Diabetic neuropathic pain: a role for testosterone metabolites

Calabrese, Donato; Giatti, Silvia; Romano, Simone; Porretta-Serapiglia, Carla; Bianchi, Roberto; Milanese, Marco; Bonanno, Giambattista; Caruso, Donatella; Viviani, Bárbara; Gardoni, Fabrizio; Garcia-Segura, Luis Miguel; Melcangi, Roberto Cosimo

doi:10.1530/joe-13-0541

Cited by 30 publications

(20 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DHT treatment was able to completely abolish astrocyte reactivity as well as to significantly reduce MHC-II staining. An effect of DHT in astrocyte and microglia reactivity is not surprising since, as demonstrated in other experimental models, these cellular components are a target for DHT [34,51,52] . This finding was further supported by TSPO expression analysis.…”

Section: Discussionmentioning

confidence: 72%

Dihydrotestosterone as a Protective Agent in Chronic Experimental Autoimmune Encephalomyelitis

et al. 2015

Self Cite

View full text Add to dashboard Cite

Multiple sclerosis is a chronic inflammatory disease affecting the central nervous system. As reported by clinical observations, variation in hormonal levels might alter disease susceptibility and progression. Specifically, decreased levels of testosterone in males are reported to be permissive for disease onset. Accordingly, testosterone seems to exert protective effects in experimental autoimmune encephalomyelitis (EAE). In this context, it is important to highlight that testosterone is further metabolized into 17ß-estradiol or dihydrotestosterone (DHT). In this study, we aimed to explore the protective effects of DHT treatment in EAE Dark Agouti rats (i.e. an experimental model showing a protracted relapsing EAE). Data obtained 45 days after EAE induction showed that DHT exerts a beneficial effect on clinical scores, coupled with decreased gliosis (i.e. glial fibrillary acidic protein and major histocompatibility complex of class II staining) and inflammation (i.e. translocator protein 18 kDa, interleukin-1ß, Toll-like receptor 4 and nuclear factor-κB expression) in the spinal cord. Moreover, parameters linked to oxidative stress and tissue damage, like thiobarbituric acid-reactive substance levels and Bcl-2-associated X protein expression, and to mitochondrial activity (i.e. content of mitochondrial DNA and proteins), were improved after DHT administration. This neuroactive steroid may be further metabolized into 3a- or 3ß-diol. However, assessment of the levels of these metabolites after DHT treatment seems to suggest that the protective effects observed here are due to DHT itself. Altogether, the present results indicate that DHT was effective in reducing the severity of chronic EAE and, consequently, may represent an interesting perspective for multiple sclerosis treatment.

show abstract

Section: Discussionmentioning

confidence: 72%

Dihydrotestosterone as a Protective Agent in Chronic Experimental Autoimmune Encephalomyelitis

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Finally, gonadal hormones could be key players in chronic pain, since both testosterone (and/or its metabolites) (Calabrese et al, 2014) and estrogen can be involved in the perception and chronification of pain (Arevalo, Santos-Galindo, Bellini, Azcoitia, & Garcia-Segura, 2010; Garcia-Segura & Melcangi, 2006; Papka et al, 2001; Shughrue, Lane, & Merchenthaler, 1997; Vanderhorst, Gustafsson, & Ulfhake, 2005), despite that fact that no association has been observed between estrogen exposure and CRPS in female patients (de Mos, Huygen, Stricker, Dieleman, & Sturkenboom, 2009). Nonetheless, the use of overiectomized mice could be useful in evaluating CRPS-related sex differences in future investigations.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in a Murine Model of Complex Regional Pain Syndrome

Tajerian

Sahbaie

Sun

et al. 2015

Neurobiology of Learning and Memory

View full text Add to dashboard Cite

Complex Regional Pain Syndrome (CRPS) is a major cause of chronic pain after surgery or trauma to the limbs. Despite evidence showing that the prevalence and severity of many forms of chronic pain, including CRPS, differ between males and females, laboratory studies on sex-related differences in animal models of CRPS are not available, and the impact of sex on the transition from acute to chronic CRPS pain and disability are unexplored. Here we make use of a tibia fracture/cast mouse model that recapitulates the nociceptive, functional, vascular, trophic, inflammatory and immune aspects of CRPS. Our aim is to describe the chronic time course of nociceptive, motor and memory changes associated with fracture/cast in male and female mice, in addition to exploring their underlying spinal mechanisms. Our behavioral data shows that, compared to males, female mice display lower nociceptive thresholds following fracture in the absence of any differences in ongoing or spontaneous pain. Furthermore, female mice show exaggerated signs of motor dysfunction, deficits in fear memory, and latent sensitization that manifests long after the normalization of nociceptive thresholds. Our biochemical data show differences in the spinal cord levels of the glutamate receptor NR2b, suggesting sex differences in mechanisms of central sensitization that could account for differences in duration and severity of CRPS symptoms between the two groups.

show abstract

“…Moreover, 5α-R metabolites of T have been also recently demonstrated as potential agents for the treatment of diabetic neuropathic pain [170]. Indeed, 5α-DHT counteracts the effect of diabetes on mechanical nociceptive threshold, pre-and post-synaptic components, glutamate release, astrocyte immunoreactivity and expression of interleukin-1β, while its metabolite, 3α-diol, was effective on tactile allodynia threshold, glutamate release, astrocyte immunoreactivity and the expression of substance P, toll-like receptor 4, tumor necrosis factor-α, transforming growth factor β-1, interleukin-1β and translocator protien 18-kDa (TSPO) [170].…”

Section: Effects Of 5α-ri Therapy On Neurobehavioral Functions and Nementioning

confidence: 99%

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

Traish

Melcangi

Bortolato

et al. 2015

Rev Endocr Metab Disord

Self Cite

View full text Add to dashboard Cite

Steroids are important physiological orchestrators of endocrine as well as peripheral and central nervous system functions. One of the key processes for regulation of these molecules lies in their enzymatic processing by a family of 5α-reductase (5α-Rs) isozymes. By catalyzing a key rate-limiting step in steroidogenesis, this family of enzymes exerts a crucial role not only in the physiological control but also in pathological events. Indeed, both 5α-R inhibition and supplementation of 5α-reduced metabolites are currently used or have been proposed as therapeutic strategies for a wide array of pathological conditions. In particular, the potent 5α-R inhibitors finasteride and dutasteride are used in the treatments of benign prostatic hyperplasia (BPH), as well as in male pattern hair loss (MPHL) known as androgenetic alopecia (AGA). Recent preclinical and clinical findings indicate that 5α-R inhibitors evoke not only beneficial, but also adverse effects. Future studies should investigate the biochemical and physiological mechanisms that underlie the persistence of the adverse sexual side effects to determine why a subset of patients is afflicted with such persistence or irreversible adverse effects. Also a better focus of clinical research is urgently needed to better define those subjects who are likely to be adversely affected by such agents. Furthermore, research on the non-sexual adverse effects such as diabetes, psychosis, depression, and cognitive function are needed to better understand the broad spectrum of the effects these drugs may elicit during their use in treatment of AGA or BPH. In this review, we will summarize the state of art on this topic, overview the key unresolved questions that have emerged on the pharmacological targeting of these enzymes and their products, and highlight the need for further studies to ascertain the severity and duration of the adverse effects of 5α-R inhibitors, as well as their biological underpinnings.

show abstract

Diabetic neuropathic pain: a role for testosterone metabolites

Cited by 30 publications

References 69 publications

Dihydrotestosterone as a Protective Agent in Chronic Experimental Autoimmune Encephalomyelitis

Dihydrotestosterone as a Protective Agent in Chronic Experimental Autoimmune Encephalomyelitis

Sex differences in a Murine Model of Complex Regional Pain Syndrome

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

Contact Info

Product

Resources

About