health ,Mice, Inbred C57BL ,Neuroprotective Agents ,030104 developmental biology ,nervous system ,chemistry ,Vesicular Monoamine Transport Proteins ,Dihydrotestosterone ,Androgens ,biology.protein ,Molecular Medicine ,Psychomotor Performance ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Dutasteride is a 5alpha-reductase inhibitor in clinical use to treat endocrine conditions. The present study investigated the neuroprotective mechanisms of action of dutasteride in intact and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice using a low dose of MPTP not affecting motor activity modeling early stages of Parkinson's disease (PD). We hypothesized that dutasteride neuroprotection is due to altered steroids levels. Dutasteride pre-treatment prevented loss of striatal dopamine (DA) and its metabolite DOPAC. Dutasteride decreased effects of MPTP on striatal dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2) and D2 DA receptor specific binding while D1 receptor specific binding remained unchanged. Dutasteride enhanced DAT specific binding and the glycosylated form of DAT in intact mice. MPTP-lesioned mice had plasma and brain testosterone and dihydrotestosterone levels lower than control mice whereas progesterone and its metabolites (dihydroprogesterone, isopregnanolone and tetrahydroprogesterone) pathway showed increases. Dutasteride treatment by inhibiting transformation of progesterone and testosterone to its metabolites elevated plasma and brain concentrations of testosterone compared to MPTP mice and decreased DHT levels in intact mice. Plasma and brain estradiol levels were low and remained unchanged by MPTP and/or dutasteride treatment. Dutasteride treatment did not affect striatal phosphorylation of Akt and its downstream substrate GSK3β as well as phosphorylation of ERK1/2 in intact and MPTP lesioned MPTP mice. Striatal glial fibrillary acidic protein (GFAP) levels were markedly elevated in MPTP compared to control mice and dutasteride reduced GFAP levels in MPTP mice. Treatment with dutasteride post-lesion left unchanged striatal DA levels. These results suggest dutasteride as promising drug for PD neuroprotection.
- Published
- 2017
38. Neuroprotective effects of low fat-protein diet in the P301L mouse model of tauopathy
- Author
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Alessia Di Giancamillo, Roberto Cosimo Melcangi, Cinzia Domeneghini, Giuliano Grignaschi, Lucia Buccarello, and Tiziana Borsello
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Tau protein ,Hippocampus ,Mice, Transgenic ,tau Proteins ,Neuroprotection ,Eating ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Weight loss ,Internal medicine ,Diet, Protein-Restricted ,In Situ Nick-End Labeling ,medicine ,Animals ,Neurons ,Analysis of Variance ,biology ,General Neuroscience ,Body Weight ,Brain ,Recognition, Psychology ,Human brain ,medicine.disease ,Disease Models, Animal ,Neuroprotective Agents ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Tauopathies ,Cerebral cortex ,Exploratory Behavior ,biology.protein ,Female ,Tauopathy ,Alzheimer's disease ,medicine.symptom ,Psychology ,Neuroscience ,Locomotion ,030217 neurology & neurosurgery - Abstract
Tauopathies are a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in the human brain. Although numerous studies in mouse models of Alzheimer disease (AD) have shown a correlation among diet, beta-amyloid and AD onset, little is known about the impact of diet on Tau. We investigated whether a low fat-protein diet (LFPD) may improve lifespan, cognitive and locomotor activity in P301L-tg mouse model of tauopathy. Our data indicate that LFPD has a beneficial effect on these parameters. Tg mice fed with standard diet shown a decrease in body weight, food intake and survival rate if compared to wild type animals. In contrast, LFPD counteracted weight loss, increased mortality and ameliorated cognitive and locomotor performances in tg mice. LFPD also reduced the abnormal accumulation of agglomerates of P-Tau (pathological features of tauopathies) and the expression of apoptotic markers (i.e., TUNEL immunopositive neurons) in the prefrontal cerebral cortex and hippocampus of P301L-tg mice. Interestingly, some of these effects are sex-dependent. For instance, tg females, but not males, fed with LFPD had a significant increase of body weight and a reduction of P-Tau agglomerates compared to tg fed with standard diet. These changes correlated with a more pronounced improvement of cognition and locomotor activity in females than in male tg fed with LFPD. Altogether, these results suggest a sex dependent neuroprotective effect of LFPD in P301L-tg mice, suggesting that lifestyle intervention strategies may be clinically relevant for delaying the onset of cognitive impairment and dementia, especially in females.
- Published
- 2017
39. Sterol regulatory element binding protein-1C knockout mice show altered neuroactive steroid levels in sciatic nerve
- Author
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Donatella Caruso, Silvia Giatti, Roberto Cosimo Melcangi, Nico Mitro, Matteo Audano, Marzia Pesaresi, Gaia Cermenati, Roberto Spezzano, and Silvia Pedretti
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Neuroactive steroid ,Metabolite ,Pharmacology ,Biochemistry ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Testosterone ,Progesterone ,Mice, Knockout ,Chemistry ,medicine.disease ,Sciatic Nerve ,Sterol ,030104 developmental biology ,Peripheral neuropathy ,Endocrinology ,Knockout mouse ,Pregnenolone ,Steroids ,Sciatic nerve ,Sterol Regulatory Element Binding Protein 1 ,030217 neurology & neurosurgery ,Chromatography, Liquid ,medicine.drug - Abstract
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.
- Published
- 2017
40. Diabetes alters myelin lipid profile in rat cerebral cortex: Protective effects of dihydroprogesterone
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Silvia Giatti, Marzia Pesaresi, Matteo Audano, Roberto Cosimo Melcangi, Gaia Cermenati, Roberto Spezzano, Nico Mitro, and Donatella Caruso
- Subjects
Male ,0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Phosphatidylinositols ,Biochemistry ,Rats, Sprague-Dawley ,Myelin ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Tandem Mass Spectrometry ,Myelin Sheath ,Progesterone ,Cerebral Cortex ,biology ,medicine.diagnostic_test ,Lipids ,Sciatic Nerve ,20-alpha-Dihydroprogesterone ,Cholesterol ,medicine.anatomical_structure ,Dihydroprogesterone ,Cerebral cortex ,Molecular Medicine ,medicine.medical_specialty ,Neuroactive steroid ,Phosphatidylserines ,Gas Chromatography-Mass Spectrometry ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Diabetes mellitus ,Internal medicine ,medicine ,Animals ,Molecular Biology ,Gene Expression Profiling ,Myelin Basic Protein ,Cell Biology ,medicine.disease ,Rats ,Myelin basic protein ,030104 developmental biology ,nervous system ,chemistry ,biology.protein ,Lipid profile ,030217 neurology & neurosurgery ,Chromatography, Liquid - Abstract
Due to the emerging association of diabetes with several psychiatric and neurodegenerative events, the evaluation of the effects of this pathology on the brain function has now a high priority in biomedical research. In particular, the effects of diabetes on myelin compartment have been poorly taken into consideration. To this purpose, we performed a deep lipidomic analysis of cortical myelin in the streptozotocin-induced diabetic rat model. In male rats three months of diabetes induced an extensive alterations in levels of phosphatidylcholines and phosphatidylethanolamines (the main species present in myelin membranes), plasmalogens as well as phosphatidylinositols and phosphatidylserines. In addition, the levels of cholesterol and myelin basic protein were also decreased. Because these lipids exert important functional and structural roles in the myelin compartment, our data indicate that cerebral cortex myelin is severely compromised in diabetic status. Treatment for one-month with a metabolite of progesterone, dihydroprogesterone, restored the lipid and protein myelin profiles to the levels observed in non-diabetic animals. These data suggest the potential of therapeutic efficacy of DHP to restore myelin in the diabetic brain.
- Published
- 2017
41. Short-term effects of diabetes on neurosteroidogenesis in the rat hippocampus
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Silvia Diviccaro, Matteo Audano, Donatella Caruso, Roberto Cosimo Melcangi, Nico Mitro, Roberto Spezzano, Luis M. Garcia-Segura, and Simone Romano
- Subjects
Central Nervous System ,Male ,0301 basic medicine ,medicine.medical_specialty ,Neuroactive steroid ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Biology ,Hippocampus ,Thiobarbituric Acid Reactive Substances ,Biochemistry ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Tandem Mass Spectrometry ,Internal medicine ,Diabetes Mellitus ,medicine ,Animals ,Homeostasis ,Testosterone ,Molecular Biology ,Progesterone ,Neurons ,SOAT1 ,Cholesterol side-chain cleavage enzyme ,Steroidogenic acute regulatory protein ,Dihydrotestosterone ,Isopregnanolone ,Cell Biology ,Mitochondria ,Rats ,Oxidative Stress ,Cholesterol ,030104 developmental biology ,Pregnenolone ,Molecular Medicine ,Steroids ,030217 neurology & neurosurgery ,Chromatography, Liquid ,medicine.drug - Abstract
Diabetes may induce neurophysiological and structural changes in the central nervous system (i.e., diabetic encephalopathy). We here explored whether the levels of neuroactive steroids (i.e., neuroprotective agents) in the hippocampus may be altered by short-term diabetes (i.e., one month). To this aim, by liquid chromatography-tandem mass spectrometry we observed that in the experimental model of the rat raised diabetic by streptozotocin injection, one month of pathology induced changes in the levels of several neuroactive steroids, such as pregnenolone, progesterone and its metabolites (i.e., tetrahydroprogesterone and isopregnanolone) and testosterone and its metabolites (i.e., dihydrotestosterone and 3α-diol). Interestingly these brain changes were not fully reflected by the plasma level changes, suggesting that early phase of diabetes directly affects steroidogenesis and/or steroid metabolism in the hippocampus. These concepts are also supported by the findings that crucial steps of steroidogenic machinery, such as the gene expression of steroidogenic acute regulatory protein (i.e., molecule involved in the translocation of cholesterol into mitochondria) and cytochrome P450 side chain cleavage (i.e., enzyme converting cholesterol into pregnenolone) and 5α-reductase (enzyme converting progesterone and testosterone into their metabolites) are also affected in the hippocampus. In addition, cholesterol homeostasis as well as the functionality of mitochondria, a key organelle in which the limiting step of neuroactive steroid synthesis takes place, are also affected. Data obtained indicate that short-term diabetes alters hippocampal steroidogenic machinery and that these changes are associated with impaired cholesterol homeostasis and mitochondrial dysfunction in the hippocampus, suggesting them as relevant factors for the development of diabetic encephalopathy.
- Published
- 2017
42. Post-finasteride syndrome: An emerging clinical problem
- Author
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Silvia Giatti, Roberto Cosimo Melcangi, and Silvia Diviccaro
- Subjects
medicine.medical_specialty ,Physiology ,media_common.quotation_subject ,Sexual dysfunction ,Orgasm ,Biochemistry ,lcsh:RC346-429 ,lcsh:RC321-571 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Drug withdrawal ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Adverse effect ,Molecular Biology ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Androgenetic alopecia ,lcsh:Neurology. Diseases of the nervous system ,media_common ,Endocrine and Autonomic Systems ,business.industry ,Depression ,lcsh:QP351-495 ,Finasteride ,Neuroactive steroids ,medicine.disease ,Dutasteride ,030227 psychiatry ,Erectile dysfunction ,lcsh:Neurophysiology and neuropsychology ,chemistry ,Articles from the Special Issue on Allopregnanolone role in the neurobiology of stress and mood disorders ,Edited by Graziano Pinna ,Anxiety ,5alpha-reductase ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
The presence of side effects during pharmacological treatment is unfortunately a quite common problem. In this review, we focused our attention on adverse events related to 5 alpha-reductase (5α-R) inhibitors (i.e., finasteride and dutasteride), approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia (AGA). Although these drugs are generally well tolerated, many reports described adverse effects in men during treatment, such as sexual dysfunction and mood alteration. In addition, it has been also reported that persistent side effects may occur in some AGA patients. This condition, termed post-finasteride syndrome (PFS) is characterized by sexual side effects (i.e., low libido, erectile dysfunction, decreased arousal and difficulty in achieving orgasm), depression, anxiety and cognitive complaints that are still present despite drug withdrawal. Indeed, some national agencies (e.g., Swedish Medical Products Agency, the Medicines and Healthcare Products Regulatory Agency of UK and the U.S. Food and Drug Administration) required to include multiple persistent side effects within the finasteride labels. As here reported, these observations are mainly based on self-reporting of the symptomatology by the patients and few clinical studies have been performed so far. In addition, molecular mechanisms and/or genetic determinants behind such adverse effects have been poorly explored both in patients and animal models. Therefore, results here discussed indicate that PFS is an emerging clinical problem that needs to be further elucidated.
- Published
- 2019
43. Lipotoxicity, neuroinflammation, glial cells and oestrogenic compounds
- Author
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George E. Barreto, Oscar Hidalgo-Lanussa, Ghulam Md Ashraf, Valentina Echeverria, Eliana Baez-Jurado, Amirhossein Sahebkar, Roberto Cosimo Melcangi, and Luis M. Garcia-Segura
- Subjects
obesity ,Cell signaling ,medicine.medical_specialty ,oestrogens ,Neuroactive steroid ,Endocrinology, Diabetes and Metabolism ,microglia ,030209 endocrinology & metabolism ,Fatty Acids, Nonesterified ,Neuroprotection ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Animals ,Humans ,Medicine ,neurodegenerative diseases ,Cognitive decline ,Neuroinflammation ,Gliogenesis ,Inflammation ,Endocrine and Autonomic Systems ,business.industry ,Neurogenesis ,Brain ,Estrogens ,lipotoxicity ,Lipotoxicity ,neurosteroids ,business ,Neuroglia ,030217 neurology & neurosurgery ,estrogens ,Signal Transduction - Abstract
peer-reviewed The high concentrations of free fatty acids as a consequence of obesity and overweight have become risk factors for the development of different diseases including neurodegenerative ailments. Free fatty acids (FAs) are strongly related to inflammatory events, causing cellular and tissue alterations in the brain, including cell death, deficits in neurogenesis and gliogenesis and cognitive decline. It has been reported that people with a high body mass index have a higher risk of suffering from Alzheimer's disease. Hormones such as estradiol not only have beneficial effects on brain tissue but also exert some adverse effects on peripheral tissues including the ovary and breast. For this reason, some studies have evaluated the protective effect of estrogen receptor (ER) agonists with more specific tissue activities, such as the neuroactive steroid tibolone. Activation of ERs positively affects the expression of pro-survival factors and cell signaling pathways, thus promoting cell survival. This review aims to discuss the relationship between lipotoxicity and the development of neurodegenerative diseases. We also elaborate on the cellular and molecular mechanisms involved in neuroprotection induced by estrogens. ACCEPTED peer-reviewed
- Published
- 2019
44. Sex differences in steroid levels and steroidogenesis in the nervous system: Physiopathological role
- Author
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Silvia Diviccaro, Silvia Giatti, Barbara Viviani, Luis M. Garcia-Segura, Donatella Caruso, Roberto Cosimo Melcangi, and Melania Maria Serafini
- Subjects
0301 basic medicine ,Nervous system ,Male ,medicine.medical_specialty ,Parkinson's disease ,Neuroactive steroid ,Diabetic neuropathy ,Multiple Sclerosis ,medicine.medical_treatment ,Biology ,TSPO ligands ,Nervous System ,Steroid ,03 medical and health sciences ,LXR ligands ,0302 clinical medicine ,Traumatic brain injury ,Alzheimer Disease ,Internal medicine ,medicine ,Animals ,Humans ,Gonadal Steroid Hormones ,Sex Characteristics ,Endocrine and Autonomic Systems ,Multiple sclerosis ,Mental Disorders ,Brain ,Neurodegenerative Diseases ,Parkinson Disease ,5α-Reductase ,Alzheimer's disease ,medicine.disease ,5α reductase ,Affective disorders ,Stroke ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Female ,Steroids ,Nervous System Diseases ,030217 neurology & neurosurgery ,Hormone - Abstract
The nervous system, in addition to be a target for steroid hormones, is the source of a variety of neuroactive steroids, which are synthesized and metabolized by neurons and glial cells. Recent evidence indicates that the expression of neurosteroidogenic proteins and enzymes and the levels of neuroactive steroids are different in the nervous system of males and females. We here summarized the state of the art of neuroactive steroids, particularly taking in consideration sex differences occurring in the synthesis and levels of these molecules. In addition, we discuss the consequences of sex differences in neurosteroidogenesis for the function of the nervous system under healthy and pathological conditions and the implications of neuroactive steroids and neurosteroidogenesis for the development of sex-specific therapeutic interventions.
- Published
- 2019
45. 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
- Author
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Silvia Diviccaro, Matteo Barcella, Elisa Borghi, Silvia Giatti, Luis M. Garcia-Segura, Francesca Borgo, José Luis Trejo, Roberto Cosimo Melcangi, Ministero dell'Istruzione, dell'Università e della Ricerca, Post-Finasteride Syndrome Foundation, Ministerio de Economía, Industria y Competitividad (España), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (España), Instituto de Salud Carlos III, and Federación Española de Enfermedades Raras
- Subjects
Male ,medicine.medical_specialty ,Cholestenone 5 alpha-Reductase ,Neuroactive steroid ,Neuroimmunomodulation ,Endocrinology, Diabetes and Metabolism ,Neurogenesis ,Hippocampus ,Gut microbiota ,Biology ,Hippocampal formation ,Subgranular zone ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,5-alpha Reductase Inhibitors ,Internal medicine ,medicine ,Animals ,Biological Psychiatry ,Neurons ,Endocrine and Autonomic Systems ,Depression ,Dentate gyrus ,Finasteride ,Neuroactive steroids ,Brain ,Granule cell ,030227 psychiatry ,Gastrointestinal Microbiome ,Rats ,Substance Withdrawal Syndrome ,Psychiatry and Mental health ,medicine.anatomical_structure ,chemistry ,Astrocytes ,Dentate Gyrus ,Cytokines ,Steroids ,030217 neurology & neurosurgery - Abstract
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., This research was supported by grants from MIUR Progetto Eccellenza. We also thank the Post-Finasteride Foundation for the financial support to R.C. Melcangi; Ministerio de Economía, Industria y Competitividad (MINECO), Spain (grant number BFU2017-82754-R), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain and Fondos Feder for the financial support to L.M. Garcia-Segura.
- Published
- 2019
46. Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: A pilot study
- Author
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Livio Casarini, Silvia Diviccaro, Daniele Santi, Manuela Simoni, Guido Cavaletti, Roberto Cosimo Melcangi, Samantha Sperduti, Silvia Giatti, Donatella Caruso, M.G. Grimoldi, Marco Marino, Melcangi, R, Casarini, L, Marino, M, Santi, D, Sperduti, S, Giatti, S, Diviccaro, S, Grimoldi, M, Caruso, D, Cavaletti, G, and Simoni, M
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Epigenetic changes ,Neuroactive steroid ,Endocrinology, Diabetes and Metabolism ,Context (language use) ,Side effect ,neuroactive steroids ,Gastroenterology ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Cerebrospinal fluid ,Internal medicine ,Internal Medicine ,medicine ,Side effects ,Testosterone ,lcsh:RC648-665 ,business.industry ,Research ,epigenetic changes ,Finasteride ,Neuroactive steroids ,Methylation ,side effects ,030104 developmental biology ,SRD5A1 ,chemistry ,5 alpha-reductase ,030220 oncology & carcinogenesis ,SRD5A2 ,Dihydrotestosterone ,business ,Epigenetic change ,medicine.drug - Abstract
Context Post-finasteride syndrome (PFS) occurs in patients with androgenic alopecia after suspension of the finasteride treatment, leading to a large variety of persistent side effects. Despite the severity of the clinical picture, the mechanism underlying the PFS symptoms onset and persistence is still unclear. Objective To study whether epigenetic modifications occur in PFS patients. Methods Retrospective analysis of a multicentric, prospective, longitudinal, case–control clinical trial, enrolling 16 PFS patients, compared to 20 age-matched healthy men. Main outcomes were methylation pattern of SRD5A1 and SRD5A2 promoters and concentration of 11 neuroactive steroids, measured by liquid chromatography-tandem mass spectrometry, in blood and cerebrospinal fluid (CSF) samples. Results SRD5A1 and SRD5A2 methylation analysis was performed in all blood samples (n = 16 PFS patients and n = 20 controls), in 16 CSF samples from PFS patients and in 13 CSF samples from controls. The SRD5A2 promoter was more frequently methylated in CSF of PFS patients compared to controls (56.3 vs 7.7%). No promoter methylation was detected in blood samples in both groups. No methylation occurred in the SRD5A1 promoter of both groups. Unmethylated controls compared to unmethylated SRD5A2 patients showed higher pregnenolone, dihydrotestosterone and dihydroprogesterone, together with lower testosterone CSF levels. Andrological and neurological assessments did not differ between methylated and unmethylated subjects. Conclusions For the first time, we demonstrate a tissue-specific methylation pattern of SRD5A2 promoter in PFS patients. Although we cannot conclude whether this pattern is prenatally established or induced by finasteride treatment, it could represent an important mechanism of neuroactive steroid levels and behavioural disturbances previously described in PFS.
- Published
- 2019
47. Physiopathological Role of Neuroactive Steroids in the Peripheral Nervous System
- Author
-
Silvia Giatti, Eva Falvo, Silvia Diviccaro, and Roberto Cosimo Melcangi
- Subjects
0301 basic medicine ,Nervous system ,steroidogenesis ,peripheral neuropathy ,Neuroactive steroid ,sex difference ,Review ,progesterone ,Bioinformatics ,Models, Biological ,Catalysis ,lcsh:Chemistry ,Inorganic Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Peripheral Nervous System ,Animals ,Humans ,Medicine ,pain ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,Testosterone ,business.industry ,Organic Chemistry ,Peripheral Nervous System Diseases ,General Medicine ,medicine.disease ,physical injury ,Computer Science Applications ,Neuroprotective Agents ,030104 developmental biology ,Peripheral neuropathy ,medicine.anatomical_structure ,lcsh:Biology (General) ,lcsh:QD1-999 ,Chemotherapy-induced peripheral neuropathy ,Peripheral nervous system ,testosterone ,diabetes mellitus ,Neuropathic pain ,business ,Neurosteroids ,030217 neurology & neurosurgery ,chemotherapy-induced peripheral neuropathy ,Hormone - Abstract
Peripheral neuropathy (PN) refers to many conditions involving damage to the peripheral nervous system (PNS). Usually, PN causes weakness, numbness and pain and is the result of traumatic injuries, infections, metabolic problems, inherited causes, or exposure to chemicals. Despite the high prevalence of PN, available treatments are still unsatisfactory. Neuroactive steroids (i.e., steroid hormones synthesized by peripheral glands as well as steroids directly synthesized in the nervous system) represent important physiological regulators of PNS functionality. Data obtained so far and here discussed, indeed show that in several experimental models of PN the levels of neuroactive steroids are affected by the pathology and that treatment with these molecules is able to exert protective effects on several PN features, including neuropathic pain. Of note, the observations that neuroactive steroid levels are sexually dimorphic not only in physiological status but also in PN, associated with the finding that PN show sex dimorphic manifestations, may suggest the possibility of a sex specific therapy based on neuroactive steroids.
- Published
- 2020
48. Levels and actions of neuroactive steroids in the nervous system under physiological and pathological conditions: Sex-specific features
- Author
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Silvia Giatti, Luis M. Garcia-Segura, Roberto Cosimo Melcangi, Fondazione Cariplo, and Ministerio de Economía y Competitividad (España)
- Subjects
Male ,0301 basic medicine ,Nervous system ,Multiple Sclerosis ,Neuroactive steroid ,Traumatic brain injury ,Cognitive Neuroscience ,Tetrahydroprogesterone ,Disease ,Neuroprotection ,5alpha-Reductase ,03 medical and health sciences ,Behavioral Neuroscience ,Aromatase ,0302 clinical medicine ,medicine ,Humans ,Testosterone ,Spinal cord injury ,Progesterone ,Neurotransmitter Agents ,Sex Characteristics ,Estradiol ,business.industry ,Multiple sclerosis ,Dihydrotestosterone ,medicine.disease ,Dihydroprogesterone ,030104 developmental biology ,Neuropsychology and Physiological Psychology ,medicine.anatomical_structure ,Peripheral neuropathy ,Pregnenolone ,Female ,Steroids ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Neuroactive steroids regulate the physiology of the central and peripheral nervous system, exert neuroprotective actions and represent interesting tools for therapeutic strategies against neurodegenerative and psychiatric disorders. Sex differences in their levels are detected not only under physiological conditions but are also modified in a sex-dependent way in different pathological alterations such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, traumatic brain injury, spinal cord injury, stroke, diabetic encephalopathy, psychiatric disorders and peripheral neuropathy. Interestingly, many of these disorders show sex differences in their incidence, symptomatology and/or neurodegenerative outcome. The neuroprotective actions of neuroactive steroids, together with the sex specific regulation of its levels might provide the basis to design sex-specific neuroprotective therapies. Indeed, some experiments here discussed suggest the viability of this approach., We acknowledge support from the Fondazione Cariplo to R.C.M. (grant number 2012-0547) and Ministerio de Economía y Competividad, Spain to L.M.G.S. (BFU2014-51836-C2-1-R).
- Published
- 2016
49. Structural and molecular brain sexual differences: A tool to understand sex differences in health and disease
- Author
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Giancarlo Panzica and Roberto Cosimo Melcangi
- Subjects
0301 basic medicine ,Kisspeptin ,Neuroactive steroid ,Dopamine ,Cognitive Neuroscience ,Biology ,Behavioral neuroscience ,Adult neurogenesis ,03 medical and health sciences ,Behavioral Neuroscience ,Vasotocin ,0302 clinical medicine ,Humans ,Epigenetics ,Gonadal Steroid Hormones ,Neurotransmitter Agents ,Sex Characteristics ,Medial preoptic region ,Brain ,Sexual dimorphism ,030104 developmental biology ,Neuropsychology and Physiological Psychology ,Estradiol: neuroactive steroids ,Vasopressin ,Evolutionary biology ,Hypothalamus ,Neuroscience ,030217 neurology & neurosurgery ,Sex characteristics ,Hormone - Abstract
Sex differences are present both in the genotype and in the phenotype of all vertebrates, and they have been evidenced also within the central and peripheral nervous system. Earlier studies on brain sex differences suggested a relatively simple view based on (1) the presence of sexually dimorphic circuits in the hypothalamus (or in regions related to reproductive behaviors), (2) the action of gonadal hormones to masculinize the brain, and (3) the gonadal steroids' action to modulate gene transcription through nuclear receptors. These assumptions are today contradicted by the findings accumulated in the last 20 years. We know now that mechanisms determining sexual dimorphisms may vary according to location and species, and may involve several factors, as genes, epigenetic factors, gonadal hormones and neurosteroids. Sex differences were also revealed by epidemiological studies in several neural pathologies. This suggests that the approach to understand the genesis of these pathologies, should involve specific attention to interactions among genes, gonadal and brain-born steroid hormones, epigenetic and environmental factors.
- Published
- 2016
50. The other side of progestins: effects in the brain
- Author
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Silvia Giatti, Marzia Pesaresi, and Roberto Cosimo Melcangi
- Subjects
0301 basic medicine ,Receptors, Steroid ,Hormone Replacement Therapy ,Hormone replacement ,Bioinformatics ,Nervous System ,Neuroprotection ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Contraceptive Agents, Female ,Animals ,Humans ,Medicine ,Testosterone ,Hormone replacement therapy ,Molecular Biology ,Progesterone ,business.industry ,Progestational agents ,Brain ,Steroid Metabolism ,Clinical Practice ,030104 developmental biology ,Models, Animal ,Progesterone metabolism ,Progestins ,business ,Metabolic Networks and Pathways ,030217 neurology & neurosurgery ,Protein Binding ,Signal Transduction ,Hormone - Abstract
Progestins are a broad class of progestational agents widely differing in their chemical structures and pharmacological properties. Despite emerging data suggest that progestins, besides their action as endometrial protection, can also have multiple nonreproductive functions, much remains to be discovered regarding the actions exerted by these molecules in the nervous system. Here, we report the role exerted by different progestins, currently used for contraception or in postmenopausal hormone replacement therapies, in regulating cognitive functions as well as social behavior and mood. We provide evidence that the effects and mechanisms underlying their actions are still confusing due to the use of different estrogens and progestins as well as different doses, duration of exposure, route of administration, baseline hormonal status and age of treated women. We also discuss the emerging issue concerning the relevant increase of these substances in the environment, able to deeply affect aquatic wildlife as well as to exert a possible influence in humans, which may be exposed to these compounds via contaminated drinking water and seafood. Finally, we report literature data showing the neurobiological action of progestins and in particular their importance during neurodegenerative events. This is extremely interesting, since some of the progestins currently used in clinical practice exert neuroprotective and anti-inflammatory effects in the nervous system, opening new promising opportunities for the use of these molecules as therapeutic agents for trauma and neurodegenerative disorders.
- Published
- 2016
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