Publications by authors named "Silvia Diviccaro"

16 Publications

  • Page 1 of 1

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

Allopregnanolone: An overview on its synthesis and effects.

J Neuroendocrinol 2021 Jun 1:e12996. Epub 2021 Jun 1.

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

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.
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http://dx.doi.org/10.1111/jne.12996DOI Listing
June 2021

Three-Dimensional Proteome-Wide Scale Screening for the 5-Alpha Reductase Inhibitor Finasteride: Identification of a Novel Off-Target.

J Med Chem 2021 04 12;64(8):4553-4566. Epub 2021 Apr 12.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.

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 -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 assay, confirming the inhibitory nature of the binding. Finally, this inhibition was also confirmed in an 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.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154553PMC
April 2021

Physiopathological Role of Neuroactive Steroids in the Peripheral Nervous System.

Int J Mol Sci 2020 Nov 26;21(23). Epub 2020 Nov 26.

Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.

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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http://dx.doi.org/10.3390/ijms21239000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731236PMC
November 2020

Post-finasteride syndrome: An emerging clinical problem.

Neurobiol Stress 2020 May 26;12:100209. Epub 2019 Dec 26.

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

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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http://dx.doi.org/10.1016/j.ynstr.2019.100209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231981PMC
May 2020

Physiopathological role of the enzymatic complex 5α-reductase and 3α/β-hydroxysteroid oxidoreductase in the generation of progesterone and testosterone neuroactive metabolites.

Front Neuroendocrinol 2020 04 23;57:100836. Epub 2020 Mar 23.

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

The enzymatic complex 5α-reductase (5α-R) and 3α/3β-hydroxysteroid oxidoreductase (HSOR) is expressed in the nervous system, where it transforms progesterone (PROG) and testosterone (T) into neuroactive metabolites. These metabolites regulate myelination, brain maturation, neurotransmission, reproductive behavior and the stress response. The expression of 5α-R and 3α-HSOR and the levels of PROG and T reduced metabolites show regional and sex differences in the nervous system and are affected by changing physiological conditions as well as by neurodegenerative and psychiatric disorders. A decrease in their nervous tissue levels may negatively impact the course and outcome of some pathological events. However, in other pathological conditions their increased levels may have a negative impact. Thus, the use of synthetic analogues of these steroids or 5α-R modulation have been proposed as therapeutic approaches for several nervous system pathologies. However, further research is needed to fully understand the consequences of these manipulations, in particular with 5α-R inhibitors.
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http://dx.doi.org/10.1016/j.yfrne.2020.100836DOI Listing
April 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

Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: a pilot study.

Endocr Connect 2019 Aug;8(8):1118-1125

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

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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http://dx.doi.org/10.1530/EC-19-0199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652249PMC
August 2019

Sex differences in the brain expression of steroidogenic molecules under basal conditions and after gonadectomy.

J Neuroendocrinol 2019 06 29;31(6):e12736. Epub 2019 May 29.

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

The brain is a steroidogenic tissue. It expresses key molecules involved in the synthesis and metabolism of neuroactive steroids, such as steroidogenic acute regulatory protein (StAR), translocator protein 18 kDa (TSPO), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenases (3β-HSD), 5α-reductases (5α-R) and 3α-hydroxysteroid oxidoreductases (3α-HSOR). Previous studies have shown that the levels of brain steroids are different in male and female rats under basal conditions and after gonadectomy. In the present study, we assessed gene expression of key neurosteroidogenic molecules in the cerebral cortex and cerebellum of gonadally intact and gonadectomised adult male and female rats. In the cerebellum, the basal mRNA levels of StAR and 3α-HSOR were significantly higher in females than in males. By contrast, the mRNA levels of TSPO and 5α-R were significantly higher in males. In the cerebral cortex, all neurosteroidogenic molecules analysed showed similar mRNA levels in males and females. Gonadectomy increased the expression of 5α-R in the brain of both sexes, although it affected the brain expression of StAR, TSPO, P450scc and 3α-HSOR in females only and with regional differences. Although protein levels were not investigated in the present study, our findings indicate that mRNA expression of steroidogenic molecules in the adult rat brain is sexually dimorphic and presents regional specificity, both under basal conditions and after gonadectomy. Thus, local steroidogenesis may contribute to the reported sex and regional differences in the levels of brain neuroactive steroids and may be involved in the generation of sex differences in the adult brain function.
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http://dx.doi.org/10.1111/jne.12736DOI Listing
June 2019

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.

Psychoneuroendocrinology 2019 01 18;99:206-215. Epub 2018 Sep 18.

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

Persistent alteration of plasma neuroactive steroid levels associated with major depression has been recently reported in men after the suspension of the treatment for androgenetic alopecia with finasteride, an inhibitor of the enzyme 5alpha-reductase. Observations in male rats confirmed persistent alterations in neuroactive steroid levels also in the brain. In the present study, we have ascertained possible effects on depressive-like behavior, neurogenesis, gliosis, neuroinflammation and gut microbiota in male rats after subchronic treatment for 20 days with finasteride and after one month of its withdrawal. At the end of treatment there was an increase in the number of pH3 immunoreactive cells in the subgranular zone of the dentate gyrus together with an increase in the mRNA levels of TNF-α in the hippocampus. By one month after the end of finasteride treatment, rats showed depressive-like behavior coupled with a decrease in the number of pH3 immunoreactive cells in the subgranular zone of the dentate gyrus, a decrease in granule cell density in the granule cell layer and an increase in the number of GFAP immunoreactive astrocytes in the dentate gyrus. Finally, alteration of gut microbiota (i.e., an increase in Bacteroidetes phylum and in Prevotellaceae family at the end of the treatment and a decrease in Ruminococcaceae family, Oscillospira and Lachnospira genus at the end of the withdrawal period) was detected. In conclusion, finasteride treatment in male rats has long term effects on depressive-like behavior, hippocampal neurogenesis and neuroinflammation and gut microbiota composition.
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http://dx.doi.org/10.1016/j.psyneuen.2018.09.021DOI Listing
January 2019

Neuroactive Steroids and Sex-Dimorphic Nervous Damage Induced by Diabetes Mellitus.

Cell Mol Neurobiol 2019 May 14;39(4):493-502. Epub 2018 Aug 14.

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

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.
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http://dx.doi.org/10.1007/s10571-018-0613-6DOI Listing
May 2019

Post-finasteride syndrome and post-SSRI sexual dysfunction: two sides of the same coin?

Endocrine 2018 08 19;61(2):180-193. Epub 2018 Apr 19.

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

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.
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http://dx.doi.org/10.1007/s12020-018-1593-5DOI Listing
August 2018

Axonal transport in a peripheral diabetic neuropathy model: sex-dimorphic features.

Biol Sex Differ 2018 01 19;9(1). Epub 2018 Jan 19.

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

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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http://dx.doi.org/10.1186/s13293-018-0164-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775621PMC
January 2018

Diabetes induces mitochondrial dysfunction and alters cholesterol homeostasis and neurosteroidogenesis in the rat cerebral cortex.

J Steroid Biochem Mol Biol 2018 04 26;178:108-116. Epub 2017 Nov 26.

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

The nervous system synthesizes and metabolizes steroids (i.e., neurosteroidogenesis). Recent observations indicate that neurosteroidogenesis is affected by different nervous pathologies. Among these, long-term type 1 diabetes, together with other functional and biochemical changes, has been shown to alter neuroactive steroid levels in the nervous system. Using an experimental model of type 1 diabetes (i.e., streptozotocin injection) we here show that the levels of these molecules are already decreased in the rat cerebral cortex after one month of the initiation of the pathology. Moreover, decreased levels of free cholesterol, together with alterations in the expression of molecules involved in cholesterol biosynthesis, bioavailability, trafficking and metabolism were detected in the rat cerebral cortex after one month of diabetes. Furthermore, mitochondrial functionality was also affected in the cerebral cortex and consequently may also contribute to the decrease in neuroactive steroid levels. Altogether, these results indicate that neurosteroidogenesis is an early target for the effect of type 1 diabetes in the cerebral cortex.
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http://dx.doi.org/10.1016/j.jsbmb.2017.11.009DOI Listing
April 2018

Neuroactive steroid levels and psychiatric and andrological features in post-finasteride patients.

J Steroid Biochem Mol Biol 2017 07 10;171:229-235. Epub 2017 Apr 10.

Experimental Neurology Unit and Milan Center for Neuroscience, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.

Recent reports show that, in patients treated with finasteride for male pattern hair loss, persistent side effects including sexual side effects, depression, anxiety and cognitive complaints may occur. We here explored the psychiatric and andrological features of patients affected by post-finasteride syndrome (PFS) and verified whether the cerebrospinal fluid (CSF) and plasma levels of neuroactive steroids (i.e., important regulators of nervous function) are modified. We found that eight out of sixteen PFS male patients considered suffered from a DSM-IV major depressive disorder (MDD). In addition, all PFS patients showed erectile dysfunction (ED); in particular, ten patients showed a severe and six a mild-moderate ED. We also reported abnormal somatosensory evoked potentials of the pudendal nerve in PFS patients with severe ED, the first objective evidence of a neuropathy involving peripheral neurogenic control of erection. Testicular volume by ultrasonography was normal in PFS patients. Data obtained on neuroactive steroid levels also indicate interesting features. Indeed, decreased levels of pregnenolone, progesterone and its metabolite (i.e., dihydroprogesterone), dihydrotestosterone and 17beta-estradiol and increased levels of dehydroepiandrosterone, testosterone and 5alpha-androstane-3alpha,17beta-diol were observed in CSF of PFS patients. Neuroactive steroid levels were also altered in plasma of PFS patients, however these changes did not reflect exactly what occurs in CSF. Finally, finasteride did not only affect, as expected, the levels of 5alpha-reduced metabolites of progesterone and testosterone, but also the further metabolites and precursors suggesting that this drug has broad consequence on neuroactive steroid levels of PFS patients.
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http://dx.doi.org/10.1016/j.jsbmb.2017.04.003DOI Listing
July 2017

Short-term effects of diabetes on neurosteroidogenesis in the rat hippocampus.

J Steroid Biochem Mol Biol 2017 03 23;167:135-143. Epub 2016 Nov 23.

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

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.
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http://dx.doi.org/10.1016/j.jsbmb.2016.11.019DOI Listing
March 2017
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