Despite its efficacy for treating androgenetic alopecia, finasteride, an inhibitor of 5α‐reductas... more Despite its efficacy for treating androgenetic alopecia, finasteride, an inhibitor of 5α‐reductase (i.e., the enzyme converting testosterone, T, into dihydrotestosterone, DHT), is associated with several side effects including sexual dysfunction (e.g., erectile dysfunction). These side effects may persist after drug suspension, inducing the so‐called post‐finasteride syndrome (PFS). The effects of subchronic treatment with finasteride (i.e., 20 days) and its withdrawal (i.e., 1 month) in rat corpus cavernosum have been explored here. Data obtained show that the treatment was able to decrease the levels of the enzyme 5α‐reductase type II in the rat corpus cavernosum with increased T and decreased DHT levels. This local change in T metabolism was linked to mechanisms associated with erectile dysfunction. Indeed, by targeted metabolomics, we reported a decrease in the nitric oxide synthase (NOS) activity, measured by the citrulline/arginine ratio and confirmed by the decrease in NO2 le...
Important complications of diabetes mellitus in the nervous system are represented by diabetic pe... more Important complications of diabetes mellitus in the nervous system are represented by diabetic peripheral neuropathy and diabetic encephalopathy. In this context, an important link is represented by neuroactive steroids (i.e., steroids coming from peripheral glands and affecting nervous functionality as well as directly synthesized in the nervous system). Indeed, diabetes does not only affect the reproductive axis and consequently the levels of sex steroid hormones, but also those of neuroactive steroids. Indeed, as will be here summarized, the levels of these neuromodulators present in the central and peripheral nervous system are affected by the pathology in a sex-dimorphic way. In addition, some of these neuroactive steroids, such as the metabolites of progesterone or testosterone, as well as pharmacological tools able to increase their levels have been demonstrated, in experimental models, to be promising protective agents against diabetic peripheral neuropathy and diabetic encephalopathy.
Background: Multiple sclerosis (MS) varies considerably in its incidence and progression in femal... more 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 genderrelated 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 genderdependent 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.
Progestins are a broad class of progestational agents widely differing in their chemical structur... more Progestins are a broad class of progestational agents widely differing in their chemical structures and pharmacological properties. Despite emerging data suggest that progestins, besides their action as endometrial protection, can also have multiple nonreproductive functions, much remains to be discovered regarding the actions exerted by these molecules in the nervous system. Here, we report the role exerted by different progestins, currently used for contraception or in postmenopausal hormone replacement therapies, in regulating cognitive functions as well as social behavior and mood. We provide evidence that the effects and mechanisms underlying their actions are still confusing due to the use of different estrogens and progestins as well as different doses, duration of exposure, route of administration, baseline hormonal status and age of treated women. We also discuss the emerging issue concerning the relevant increase of these substances in the environment, able to deeply affect aquatic wildlife as well as to exert a possible influence in humans, which may be exposed to these compounds via contaminated drinking water and seafood. Finally, we report literature data showing the neurobiological action of progestins and in particular their importance during neurodegenerative events. This is extremely interesting, since some of the progestins currently used in clinical practice exert neuroprotective and anti-inflammatory effects in the nervous system, opening new promising opportunities for the use of these molecules as therapeutic agents for trauma and neurodegenerative disorders.
Neuroactive steroid levels are altered in several experimental models of peripheral neuropathy, a... more Neuroactive steroid levels are altered in several experimental models of peripheral neuropathy, and on this basis, they have been proposed as protective agents. For the first time, the levels of these molecules were assessed here in sterol regulatory element binding protein-1c knockout male mice (i.e., an experimental model of peripheral neuropathy) and compared with observations in wild type animals. The levels of neuroactive steroids have been evaluated by liquid chromatography-tandem mass spectrometry in plasma and sciatic nerve at 2 and 10 months of age and these analyses were implemented analyzing the gene expression of crucial steroidogenic enzymes in sciatic nerve. Data obtained at 2 months of age showed high levels of pregnenolone in sciatic nerve, associated with low levels of its first metabolite, progesterone, and further metabolites (i.e., 5a-pregnane-3,20-dione and 5a-pregnan-3b-ol-20-one). High levels of testosterone and 17b-estradiol were also observed. At 10 months of age, the neuroactive steroid profile showed some differences. Indeed, low levels of pregnenolone and high levels of 5a-pregnan-3a-ol-20-one and 5a-pregnan-3bol-20-one were observed. The analysis of the gene expression of steroidogenic enzymes considered here generally followed these changes. Interestingly, the levels of pregnenolone and progesterone were unmodified in plasma suggesting a specific effect of sterol regulatory element binding protein-1c on neurosteroidogenesis. Because this peripheral neuropathy is due to altered fatty acid biosynthesis, data reported here support the belief that the cross-talk between this biosynthetic pathway and neuroactive steroids may represent a possible therapeutic strategy for peripheral neuropathy.
Deleterious effects of diabetes on the nervous system are responsible for several disorders inclu... more Deleterious effects of diabetes on the nervous system are responsible for several disorders including damage to the peripheral nervous system. However, in spite of the number of studies on human and experimental diabetic neuropathy, the current therapeutic arsenal is meagre. Consequently, the search for substances to protect the nervous system from the degenerative effects of diabetes has high priority in biomedical research. Because of the importance of neuroactive steroids in the control of the nervous system functions and of their neuroprotective effects in several experimental models of neurodegenerative diseases, we have assessed whether chronic treatment with progesterone (P), and its derivatives, dihydroprogesterone (DHP) and tetrahydroprogesterone (THP), had protective effects against (STZ)-induced peripheral neuropathy at the neurophysiological, functional, biochemical and neuropathological levels. Data obtained have indicated that chronic treatment for 1 month with P, or with its derivatives, DHP and THP, counteracted the impairment of nerve conduction velocity (NCV) and thermal threshold, restored skin innervation density, and improved Na+,K+-ATPase activity and mRNA levels of myelin proteins, such as glycoprotein zero and peripheral myelin protein 22. Moreover, protective effects of these neuroactive steroids in STZ-rat were also evident on morphological degeneration of the sciatic nerve. Indeed, treatment with P or DHP induced a significant reduction in the number of fibers with myelin infoldings. Altogether these observations suggest that these neuroactive steroids might be useful protective agents in diabetic neuropathy. Interestingly, different receptors seem to be involved in these effects. Thus, while morphological integrity of myelin, the expression of myelin proteins and Na+,K+-ATPase activity are only influenced by P and DHP, (i.e., two neuroactive steroids interacting with P receptor, PR), NCV, thermal nociceptive threshold and intra-epidermal nerve fiber density are also affected by THP, which interacts with GABA-A receptor. Because, a therapeutic approach with specific synthetic receptor ligands could avoid the typical side effects of steroids, future experiments will be devoid to evaluate the role of PR and GABA-A receptor in these protective effects. (PRIN-2005060584_004 and FIRST from University of Milan)
Nutrition Metabolism and Cardiovascular Diseases, 2017
bioimpedentiometry, ultrasonographic VFA, liver steatosis, flow mediated dilation (FMD), echocard... more bioimpedentiometry, ultrasonographic VFA, liver steatosis, flow mediated dilation (FMD), echocardiography. Patients who normalized glycosilated haemoglobin (HbA1c) experienced a larger weight loss (p¼ .028). The probability of normalizing HbA1c was directly correlated to TWL (rho¼ .461; p¼ .027). Diabetics experienced a greater improvement of systolic blood pressure (p¼.008), VFA (p¼.036), HDL (p¼.046), HOMA (p¼.001) and HbA1c (p<.001) than non hypertensive. Conclusion: According to our data, in diabetics the most important determinant of glucose control after surgery is weight loss. Diabetics and hypertensive patients experienced a greater improvement of vascular and metabolic status than non diabetics and non hypertensive; hence these data strengthen indications to bariatric surgery in presence of comorbidities. No parameter seems to be directly responsible for surgery-associated cardiovascular improvement, suggesting the presence of others mechanisms involved.
Neuroinflammatory condition is a common characteristic shared by different neurodegenerative dise... more Neuroinflammatory condition is a common characteristic shared by different neurodegenerative diseases. To date, therapeutic interventions able to stop neuroinflammation and promote repair is still lacking. Neuroactive steroids are cholesterol-derived molecules that exert their functions acting on the central nervous system. They modulate important physiological pathways both during development and during adulthood. Moreover, neuroactive steroids are able to exert important protective effects in pathological conditions. Here, we will present an overview of the protective effects exerted by neuroactive steroids on neuroinflammation, with a particular focus in multiple sclerosis and its experimental models.
International Journal of Molecular Sciences, Nov 26, 2020
Peripheral neuropathy (PN) refers to many conditions involving damage to the peripheral nervous s... more 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.
The Journal of Steroid Biochemistry and Molecular Biology, Oct 1, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The pathological consequences of type 2 diabetes mellitus (T2DM) also involve the central nervous... more The pathological consequences of type 2 diabetes mellitus (T2DM) also involve the central nervous system; indeed, T2DM patients suffer from learning and memory disabilities with a higher risk of developing dementia. Although several factors have been proposed as possible contributors, how neuroactive steroids and the gut microbiome impact brain pathophysiology in T2DM remain unexplored. On this basis, in male Zucker diabetic fatty (ZDF) rats, we studied whether T2DM alters memory abilities using the novel object recognition test, neuroactive steroid levels by liquid chromatography–tandem mass spectrometry, hippocampal parameters using molecular assessments, and gut microbiome composition using 16S next-generation sequencing. Results obtained reveal that T2DM worsens memory abilities and that these are correlated with increased levels of corticosterone in plasma and with a decrease in allopregnanolone in the hippocampus, where neuroinflammation, oxidative stress, and mitochondrial dy...
The development and progression of diabetic polyneuropathy (DPN) are due to multiple mechanisms. ... more The development and progression of diabetic polyneuropathy (DPN) are due to multiple mechanisms. The creation of reliable animal models of DPN has been challenging and this issue has not yet been solved. However, despite some recognized differences from humans, most of the current knowledge on the pathogenesis of DPN relies on results achieved using rodent animal models. The simplest experimental DPN model reproduces type 1 diabetes, induced by massive chemical destruction of pancreatic beta cells with streptozotocin (STZ). Spontaneous/transgenic models of diabetes are less frequently used, mostly because they are less predictable in clinical course, more expensive, and require a variable time to achieve homogeneous metabolic conditions. Among them, Zucker diabetic fatty (ZDF) rats represent a typical type 2 diabetes model. Both STZ-induced and ZDF rats have been extensively used, but only very few studies have compared the long-term similarities and differences existing between the...
Patients affected by diabetes mellitus (DM) show diabetic encephalopathy with an increased risk o... more Patients affected by diabetes mellitus (DM) show diabetic encephalopathy with an increased risk of cognitive deficits, dementia and Alzheimer’s disease, but the mechanisms are not fully explored. In the male animal models of DM, the development of cognitive impairment seems to be the result of the concomitance of different processes such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and aberrant synaptogenesis. However, even if diabetic encephalopathy shows some sex-dimorphic features, no observations in female rats have been so far reported on these aspects. Therefore, in an experimental model of type 1 DM (T1DM), we explored the impact of one month of pathology on memory abilities by the novel object recognition test and on neuroinflammation, synaptogenesis and mitochondrial functionality. Moreover, given that steroids are involved in memory and learning, we also analysed their levels and receptors. We reported that memory dysfunction can be associated with di...
Context Post-finasteride syndrome (PFS) occurs in patients with androgenic alopecia after suspens... more 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 pr...
Despite its efficacy for treating androgenetic alopecia, finasteride, an inhibitor of 5α‐reductas... more Despite its efficacy for treating androgenetic alopecia, finasteride, an inhibitor of 5α‐reductase (i.e., the enzyme converting testosterone, T, into dihydrotestosterone, DHT), is associated with several side effects including sexual dysfunction (e.g., erectile dysfunction). These side effects may persist after drug suspension, inducing the so‐called post‐finasteride syndrome (PFS). The effects of subchronic treatment with finasteride (i.e., 20 days) and its withdrawal (i.e., 1 month) in rat corpus cavernosum have been explored here. Data obtained show that the treatment was able to decrease the levels of the enzyme 5α‐reductase type II in the rat corpus cavernosum with increased T and decreased DHT levels. This local change in T metabolism was linked to mechanisms associated with erectile dysfunction. Indeed, by targeted metabolomics, we reported a decrease in the nitric oxide synthase (NOS) activity, measured by the citrulline/arginine ratio and confirmed by the decrease in NO2 le...
Important complications of diabetes mellitus in the nervous system are represented by diabetic pe... more Important complications of diabetes mellitus in the nervous system are represented by diabetic peripheral neuropathy and diabetic encephalopathy. In this context, an important link is represented by neuroactive steroids (i.e., steroids coming from peripheral glands and affecting nervous functionality as well as directly synthesized in the nervous system). Indeed, diabetes does not only affect the reproductive axis and consequently the levels of sex steroid hormones, but also those of neuroactive steroids. Indeed, as will be here summarized, the levels of these neuromodulators present in the central and peripheral nervous system are affected by the pathology in a sex-dimorphic way. In addition, some of these neuroactive steroids, such as the metabolites of progesterone or testosterone, as well as pharmacological tools able to increase their levels have been demonstrated, in experimental models, to be promising protective agents against diabetic peripheral neuropathy and diabetic encephalopathy.
Background: Multiple sclerosis (MS) varies considerably in its incidence and progression in femal... more 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 genderrelated 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 genderdependent 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.
Progestins are a broad class of progestational agents widely differing in their chemical structur... more Progestins are a broad class of progestational agents widely differing in their chemical structures and pharmacological properties. Despite emerging data suggest that progestins, besides their action as endometrial protection, can also have multiple nonreproductive functions, much remains to be discovered regarding the actions exerted by these molecules in the nervous system. Here, we report the role exerted by different progestins, currently used for contraception or in postmenopausal hormone replacement therapies, in regulating cognitive functions as well as social behavior and mood. We provide evidence that the effects and mechanisms underlying their actions are still confusing due to the use of different estrogens and progestins as well as different doses, duration of exposure, route of administration, baseline hormonal status and age of treated women. We also discuss the emerging issue concerning the relevant increase of these substances in the environment, able to deeply affect aquatic wildlife as well as to exert a possible influence in humans, which may be exposed to these compounds via contaminated drinking water and seafood. Finally, we report literature data showing the neurobiological action of progestins and in particular their importance during neurodegenerative events. This is extremely interesting, since some of the progestins currently used in clinical practice exert neuroprotective and anti-inflammatory effects in the nervous system, opening new promising opportunities for the use of these molecules as therapeutic agents for trauma and neurodegenerative disorders.
Neuroactive steroid levels are altered in several experimental models of peripheral neuropathy, a... more Neuroactive steroid levels are altered in several experimental models of peripheral neuropathy, and on this basis, they have been proposed as protective agents. For the first time, the levels of these molecules were assessed here in sterol regulatory element binding protein-1c knockout male mice (i.e., an experimental model of peripheral neuropathy) and compared with observations in wild type animals. The levels of neuroactive steroids have been evaluated by liquid chromatography-tandem mass spectrometry in plasma and sciatic nerve at 2 and 10 months of age and these analyses were implemented analyzing the gene expression of crucial steroidogenic enzymes in sciatic nerve. Data obtained at 2 months of age showed high levels of pregnenolone in sciatic nerve, associated with low levels of its first metabolite, progesterone, and further metabolites (i.e., 5a-pregnane-3,20-dione and 5a-pregnan-3b-ol-20-one). High levels of testosterone and 17b-estradiol were also observed. At 10 months of age, the neuroactive steroid profile showed some differences. Indeed, low levels of pregnenolone and high levels of 5a-pregnan-3a-ol-20-one and 5a-pregnan-3bol-20-one were observed. The analysis of the gene expression of steroidogenic enzymes considered here generally followed these changes. Interestingly, the levels of pregnenolone and progesterone were unmodified in plasma suggesting a specific effect of sterol regulatory element binding protein-1c on neurosteroidogenesis. Because this peripheral neuropathy is due to altered fatty acid biosynthesis, data reported here support the belief that the cross-talk between this biosynthetic pathway and neuroactive steroids may represent a possible therapeutic strategy for peripheral neuropathy.
Deleterious effects of diabetes on the nervous system are responsible for several disorders inclu... more Deleterious effects of diabetes on the nervous system are responsible for several disorders including damage to the peripheral nervous system. However, in spite of the number of studies on human and experimental diabetic neuropathy, the current therapeutic arsenal is meagre. Consequently, the search for substances to protect the nervous system from the degenerative effects of diabetes has high priority in biomedical research. Because of the importance of neuroactive steroids in the control of the nervous system functions and of their neuroprotective effects in several experimental models of neurodegenerative diseases, we have assessed whether chronic treatment with progesterone (P), and its derivatives, dihydroprogesterone (DHP) and tetrahydroprogesterone (THP), had protective effects against (STZ)-induced peripheral neuropathy at the neurophysiological, functional, biochemical and neuropathological levels. Data obtained have indicated that chronic treatment for 1 month with P, or with its derivatives, DHP and THP, counteracted the impairment of nerve conduction velocity (NCV) and thermal threshold, restored skin innervation density, and improved Na+,K+-ATPase activity and mRNA levels of myelin proteins, such as glycoprotein zero and peripheral myelin protein 22. Moreover, protective effects of these neuroactive steroids in STZ-rat were also evident on morphological degeneration of the sciatic nerve. Indeed, treatment with P or DHP induced a significant reduction in the number of fibers with myelin infoldings. Altogether these observations suggest that these neuroactive steroids might be useful protective agents in diabetic neuropathy. Interestingly, different receptors seem to be involved in these effects. Thus, while morphological integrity of myelin, the expression of myelin proteins and Na+,K+-ATPase activity are only influenced by P and DHP, (i.e., two neuroactive steroids interacting with P receptor, PR), NCV, thermal nociceptive threshold and intra-epidermal nerve fiber density are also affected by THP, which interacts with GABA-A receptor. Because, a therapeutic approach with specific synthetic receptor ligands could avoid the typical side effects of steroids, future experiments will be devoid to evaluate the role of PR and GABA-A receptor in these protective effects. (PRIN-2005060584_004 and FIRST from University of Milan)
Nutrition Metabolism and Cardiovascular Diseases, 2017
bioimpedentiometry, ultrasonographic VFA, liver steatosis, flow mediated dilation (FMD), echocard... more bioimpedentiometry, ultrasonographic VFA, liver steatosis, flow mediated dilation (FMD), echocardiography. Patients who normalized glycosilated haemoglobin (HbA1c) experienced a larger weight loss (p¼ .028). The probability of normalizing HbA1c was directly correlated to TWL (rho¼ .461; p¼ .027). Diabetics experienced a greater improvement of systolic blood pressure (p¼.008), VFA (p¼.036), HDL (p¼.046), HOMA (p¼.001) and HbA1c (p<.001) than non hypertensive. Conclusion: According to our data, in diabetics the most important determinant of glucose control after surgery is weight loss. Diabetics and hypertensive patients experienced a greater improvement of vascular and metabolic status than non diabetics and non hypertensive; hence these data strengthen indications to bariatric surgery in presence of comorbidities. No parameter seems to be directly responsible for surgery-associated cardiovascular improvement, suggesting the presence of others mechanisms involved.
Neuroinflammatory condition is a common characteristic shared by different neurodegenerative dise... more Neuroinflammatory condition is a common characteristic shared by different neurodegenerative diseases. To date, therapeutic interventions able to stop neuroinflammation and promote repair is still lacking. Neuroactive steroids are cholesterol-derived molecules that exert their functions acting on the central nervous system. They modulate important physiological pathways both during development and during adulthood. Moreover, neuroactive steroids are able to exert important protective effects in pathological conditions. Here, we will present an overview of the protective effects exerted by neuroactive steroids on neuroinflammation, with a particular focus in multiple sclerosis and its experimental models.
International Journal of Molecular Sciences, Nov 26, 2020
Peripheral neuropathy (PN) refers to many conditions involving damage to the peripheral nervous s... more 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.
The Journal of Steroid Biochemistry and Molecular Biology, Oct 1, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The pathological consequences of type 2 diabetes mellitus (T2DM) also involve the central nervous... more The pathological consequences of type 2 diabetes mellitus (T2DM) also involve the central nervous system; indeed, T2DM patients suffer from learning and memory disabilities with a higher risk of developing dementia. Although several factors have been proposed as possible contributors, how neuroactive steroids and the gut microbiome impact brain pathophysiology in T2DM remain unexplored. On this basis, in male Zucker diabetic fatty (ZDF) rats, we studied whether T2DM alters memory abilities using the novel object recognition test, neuroactive steroid levels by liquid chromatography–tandem mass spectrometry, hippocampal parameters using molecular assessments, and gut microbiome composition using 16S next-generation sequencing. Results obtained reveal that T2DM worsens memory abilities and that these are correlated with increased levels of corticosterone in plasma and with a decrease in allopregnanolone in the hippocampus, where neuroinflammation, oxidative stress, and mitochondrial dy...
The development and progression of diabetic polyneuropathy (DPN) are due to multiple mechanisms. ... more The development and progression of diabetic polyneuropathy (DPN) are due to multiple mechanisms. The creation of reliable animal models of DPN has been challenging and this issue has not yet been solved. However, despite some recognized differences from humans, most of the current knowledge on the pathogenesis of DPN relies on results achieved using rodent animal models. The simplest experimental DPN model reproduces type 1 diabetes, induced by massive chemical destruction of pancreatic beta cells with streptozotocin (STZ). Spontaneous/transgenic models of diabetes are less frequently used, mostly because they are less predictable in clinical course, more expensive, and require a variable time to achieve homogeneous metabolic conditions. Among them, Zucker diabetic fatty (ZDF) rats represent a typical type 2 diabetes model. Both STZ-induced and ZDF rats have been extensively used, but only very few studies have compared the long-term similarities and differences existing between the...
Patients affected by diabetes mellitus (DM) show diabetic encephalopathy with an increased risk o... more Patients affected by diabetes mellitus (DM) show diabetic encephalopathy with an increased risk of cognitive deficits, dementia and Alzheimer’s disease, but the mechanisms are not fully explored. In the male animal models of DM, the development of cognitive impairment seems to be the result of the concomitance of different processes such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and aberrant synaptogenesis. However, even if diabetic encephalopathy shows some sex-dimorphic features, no observations in female rats have been so far reported on these aspects. Therefore, in an experimental model of type 1 DM (T1DM), we explored the impact of one month of pathology on memory abilities by the novel object recognition test and on neuroinflammation, synaptogenesis and mitochondrial functionality. Moreover, given that steroids are involved in memory and learning, we also analysed their levels and receptors. We reported that memory dysfunction can be associated with di...
Context Post-finasteride syndrome (PFS) occurs in patients with androgenic alopecia after suspens... more 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 pr...
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