Age-related changes in neuroactive steroid levels in 3xTg-AD mice

Caruso, Donatella; Barron, Anna M.; Brown, Meghan; Abbiati, Federico; Carrero, Paloma; Pike, Christian J.; Garcia-Segura, Luis Miguel; Melcangi, Roberto Cosimo

doi:10.1016/j.neurobiolaging.2012.10.007

Cited by 103 publications

(71 citation statements)

References 51 publications

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“…This is in agreement with the general decrease of neuroactive steroid levels observed in different animal models of neurodegeneration, such as Parkinson's disease, multiple sclerosis, peripheral neuropathies and diabetic encephalopathy [31,171,[183][184][185][186][187][188][189][190][191][192][193].…”

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

confidence: 84%

“…Alteration in PROG metabolism has been also further confirmed in male brains from a mouse model of AD (i.e., 3xTg-AD mice) [186]. An age-related decrease in the levels of PROG, together with an increase in the levels of its metabolite 5α-DHP, was detected in the limbic region of wild type (WT) and 3xTg-AD mice.…”

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

confidence: 71%

“…These correlations were not detected in WT mice. In contrast, 3xTg-AD mice did not show the positive correlations in the levels of PREG and DHP and in the levels of THP and isopregnanolone that were detected in young and older WT mice, respectively [186]. In addition, THP, and therefore 5α-Rs, participates in brain maturation and protection during late gestation and in newborns [195].…”

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

confidence: 82%

See 2 more Smart Citations

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

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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.

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

confidence: 84%

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

confidence: 71%

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

confidence: 82%

See 1 more Smart Citation

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

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“…Studies performed in humans, animals, and cellular models have shown alterations in the synthesis of neurosteroids that declined during brain aging paralleled by a loss of important nervous functions, such as memory, and were further associated with PD and AD [14][15][16]. Thus, several neurosteroids have been quantified in various brain regions of aged AD patients and aged non-demented controls.…”

Section: Introductionmentioning

confidence: 99%

Improvement of neuronal bioenergetics by neurosteroids: Implications for age-related neurodegenerative disorders

Grimm

Schmitt

Lang

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The brain has high energy requirements to maintain neuronal activity. Consequently impaired mitochondrial function will lead to disease. Normal aging is associated with several alterations in neurosteroid production and secretion. Decreases in neurosteroid levels might contribute to brain aging and loss of important nervous functions, such as memory. Up to now, extensive studies only focused on estradiol as a promising neurosteroid compound that is able to ameliorate cellular bioenergetics, while the effects of other steroids on brain mitochondria are poorly understood or not investigated at all. Thus, we aimed to characterize the bioenergetic modulating profile of a panel of seven structurally diverse neurosteroids (progesterone, estradiol, estrone, testosterone, 3α-androstanediol, DHEA and allopregnanolone), known to be involved in brain function regulation. Of note, most of the steroids tested were able to improve bioenergetic activity in neuronal cells by increasing ATP levels, mitochondrial membrane potential and basal mitochondrial respiration. In parallel, they modulated redox homeostasis by increasing antioxidant activity, probably as a compensatory mechanism to a slight enhancement of ROS which might result from the rise in oxygen consumption. Thereby, neurosteroids appeared to act via their corresponding receptors and exhibited specific bioenergetic profiles. Taken together, our results indicate that the ability to boost mitochondria is not unique to estradiol, but seems to be a rather common mechanism of different steroids in the brain. Thus, neurosteroids may act upon neuronal bioenergetics in a delicate balance and an age-related steroid disturbance might be involved in mitochondrial dysfunction underlying neurodegenerative disorders.

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“…Indeed, as demonstrated in experimental models and clinical studies, neurodegenerative and psychiatric disorders affect neuroactive steroid levels [13,[49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. For instance, neuroactive steroid levels are modified in experimental models of acquired peripheral neuropathy, such as those due to trauma [68] or diabetes [50,61] and inherited peripheral neuropathy (e.g., Charcot-Marie-Tooth type 1A, CMT1A) [49].…”

Section: Neural Pathology Influences Neuroactive Steroid Levelsmentioning

confidence: 99%