Publications by authors named "Roberto C Melcangi"

49 Publications

Effects of paroxetine treatment and its withdrawal on neurosteroidogenesis.

Psychoneuroendocrinology 2021 Jul 21;132:105364. Epub 2021 Jul 21.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy. Electronic address:

Selective serotonin reuptake inhibitors (SSRI) show high efficacy in treating depression, however during treatment side effects, like for instance sexual dysfunction, may appear, decreasing compliance. In some cases, this condition will last after drug discontinuation, leading to the so-called post-SSRI sexual dysfunction (PSSD). The etiology of PSSD is still unknown, however a role for neuroactive steroids may be hypothesized. Indeed, these molecules are key physiological regulators of the nervous system, and their alteration has been associated with several neuropathological conditions, including depression. Additionally, neuroactive steroids are also involved in the control of sexual function. Interestingly, sexual dysfunction induced by SSRI treatment has been also observed in animal models. On this basis, we have here evaluated whether a subchronic treatment with paroxetine for two weeks and/or its withdrawal (i.e., a month) may affect the levels of neuroactive steroids in brain areas (i.e., hippocampus, hypothalamus, and cerebral cortex) and/or in plasma and cerebrospinal fluid of male rats. Data obtained indicate that the SSRI treatment alters neuroactive steroid levels and the expression of key enzymes of the steroidogenesis in a brain tissue- and time-dependent manner. Indeed, these observations with the finding that plasma levels of neuroactive steroids are not affected suggest that the effect of paroxetine treatment is directly on neurosteroidogenesis. In particular, a negative impact on the expression of steroidogenic enzymes was observed at the withdrawal. Therefore, it is possible to hypothesize that altered neurosteroidogenesis may also occur in PSSD and consequently it may represent a possible pharmacological target for this disorder.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105364DOI Listing
July 2021

Neuroactive steroids and the new decade.

J Neuroendocrinol 2020 01 22;32(1):e12832. Epub 2020 Jan 22.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.

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http://dx.doi.org/10.1111/jne.12832DOI Listing
January 2020

Sex differences in steroid levels and steroidogenesis in the nervous system: Physiopathological role.

Front Neuroendocrinol 2020 01 2;56:100804. Epub 2019 Nov 2.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.yfrne.2019.100804DOI Listing
January 2020

Lipotoxicity, neuroinflammation, glial cells and oestrogenic compounds.

J Neuroendocrinol 2020 01 8;32(1):e12776. Epub 2019 Aug 8.

Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia.

The high concentrations of free fatty acids as a consequence of obesity and being overweight have become risk factors for the development of different diseases, including neurodegenerative ailments. Free fatty acids 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 oestradiol 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 oestrogen 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 signalling 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 oestrogens.
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http://dx.doi.org/10.1111/jne.12776DOI Listing
January 2020

Neuroactive steroids, neurosteroidogenesis and sex.

Prog Neurobiol 2019 05 4;176:1-17. Epub 2018 Jul 4.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.pneurobio.2018.06.007DOI Listing
May 2019

Effect of the 5α-reductase enzyme inhibitor dutasteride in the brain of intact and parkinsonian mice.

J Steroid Biochem Mol Biol 2017 11 2;174:242-256. Epub 2017 Oct 2.

Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Canada; Faculty of Pharmacy, Laval University, Quebec City, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jsbmb.2017.09.021DOI Listing
November 2017

Profiling Neuroactive Steroid Levels After Traumatic Brain Injury in Male Mice.

Endocrinology 2016 Oct 22;157(10):3983-3993. Epub 2016 Aug 22.

Instituto Cajal (A.B.L.-R., E.A.-F., L.M.G.-S.), Consejo Superior de Investigaciones Científicas (CSIC), 28002 Madrid, Spain; Department of Animal Physiology (Animal Physiology II) (A.B.L.-R., M.-P.V.), Faculty of Biology, Complutense University of Madrid, 28040 Madrid, Spain; and Department of Pharmacological and Biomolecular Sciences (P.S., S.G., D.C., R.C.M.), Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, 20133 Milano, Italy.

The incidence of traumatic brain injuries (TBIs) in humans has rapidly increased in the last ten years. The most common causes are falls and car accidents. Approximately 80 000-90 000 persons per year will suffer some permanent disability as a result of the lesion, and one of the most common symptoms is the decline of hormone levels, also known as post-TBI hormonal deficiency syndrome. This issue has become more and more important, and many studies have focused on shedding some light on it. The hormonal decline affects not only gonadal steroid hormones but also neuroactive steroids, which play an important role in TBI recovery by neuroprotective and neurotrophic actions. The present work used an adolescent close-head murine model to analyze brain and plasma neurosteroid level changes after TBI and to establish correlations with edema and neurological impairments, 2 of the hallmarks of TBI. Our results showed changes in brain pregnenolone, testosterone, dihydrotestosterone (DHT), and 3α-diol levels whereas in plasma, the changes were present in progesterone, DHT, 3α-diol, and 3β-diol. Within them, pregnenolone, progesterone, DHT, and 3α-diol levels positively correlated with edema formation and neurological score, whereas testosterone inversely correlated with these 2 variables. These findings suggest that changes in the brain levels of some neuroactive steroids may contribute to the alterations in brain function caused by the lesion and that plasma levels of some neuroactive steroids could be good candidates of blood markers to predict TBI outcome.
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http://dx.doi.org/10.1210/en.2016-1316DOI Listing
October 2016

Structural and molecular brain sexual differences: A tool to understand sex differences in health and disease.

Neurosci Biobehav Rev 2016 Aug 23;67:2-8. Epub 2016 Apr 23.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.

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.
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http://dx.doi.org/10.1016/j.neubiorev.2016.04.017DOI Listing
August 2016

Editorial.

J Steroid Biochem Mol Biol 2016 06 2;160. Epub 2016 Mar 2.

Dipartimento di Neuroscienze "Rita Levi Montalcini", Università degli Studi di Torino, and Neuroscience Institute Cavalieri Ottolenghi (NICO), Orbassano, Italy, Italy.

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http://dx.doi.org/10.1016/j.jsbmb.2016.03.001DOI Listing
June 2016

Levels and actions of neuroactive steroids in the nervous system under physiological and pathological conditions: Sex-specific features.

Neurosci Biobehav Rev 2016 Aug 2;67:25-40. Epub 2015 Dec 2.

Instituto Cajal, CSIC, Avenida Doctor Arce 37, 28002 Madrid, Spain.

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.
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http://dx.doi.org/10.1016/j.neubiorev.2015.09.023DOI Listing
August 2016

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice.

Neuroendocrinology 2016 24;103(3-4):300-14. Epub 2015 Jul 24.

Neuroscience Research Unit, Centre Hospitalier Universitaire de Qux00E9;bec, Centre Hospitalier de l'Universitx00E9; Laval, Quebec City, Que., Canada.

Background: Numerous studies have reported on the neuroprotective activity of estradiol, whereas the effect of the other ovarian steroid, progesterone, is much less documented.

Methods: This study sought to investigate neuroprotection with a low dose of progesterone (1 µg) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male mice to model Parkinson's disease and compare it to the effect of this steroid in intact mice (experiment 1). We also investigated if high doses of progesterone could protect dopaminergic neurons already exposed to MPTP (experiment 2). We measured progesterone effects on various dopaminergic markers [dopamine and its metabolites, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2)] and on neuroactive steroids in both plasma and the brain.

Results: For experiment 1, our results showed that progesterone completely prevented the effect of MPTP toxicity on dopamine concentrations, on the increase in the 3-methoxytyramine/dopamine ratio, as well as on VMAT2-specific binding in the striatum and the substantia nigra. Progesterone decreased MPTP effects on 3,4-dihydroxyphenylacetic acid concentrations and DAT-specific binding in the lateral part of the anterior striatum and in the middle striatum (medial and lateral parts). Progesterone treatment of intact mice had no effect on the markers investigated. For experiment 2, measures of dopaminergic markers in the striatum showed that 8 mg/kg of progesterone was the most effective dose to reduce MPTP effects, and more limited effects were observed with 16 mg/kg. We found that progesterone treatment increases the levels of brain progesterone itself as well as of its metabolites.

Conclusion: Our result showed that progesterone has neuroprotective effects on dopaminergic neurons in MPTP-treated male mice.
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http://dx.doi.org/10.1159/000438789DOI Listing
May 2017

The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity.

Neurobiol Aging 2015 Jul 1;36(7):2282-2295. Epub 2015 Apr 1.

Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address:

The perimenopause is an aging transition unique to the female that leads to reproductive senescence which can be characterized by multiple neurological symptoms. To better understand potential underlying mechanisms of neurological symptoms of perimenopause, the present study determined genomic, biochemical, brain metabolic, and electrophysiological transformations that occur during this transition using a rat model recapitulating fundamental characteristics of the human perimenopause. Gene expression analyses indicated two distinct aging programs: chronological and endocrine. A critical period emerged during the endocrine transition from regular to irregular cycling characterized by decline in bioenergetic gene expression, confirmed by deficits in fluorodeoxyglucose-positron emission tomography (FDG-PET) brain metabolism, mitochondrial function, and long-term potentiation. Bioinformatic analysis predicted insulin/insulin-like growth factor 1 and adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (AMPK/PGC1α) signaling pathways as upstream regulators. Onset of acyclicity was accompanied by a rise in genes required for fatty acid metabolism, inflammation, and mitochondrial function. Subsequent chronological aging resulted in decline of genes required for mitochondrial function and β-amyloid degradation. Emergence of glucose hypometabolism and impaired synaptic function in brain provide plausible mechanisms of neurological symptoms of perimenopause and may be predictive of later-life vulnerability to hypometabolic conditions such as Alzheimer's.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416218PMC
July 2015

Neuroactive steroids and the peripheral nervous system: An update.

Steroids 2015 Nov 28;103:23-30. Epub 2015 Mar 28.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy. Electronic address:

In the present review we summarize observations to date supporting the concept that neuroactive steroids are synthesized in the peripheral nervous system, regulate the physiology of peripheral nerves and exert notable neuroprotective actions. Indeed, neuroactive steroids have been recently proposed as therapies for different types of peripheral neuropathy, like for instance those occurring during aging, chemotherapy, physical injury and diabetes. Moreover, pharmacological tools able to increase the synthesis of neuroactive steroids might represent new interesting therapeutic strategy to be applied in case of peripheral neuropathy.
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http://dx.doi.org/10.1016/j.steroids.2015.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314841PMC
November 2015

Lack of sterol regulatory element binding factor-1c imposes glial Fatty Acid utilization leading to peripheral neuropathy.

Cell Metab 2015 Apr 26;21(4):571-83. Epub 2015 Mar 26.

DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, 20133, Italy. Electronic address:

Myelin is a membrane characterized by high lipid content to facilitate impulse propagation. Changes in myelin fatty acid (FA) composition have been associated with peripheral neuropathy, but the specific role of peripheral nerve FA synthesis in myelin formation and function is poorly understood. We have found that mice lacking sterol regulatory element-binding factor-1c (Srebf1c) have blunted peripheral nerve FA synthesis that results in development of peripheral neuropathy. Srebf1c-null mice develop Remak bundle alterations and hypermyelination of small-caliber fibers that impair nerve function. Peripheral nerves lacking Srebf1c show decreased FA synthesis and glycolytic flux, but increased FA catabolism and mitochondrial function. These metabolic alterations are the result of local accumulation of two endogenous peroxisome proliferator-activated receptor-α (Pparα) ligands, 1-palmitoyl-2-oleyl-sn-glycerol-3-phosphatidylcholine and 1-stearoyl-2-oleyl-sn-glycerol-3-phosphatidylcholine. Treatment with a Pparα antagonist rescues the neuropathy of Srebf1c-null mice. These findings reveal the importance of peripheral nerve FA synthesis to sustain myelin structure and function.
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http://dx.doi.org/10.1016/j.cmet.2015.02.016DOI Listing
April 2015

Correlation of brain levels of progesterone and dehydroepiandrosterone with neurological recovery after traumatic brain injury in female mice.

Psychoneuroendocrinology 2015 Jun 3;56:1-11. Epub 2015 Mar 3.

Instituto Cajal, CSIC, Avenida Doctor Arce 37, 28002 Madrid, Spain.

Traumatic brain injury (TBI) is an important cause of disability in humans. Neuroactive steroids, such as progesterone and dehydroepiandrosterone (DHEA), are neuroprotective in TBI models. However in order to design potential neuroprotective strategies based on neuroactive steroids it is important to determine whether its brain levels are altered by TBI. In this study we have used a weight-drop model of TBI in young adult female mice to determine the levels of neuroactive steroids in the brain and plasma at 24h, 72 h and 2 weeks after injury. We have also analyzed whether the levels of neuroactive steroids after TBI correlated with the neurological score of the animals. TBI caused neurological deficit detectable at 24 and 72 h, which recovered by 2 weeks after injury. Brain levels of progesterone, tetrahydroprogesterone (THP), isopregnanolone and 17β-estradiol were decreased 24h, 72 h and 2 weeks after TBI. DHEA and brain testosterone levels presented a transient decrease at 24h after lesion. Brain levels of progesterone and DHEA showed a positive correlation with neurological recovery. Plasma analyses showed that progesterone was decreased 72 h after lesion but, in contrast with brain progesterone, its levels did not correlate with neurological deficit. These findings indicate that TBI alters the levels of neuroactive steroids in the brain with independence of its plasma levels and suggest that the pharmacological increase in the brain of the levels of progesterone and DHEA may result in the improvement of neurological recovery after TBI.
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http://dx.doi.org/10.1016/j.psyneuen.2015.02.018DOI Listing
June 2015

Lipids in the nervous system: from biochemistry and molecular biology to patho-physiology.

Biochim Biophys Acta 2015 Jan 20;1851(1):51-60. Epub 2014 Aug 20.

DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy. Electronic address:

Lipids in the nervous system accomplish a great number of key functions, from synaptogenesis to impulse conduction, and more. Most of the lipids of the nervous system are localized in myelin sheaths. It has long been known that myelin structure and brain homeostasis rely on specific lipid-protein interactions and on specific cell-to-cell signaling. In more recent years, the growing advances in large-scale technologies and genetically modified animal models have provided valuable insights into the role of lipids in the nervous system. Key findings recently emerged in these areas are here summarized. In addition, we briefly discuss how this new knowledge can open novel approaches for the treatment of diseases associated with alteration of lipid metabolism/homeostasis in the nervous system. This article is part of a Special Issue entitled Linking transcription to physiology in lipidomics.
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http://dx.doi.org/10.1016/j.bbalip.2014.08.011DOI Listing
January 2015

Ligand for translocator protein reverses pathology in a mouse model of Alzheimer's disease.

J Neurosci 2013 May;33(20):8891-7

Davis School of Gerontology, University of Southern California, Los Angeles, California 90089, USA.

Ligands of the translocator protein (TSPO) elicit pleiotropic neuroprotective effects that represent emerging treatment strategies for several neurodegenerative conditions. To investigate the potential of TSPO as a therapeutic target for Alzheimer's disease (AD), the current study assessed the effects of the TSPO ligand Ro5-4864 on the development of neuropathology in 3xTgAD mice. The effects of the TSPO ligand on neurosteroidogenesis and AD-related neuropathology, including β-amyloid accumulation, gliosis, and behavioral impairment, were examined under both early intervention (7-month-old young-adult male mice with low pathology) and treatment (24-month-old, aged male mice with advanced neuropathology) conditions. Ro5-4864 treatment not only effectively attenuated development of neuropathology and behavioral impairment in young-adult mice but also reversed these indices in aged 3xTgAD mice. Reduced levels of soluble β-amyloid were also observed by the combination of TSPO ligands Ro5-4864 and PK11195 in nontransgenic mice. These findings suggest that TSPO is a promising target for the development of pleiotropic treatment strategies for the management of AD.
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http://dx.doi.org/10.1523/JNEUROSCI.1350-13.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733563PMC
May 2013

Age-related changes in neuroactive steroid levels in 3xTg-AD mice.

Neurobiol Aging 2013 Apr 2;34(4):1080-9. Epub 2012 Nov 2.

Department of Pharmacological and Biomolecular Sciences, Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milano, Italy.

Although neuroactive steroids exert neuroprotective actions in different experimental models of neurodegenerative diseases, including those of Alzheimer's disease (AD), their relationships with aged related physiologic and pathologic brain changes remain to be clarified. In this study the levels of pregnenolone, dehydroepiandrosterone, progesterone, dihydroprogesterone, tetrahydroprogesterone, isopregnanolone, testosterone, dihydrotestosterone, 5α-androstane-3α,17β-diol, 5α-androstane-3β,17β-diol, 17α-estradiol, and 17β-estradiol were assessed in the limbic region of young adult (7 months) and aged (24 months) male wild type and triple transgenic AD mice. Age related neuropathological changes in AD brains, such as β-amyloid accumulation and gliosis, were associated with modified levels of specific neuroactive steroids and particularly with changes in the levels of progesterone and testosterone metabolites. The altered levels of neuroactive steroids in aged AD brains might impact on the activation of neuroprotective signaling mediated by classic and nonclassic steroid receptors, like the gamma-aminobuttyric acid (GABA)-A receptor.
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http://dx.doi.org/10.1016/j.neurobiolaging.2012.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545103PMC
April 2013

LXR and TSPO as new therapeutic targets to increase the levels of neuroactive steroids in the central nervous system of diabetic animals.

Neurochem Int 2012 May 3;60(6):616-21. Epub 2012 Mar 3.

Dept. of Pharmacological Sciences, Università degli Studi di Milano, Milano, Italy.

Neuroactive steroid levels are decreased in the central nervous system (CNS) of streptozotocin (STZ) diabetic rats. In agreement, they exert protective effects in this experimental model, counteracting degenerative events occurring in the CNS. Therefore, an interesting therapeutic strategy could be to increase their levels directly in the CNS. In this study we have evaluated whether activation of translocator protein-18kDa (TSPO) or liver X receptors (LXRs) may affect the levels of neuroactive steroids present in the CNS of diabetic and non-diabetic animals. We observed that the treatment with either Ro5-4864 (i.e., a ligand of TSPO) or with GW3965 (i.e., a ligand of LXRs) induced an increase of neuroactive steroids in the spinal cord, the cerebellum and the cerebral cortex of STZ-rats, but not in the CNS of non-pathological animals. Interestingly, the pattern of induction was different among the three CNS areas analyzed and between the two pharmacological tools. In particular, the activation of LXRs might represent a promising neuroprotective strategy, because the treatment with GW3965, at variance to Ro5-4864 treatment, did not induce significant changes in the plasma levels of neuroactive steroids. This suggests that activation of LXRs may selectively increase the CNS levels of neuroactive steroids avoiding possible endocrine side effects exerted by the systemic treatment with these molecules. Interestingly GW3965 treatment induced an increase of dihydroprogesterone in the spinal cord of diabetic animals in association with an increase of myelin basic protein expression. Thus we demonstrated that LXR activation was able to rescue CNS symptoms of diabetes.
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http://dx.doi.org/10.1016/j.neuint.2012.02.025DOI Listing
May 2012

Gender effect on neurodegeneration and myelin markers in an animal model for multiple sclerosis.

BMC Neurosci 2012 Jan 24;13:12. Epub 2012 Jan 24.

Department of Veterinary Medicine, University of Bologna, Via Tolara di Sopra 50, 40064 Ozzano Emilia, Italy.

Background: Multiple sclerosis (MS) varies considerably in its incidence and progression in females and males. In spite of clinical evidence, relatively few studies have explored molecular mechanisms possibly involved in gender-related differences. The present study describes possible cellular- and molecular-involved markers which are differentially regulated in male and female rats and result in gender-dependent EAE evolution and progression. Attention was focused on markers of myelination (MBP and PDGFαR) and neuronal distress and/or damage (GABA synthesis enzymes, GAD65 and GAD67, NGF, BDNF and related receptors), in two CNS areas, i.e. spinal cord and cerebellum, which are respectively severely and mildly affected by inflammation and demyelination. Tissues were sampled during acute, relapse/remission and chronic phases and results were analysed by two-way ANOVA.

Results: 1. A strong gender-dependent difference in myelin (MBP) and myelin precursor (PDGFαR) marker mRNA expression levels is observed in control animals in the spinal cord, but not in the cerebellum. This is the only gender-dependent difference in the expression level of the indicated markers in healthy animals; 2. both PDGFαR and MBP mRNAs in the spinal cord and MBP in the cerebellum are down-regulated during EAE in gender-dependent manner; 3. in the cerebellum, the expression profile of neuron-associated markers (GAD65, GAD67) is characterized by a substantial down-regulation during the inflammatory phase of the disease, which does not differ between male and female rats (two-way ANOVA); 4. there is an up-regulation of NGF, trkA and p75 mRNA expression in the early phases of the disease (14 and 21 days post-immunization), which is not different between male and female.

Conclusions: It is reported herein that the regulation of markers involved in demyelination and neuroprotection processes occurring during EAE, a well-established MS animal model, is gender- and time-dependent. These findings might contribute to gender- and phase disease-based therapy strategies.
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http://dx.doi.org/10.1186/1471-2202-13-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282645PMC
January 2012

Diabetes-induced myelin abnormalities are associated with an altered lipid pattern: protective effects of LXR activation.

J Lipid Res 2012 Feb 7;53(2):300-10. Epub 2011 Dec 7.

Department of Pharmacological Sciences, Università degli Studi di Milano, Milano, Italy.

Diabetic peripheral neuropathy (DPN) is characterized by myelin abnormalities; however, the molecular mechanisms underlying such deficits remain obscure. To uncover the effects of diabetes on myelin alterations, we have analyzed myelin composition. In a streptozotocin-treated rat model of diabetic neuropathy, analysis of sciatic nerve myelin lipids revealed that diabetes alters myelin's phospholipid, FA, and cholesterol content in a pattern that can modify membrane fluidity. Reduced expression of relevant genes in the FA biosynthetic pathway and decreased levels of the transcriptionally active form of the lipogenic factor sterol-regulatory element binding factor-1c (SREBF-1c) were found in diabetic sciatic nerve. Expression of myelin's major protein, myelin protein zero (P0), was also suppressed by diabetes. In addition, we confirmed that diabetes induces sciatic nerve myelin abnormalities, primarily infoldings that have previously been associated with altered membrane fluidity. In a diabetic setting, synthetic activator of the nuclear receptor liver X receptor (LXR) increased SREBF-1c function and restored myelin lipid species and P0 expression levels to normal. These LXR-modulated improvements were associated with restored myelin structure in sciatic nerve and enhanced performance in functional tests such as thermal nociceptive threshold and nerve conduction velocity. These findings demonstrate an important role for the LXR-SREBF-1c axis in protection from diabetes-induced myelin abnormalities.
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http://dx.doi.org/10.1194/jlr.M021188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269154PMC
February 2012

Evidences for antinociceptive effect of 17-α-hydroxyprogesterone caproate in carpal tunnel syndrome.

J Mol Neurosci 2012 May 24;47(1):59-66. Epub 2011 Nov 24.

Department of Neurological, Neurosurgical and Behavioural Sciences, Clinical Neurophysiology Unit, University of Siena, Policlinico Le Scotte, Viale Bracci 1, 53100 Siena, Italy.

Growing evidence of neuroprotective and analgesic effects by progesterone (PROG) has been obtained in experimental animal models of neuropathy. In this paper, we report the results of the first experimental study to test the efficacy of PROG in a human neuropathy. The effects of a local administration of 17-alpha-hydroxyprogesterone caproate (17HPC) has been studied in patients with carpal tunnel syndrome (CTS) and compared with those of a local administration of corticosteroid (CS) in a analogous CTS group. Sixteen women affected by mild CTS were selected. Clinical, electrophysiological and ultrasonographic data of the median nerve were quantified at 0 (pre-injection), 1 and 6 months after CS or 17HPC injection. One month after injection, both 17HPC and CS groups exhibited similar reduction in pain scores, whereas only the 17HPC-treated group still manifested symptoms relief 6 months after. Only in CS-treated patients, improvement of the clinical data correlated with ultrasonographic and electrophysiological changes of the median nerve. The present study indicates that intra-carpal injection with a long-acting PROG derivative is effective for relief of symptoms in CTS. This effect is apparently mediated by a mechanism distinct from that of the CS.
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http://dx.doi.org/10.1007/s12031-011-9679-zDOI Listing
May 2012

Sex differences in the manifestation of peripheral diabetic neuropathy in gonadectomized rats: a correlation with the levels of neuroactive steroids in the sciatic nerve.

Exp Neurol 2011 Apr 15;228(2):215-21. Epub 2011 Jan 15.

Dept of Endocrinology, Pathophysiology and Applied Biology, Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milano, Italy.

Clinical observations suggest a sex-dimorphism in the incidence and symptomatology of diabetic neuropathy, but this possible gender effect has never been investigated in detail in a well-characterized experimental model such as streptozotocin (STZ)-induced diabetes. Therefore, in this study we have compared with a multimodal set of tests the impact of diabetes on the sciatic nerve in male and female rats. To assess whether sex-dimorphism in peripheral diabetic neuropathy is dependent on gonadal hormones we have also analyzed the effect of ovariectomy and orchidectomy on the sciatic nerve of STZ-diabetic rats. Nerve conduction velocity (NCV), Na(+),K(+)-ATPase activity, expression of myelin proteins, thermal sensitivity and reactive oxygen species production were similarly affected in male and female animals by STZ. However, ovariectomy, but not orchidectomy, significantly counteracted STZ-induced alterations on NCV, Na(+),K(+)-ATPase activity, and expression of myelin proteins. This effect of ovariactomy was associated to an increase in the levels of neuroactive steroids, such as dehydroepiandrosterone, testosterone and dihydrotestosterone, in the sciatic nerve of diabetic rats. These neuroactive steroids have been demonstrated to be protective agents in this experimental model of diabetic neuropathy. However, their efficacy has been so far tested only in male animals. Therefore, the present data might represent an important background to evaluate their efficacy also in female diabetic animals.
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http://dx.doi.org/10.1016/j.expneurol.2011.01.005DOI Listing
April 2011

Sex-dimorphic changes in neuroactive steroid levels after chronic experimental autoimmune encephalomyelitis.

J Neurochem 2010 Aug 21;114(3):921-32. Epub 2010 May 21.

Department of Pharmacological Sciences, Università degli Studi di Milano, Milano, Italy.

Our previous observations have shown that neuroactive steroid levels in the brain are affected by acute experimental autoimmune encephalomyelitis (EAE) with sex and regional specificity (Giatti et al. 2010). To better understand the effect of EAE on neuroactive steroids, we have here assessed the levels of pregnenolone, progesterone and its derivatives (i.e. dihydroprogesterone, tetrahydroprogesterone and isopregnanolone), testosterone and its derivatives (dihydrotestosterone and 5alpha-androstane-3alpha, 17beta-diol) in different CNS regions of male and female rats affected by chronic EAE. Data obtained by liquid chromatography tandem mass spectrometry revealed that chronic EAE results in sex and regional specific alterations in the levels of neuroactive steroids in the brain, which are in many cases different to those produced by acute EAE. The specific changes in neuroactive steroid levels after chronic EAE may be of relevance to design new possible therapeutic strategies for the disease.
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http://dx.doi.org/10.1111/j.1471-4159.2010.06825.xDOI Listing
August 2010

Docetaxel-induced peripheral neuropathy: protective effects of dihydroprogesterone and progesterone in an experimental model.

J Peripher Nerv Syst 2009 Mar;14(1):36-44

Department of Endocrinology and Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy.

Peripheral neurotoxicity is a frequent complication limiting docetaxel chemotherapy in patients with cancer. We developed an experimental model that closely mimics the course of neuropathy in patients, aiming to investigate both the mechanisms of neurotoxicity at biochemical, functional and morphological levels and the potential neuroprotective role of neuroactive steroids. We demonstrated that treatment with dihydroprogesterone (DHP) or progesterone (P) counteracts docetaxel-induced neuropathy, preventing nerve conduction and thermal threshold changes, and degeneration of skin nerves in the foodpad. Neuroactive steroids also counteract the changes in gene expression of several myelin proteins and calcitonin gene-related peptide induced by docetaxel in sciatic nerve and lumbar spinal cord, respectively. Most nerve abnormalities observed during the treatment with docetaxel spontaneously recovered after drug withdrawal, similarly to what occurs in patients. However, results of midterm follow-up experiments indicated that animals cotreated with DHP or P have a faster recovery of the neuropathy compared with docetaxel-treated rats. Our study confirmed that neuroactive steroids exert a protective effect on peripheral nerves at different levels, suggesting that they might represent a new therapeutic frontier for patients with chemotherapy-induced neuropathy.
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http://dx.doi.org/10.1111/j.1529-8027.2009.00204.xDOI Listing
March 2009

Neuroactive Steroid Levels in a transgenic rat model of CMT1A Neuropathy.

J Mol Neurosci 2008 Mar 9;34(3):249-53. Epub 2008 Jan 9.

Department of Pharmacological Sciences and Center for Metrological Traceability in Laboratory Medicine, University of Milan, Milan, Italy.

Charcot-Marie-Tooth type 1A (CMT1A) represents 80% of all the demyelinating hereditary motor and sensory neuropathies. As recently suggested, neuroactive steroids may have a role in a therapeutic strategy for peripheral neuropathies, including CMT1A. To this aim, an accurate qualitative and quantitative analysis of neuroactive steroid levels in this disease could be extremely important to define effective pharmacological strategies. We here analyzed by liquid chromatography-tandem mass spectrometry the levels of neuroactive steroids present in the sciatic nerve of male and female peripheral myelin protein 22 transgenic rats (PMP22(tg) rats; i.e., an experimental model of CMT1A) and of the corresponding wild-type littermates. We observed that, both in PMP22(tg) rats and in the wild types, the levels of neuroactive steroids, such as progesterone, tetrahydroprogesterone (THP), isopregnanolone (3beta,5alpha-THP), testosterone, dihydrotestosterone, and 5alpha-androstane-3alpha, 17beta-diol (3alpha-diol) are sexually dimorphic. It is interesting to note that the levels of 3beta,5alpha-THP and of 3alpha-diol, which are exclusively detectable in sciatic nerve of female and male rats, respectively, are strongly decreased in PMP22(tg) rats. 3beta,5alpha-THP and 3alpha-diol are modulators of gamma-amino butyric acid A receptor. Thus, the present findings may be considered an interesting background for experiments aimed to evaluate the possible therapeutic effects of modulators of this neurotransmitter receptor in male and female PMP22(tg) rats.
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http://dx.doi.org/10.1007/s12031-007-9029-3DOI Listing
March 2008

Evaluation of neuroactive steroid levels by liquid chromatography-tandem mass spectrometry in central and peripheral nervous system: effect of diabetes.

Neurochem Int 2008 Mar-Apr;52(4-5):560-8. Epub 2007 Jun 19.

Department of Pharmacological Sciences, University of Milan, Milano, Italy.

The nervous system is a target for physiological and protective effects of neuroactive steroids. Consequently, the assessment of their levels in nervous structures under physiological and pathological conditions is a top priority. To this aim, identification and quantification of pregnenolone (PREG), progesterone (PROG), dihydroprogesterone (DHP), tetrahydroprogesterone (THP), testosterone (T), dihydrotestosterone (DHT), 5alpha-androstan-3alpha, 17beta-diol (3alpha-diol), 17alpha- and 17beta-estradiol (17alpha-E and 17beta-E) by liquid chromatography and tandem mass spectrometry (LC-MS/MS) has been set up. After validation, this method was applied to determine the levels of neuroactive steroids in central (i.e., cerebral cortex, cerebellum and spinal cord) and peripheral (i.e., brachial nerve) nervous system of control and diabetic rats. In controls only the brachial nerve had detectable levels of all these neuroactive steroids. In contrast, 17alpha-E in cerebellum, 17alpha-E, 17beta-E, DHP and THP in cerebral cortex, and 17alpha-E, 17beta-E and DHP in spinal cord were under the detection limit. Diabetes, induced by injection with streptozotocin, strongly affected the levels of some neuroactive steroids. In particular, the levels of PREG, PROG and T in cerebellum, of PROG, T and 3alpha-diol in cerebral cortex, of PROG, DHT and 3alpha-diol in spinal cord and of PREG, DHP, THP, T, DHT and 3alpha-diol in brachial nerve were significantly decreased. In conclusion, the data here reported demonstrate that the LC-MS/MS method allows the assessment of neuroactive steroids in the nervous system with high sensitivity and specificity and that diabetes strongly affects their levels, providing a further basis for new therapeutic tools based on neuroactive steroids aimed at counteracting diabetic neuropathy.
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http://dx.doi.org/10.1016/j.neuint.2007.06.004DOI Listing
June 2008

Progesterone derivatives increase expression of Krox-20 and Sox-10 in rat Schwann cells.

J Mol Neurosci 2007 ;31(2):149-57

Department of Endocrinology and Center of Excellence of Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy.

Neuroactive steroids, like progesterone (P) and its 5alpha-reduced derivatives dihydroprogesterone (DHP) and tetrahydroprogesterone (THP), are involved in the control of Schwann cell proliferation and in the myelinating program of these cells. Here, we demonstrate that in culture of rat Schwann cells, P and its derivatives also increase expression of Sox-10 and Krox-20 (i.e., two transcription factors with a key role in Schwann cell physiology and in their myelinating program). Data obtained by quantitative RT-PCR analysis show that treatment with P, DHP, or THP increases mRNA levels of Krox-20. This stimulatory effect anticipates that exerted by P and DHP on Sox-10 gene expression. Thus, although the effect on Krox-20 occurs after 1 h, that on Sox-10 reaches a peak after 2 h. A similar pattern of effect is also evident on their protein levels. As evaluated by Western blot analysis, Krox-20 is increased after 3 h of treatment with P, DHP, or THP, whereas P or DHP stimulates the expression of Sox-10 after 6 h of exposure. A computer analysis performed on rat and human promoters of these two transcription factors shows that putative P-responsive elements are present in Krox-20 but not in Sox-10. Interestingly, many putative binding sites for Krox-20 are present in the Sox-10 promoter. The observations reported here, together with the concept that P and its derivatives are able to influence directly the expression of myelin proteins, suggest that these neuroactive steroids might coordinate the Schwann cell-myelinating program utilizing different intracellular pathways.
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http://dx.doi.org/10.1385/jmn/31:02:149DOI Listing
February 2008

Steroids and glial cell function.

Glia 2006 Nov;54(6):485-98

Instituto Cajal, C.S.I.C., Madrid, Spain.

Hormonal and locally produced steroids act in the nervous system as neuroendocrine regulators, as trophic factors and as neuromodulators and have a major impact on neural development and function. Glial cells play a prominent role in the local production of steroids and in the mediation of steroid effects on neurons and other glial cells. In this review, we examine the role of glia in the synthesis and metabolism of steroids and the functional implications of glial steroidogenesis. We analyze the mechanisms of steroid signaling on glia, including the role of nuclear receptors and the mechanisms of membrane and cytoplasmic signaling mediated by changes in intracellular calcium levels and activation of signaling kinases. Effects of steroids on functional parameters of glia, such as proliferation, myelin formation, metabolism, cytoskeletal reorganization, and gliosis are also reviewed, as well as the implications of steroid actions on glia for the regulation of synaptic function and connectivity, the regulation of neuroendocrine events, and the response of neural tissue to injury.
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http://dx.doi.org/10.1002/glia.20404DOI Listing
November 2006
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