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Multiple sclerosis (MS) is an autoimmune pathology characterized by inflammatory and demyelinating phases. Clinical observations indicate an involvement for sex hormones in thepathology, so that, recently, a therapy for MS based on hormones has been proposed. A clinicaltrial, involving male MS patients, revealed improvement in cognitive performances after one yeartreatment with testosterone (Sicotte et al., 2007). In the experimental autoimmune encephalomyelitis (EAE) mice, a MS animal model, neuroprotective effects of testosterone, and of its metabolite dihydrotestosterone (DHT), were observed (Dalal et al., 1997; Palaszynski et al.,2004). In the same model, castration has deleterious effects on clinical course, suggesting a protective role for androgens (Bebo et al., 1998). Moreover, in vitro evidences showed that testosterone is able to reduce inflammatory cytokines produced by human macrophages (D’Agostino et al., 1999) and monocytes (Li et al., 1993; Liva and Voskuhl, 2001). These antiinflammatory properties may be mediated by the conversion of testosterone into estradiol, or, alternatively, by some direct effects on androgen receptor (AR), mediated by DHT. This steroid can be subsequently converted into 3 alpha-diol, a GABAA receptor agonist, acting as antiinflammatory agent. Based on these evidences, we were interested in explore the protective effects of androgens treatment in a rat EAE model characterized by acute inflammatory events. We induced male Lewis rats with myelin basic protein in order to develop EAE; animals were treated with 3 alpha-diol or vehicle (sesame oil) every other day for two weeks, whereas control rats (i.e., rats not induced with EAE) received in same days only vehicle. Neurological deficits were assessed throughout the experiment (i.e., until 15 days post induction; dpi), and, at 15dpi, spinal cords were dissected. The clinical course and the weight loss of EAE rats treated with 3 alpha-diol were not different when compared to vehicle treated animals. Significant differences between these two groups were instead observed in the spinal cord after immunostaining analysis for the glial fibrillary acidic protein and the major histocompatibility complex class II, where 3 alpha-diol treatment was able to reduce the inflammatory parameters. In agreement with this observation, gene expression for tumor necrosis factor alpha, a pro-inflammatory cytokine, was decreased after 3 alpha-diol administration compared to oil-treated EAE animals. This effect seems specific for proinflammatory cytokine, because the expression of transforming growth factor beta 1, an antiinflammatory cytokine, was not different between vehicle and 3 alpha-diol treated EAE rats. To asses the metabolic fate of the injected 3 alpha-diol, liquid chromatography tandem mass spectrometry analysis were performed in spinal cord from all groups. 3 alpha-diol levels were significantly increased in steroid treated animals; moreover, a significant raise in DHT levels was observed in the same animals, indicating a retroconversion of 3 alpha-diol into DHT. The data we obtained may suggest that the reduction of inflammatory parameters could be due by both the action of DHT on AR and/or of 3 alpha-diol on GABAA receptor. These observations pointed out, for the first time, the effects of 3 alpha-diol on inflammatory parameters in EAE Lewis rats. Future studies will be aimed to elucidate the involvement of androgen and/or GABAA receptors on the observed effects.

Background: The advent of COVID-19 worldwide has led to consequences for people’s health, both physical and psychological, such as fear and anxiety. This is the case in Italy, one of the countries most affected by the pandemic. Given the heightened fear concerning COVID-19 in Italy., the present study analyzed the psychometric properties of the Italian version of the Fear of COVID-19 Scale (FCV-19S).\ud \ud Methods: The sample comprised 250 Italian participants who were administered Italian versions of the FCV-19S, the Hospital Anxiety and Depression Scale (HADS), and the Severity Measure for Specific Phobia–Adult (SMSP-A). Several psychometric tests were performed to investigate the validity and reliability of the test including confirmatory factor analysis.\ud \ud Results: Analysis of the data showed satisfactory psychometric characteristics and confirmed the scale’s unidimensional properties. The seven FCV-19S items had acceptable correlations with the test total (from .443 to .784). Furthermore, the loadings on the factor were significant and strong (from .684 to .897). The internal consistency was very good (α = .871). Construct validity for the FCV-19S was supported by significant and positive correlations with the HADS (r=.649) and SMSP-A (r=.703).\ud \ud Conclusions: The Italian version of the Fear of COVID-19 Scale is valid and reliable in assessing fear of COVID-19 among the general Italian population.

Introduction Observations performed in a subset of subjects treated with finasteride (an inhibitor of the enzyme 5α‐reductase) for male pattern hair loss seem to indicate that sexual dysfunction as well as anxious/depressive symptomatology may occur at the end of the treatment and continue after discontinuation. Aim A possible hypothesis to explain depression symptoms after finasteride treatment might be impairment in the levels of neuroactive steroids. Therefore, neuroactive steroid levels were evaluated in paired plasma and cerebrospinal fluid samples obtained from male patients who received finasteride for the treatment of androgenic alopecia and who, after drug discontinuation, still show long‐term sexual side effects as well as anxious/depressive symptomatology. Methods The levels of neuroactive steroids were evaluated by liquid chromatography–tandem mass spectrometry in three postfinasteride patients and compared to those of five healthy controls. Main Outcome Measures Neuroactive steroid levels in plasma and cerebrospinal fluid of postfinasteride patients and healthy controls. Results At the examination, the three postfinasteride patients reported muscular stiffness, cramps, tremors, and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Severity and frequency of the anxious/depressive symptoms were quite variable; overall, all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of neuroactive steroid levels in patients showed some interindividual differences. However, the most important finding was the comparison of their neuroactive steroid levels with those of healthy controls. Indeed, decreased levels of tetrahydroprogesterone, isopregnanolone and dihydrotestosterone and increased levels of testosterone and 17β‐estradiol were reported in cerebrospinal fluid of postfinasteride patients. Moreover, decreased levels of dihydroprogesterone and increased levels of 5α‐androstane‐3α,17β‐diol and 17β‐estradiol were observed in plasma. Conclusion The present observations confirm that an impairment of neuroactive steroid levels, associated with depression symptoms, is still present in androgenic alopecia patients treated with finasteride despite the discontinuation of the treatment. Melcangi RC, Caruso D, Abbiati F, Giatti S, Calabrese D, Piazza F, and Cavaletti G. Neuroactive steroid levels are modified in cerebrospinal fluid and plasma of postfinasteride patients showing persistent sexual side effects and anxious/depressive symptomatology. J Sex Med 2013;10:2598–2603.

Neuroactive steroids act in the peripheral nervous system as physiological regulators and as protective agents for acquired or inherited peripheral neuropathy. In recent years, modulation of neuroactive steroids levels has been studied as a potential therapeutic approach to protect peripheral nerves from damage induced by diabetes. Nuclear receptors of the liver X receptor (LXR) family regulate adrenal steroidogenesis via their ability to control cholesterol homeostasis. Here we show that rat sciatic nerve expresses both LRXα and β isoforms and that these receptors are functional. Activation of liver X receptors using a synthetic ligand results in increased levels of neurosteroids and protection of the sciatic nerve from neuropathy induced by diabetes. LXR ligand treatment of streptozotocin-treated rats increases expression in the sciatic nerve of steroidogenic acute regulatory protein (a molecule involved in the transfer of cholesterol into mitochondria), of the enzyme P450scc (responsible for conversion of cholesterol into pregnenolone), of 5α-reductase (an enzyme involved in the generation of neuroactive steroids) and of classical LXR targets involved in cholesterol efflux, such as ABCA1 and ABCG1. These effects were associated with increased levels of neuroactive steroids (e.g., pregnenolone, progesterone, dihydroprogesterone and 3α-diol) in the sciatic nerve, and with neuroprotective effects on thermal nociceptive activity, nerve conduction velocity, and Na+, K+-ATPase activity. These results suggest that LXR activation may represent a new pharmacological avenue to increase local neuroactive steroid levels that exert neuroprotective effects in diabetic neuropathy.

Observations performed in a subset of patients treated for male pattern hair loss indicate that persistent sexual side effects as well as anxious/depressive symptomatology have been reported even after discontinuation of finasteride treatment. Due to the capability of finasteride to block the metabolism of progesterone (PROG) and/or testosterone (T) we have evaluated, by liquid chromatography–tandem mass spectrometry, the levels of several neuroactive steroids in paired plasma and cerebrospinal fluid (CSF) samples obtained from post-finasteride patients and in healthy controls. At the examination, post-finasteride patients reported muscular stiffness, cramps, tremors and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Although severity of the anxious/depressive symptoms was quite variable in their frequency, overall all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of neuroactive steroid levels in CSF showed a decrease of PROG and its metabolites, dihydroprogesterone (DHP) and tetrahydroprogesterone (THP), associated with an increase of its precursor pregnenolone (PREG). Altered levels were also observed for T and its metabolites. Thus, a significant decrease of dihydrotestosterone (DHT) associated with an increase of T as well as of 3α-diol was detected. Changes in neuroactive steroid levels also occurred in plasma. An increase of PREG, T, 3α-diol, 3β-diol and 17β-estradiol was associated with decreased levels of DHP and THP. The present observations show that altered levels of neuroactive steroids, associated with depression symptoms, are present in androgenic alopecia patients even after discontinuation of the finasteride treatment. This article is part of a Special Issue entitled ‘Sex steroids and brain disorders’.

Saggio sull'estetica del giardino del letterato durante i Bei Song (960-1127), attraverso l'analisi delle fonti letterarie

Different experimental autoimmune encephalomyelitis models (EAE) have been developed. However, due to the different experimental conditions applied, observations simultaneously considering different pathological targets are still scarce. Using EAE induced in Dark Agouti rats with syngenic whole spinal cord homogenate suspended in incomplete Freund's adjuvant, we here analyze neurosteroidogenic machinery, cytokine levels, microglial cells, infiltration of inflammatory cells, myelin proteins and Na(+), K(+)-ATPase pump activity in the spinal cord. Data obtained in the acute phase of the disease confirmed that neurological signs were accompanied by the presence of perivascular infiltrating T cells (CD3(+) cells) and activated monocytic/microglial cells (ED1(+) and MHC-II(+)) in the spinal cord. In particular, the number of MHC-II(+) cells was significantly increased in association with increased expression of pro- (i.e., TNF-α, IL-1β) and anti-inflammatory (i.e., TGF-β) cytokines as well as with decreased expression of proteolipid protein and myelin basic protein. During the chronic phase of the disease, the number of MHC-II(+) cells was still increased, although less than in the acute phase. Changes in the number of MHC-II(+) cells were associated with decreased Na(+),K(+)-ATPase enzymatic activity. A general decrease in the levels of neuroactive steroids, with the exception of an increase in tetrahydroprogesterone and 17β-estradiol, was detected in the acute phase. These changes were maintained or reverted in the chronic phase of EAE. In conclusion, we report that modifications in the neuroimmune response in the acute and chronic phases of EAE are associated with specific changes in myelin proteins, Na(+),K(+)-ATPase pump and in the levels of neuroactive steroids.

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 streptozotocintreated 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. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc.

Observations so far obtained in experimental autoimmune encephalomyelitis (EAE) have revealed the promising neuroprotective effects exerted by progesterone (PROG). The findings suggest that this neuroactive steroid may potentially represent a therapeutic tool for multiple sclerosis (MS). However, up to now, the efficacy of PROG has been only tested in the acute phase of the disease, whereas it is well known that MS expresses different features depending on the phase of the disease. Accordingly, we have evaluated the effect of PROG treatment in EAE induced in Dark Agouti rats (i.e. an experimental model showing a protracted relapsing EAE). Data obtained 45days after EAE induction show that PROG treatment exerts a beneficial effect on clinical score, confirming surrogate parameters of spinal cord damage in chronic EAE (i.e. reactive microglia, cytokine levels, activity of the Na +,K +-ATPase pump and myelin basic protein expression). An increase of the levels of dihydroprogesterone and isopregnanolone (i.e. two PROG metabolites) was also observed in the spinal cord after PROG treatment. Taken together, these results indicate that PROG is effective in reducing the severity of chronic EAE and, consequently, may have potential with respect to MS treatment. © 2012 The Authors. Journal of Neuroendocrinology © 2012 Blackwell Publishing Ltd.

Our recent observations have demonstrated that gonadectomy in female, but not in male diabetic animals, exert protection in the peripheral nervous system and that these effects were associated with an increase in the levels of dehydroepiandrosterone (DHEA) in the female sciatic nerve [Pesaresi M, Giatti S, Cavaletti G, Abbiati F, Calabrese D, Bianchi R, Caruso D, Garcia-Segura LM, Melcangi RC (2011) Exp Neurol 228:215-221]. That is interesting because the neuroprotective effects of this neuroactive steroid have so far only been analyzed in male diabetic animals. Using the experimental model of streptozotocin-induced diabetic neuropathy, we have here compared the effect of DHEA treatment in male and in female animals. Data obtained indicate that DHEA treatment is able to counteract the decrease in nerve conduction velocity (NCV) induced by diabetes in both sexes. However, it was only in females that this neuroactive steroid was able to reestablish NCV to control levels. In addition, it was only in females that DHEA exerted neuroprotective actions on functional (i.e., thermal sensitivity) or molecular parameters, such as gene expression of myelin proteins. Sex-depending neuroprotective effects of DHEA were also confirmed by the finding that it was only in females that this neuroactive steroid fully restored the intra-epidermal nerve fiber density, which was decreased by diabetes. Interestingly, the metabolic fate of DHEA is also different in males and females. Thus, analysis of the neuroactive steroid levels after the treatment with DHEA indicates that in the sciatic nerve of male diabetic animals 17α-estradiol levels decrease in association with an increase of its isomer 17β-estradiol and with a decrease in the levels of α-androstane-3α, 17β-diol. These changes were not observed in the sciatic nerve of females. Altogether, these results suggest that DHEA could be considered as a candidate for a sex-specific therapy based on neuroactive steroids. © 2011 IBRO.

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. © 2011 Elsevier Inc.