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...
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)
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.
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...
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)
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.
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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