5α-Reductase Isozymes in the Central Nervous System

Poletti, Angelo; Coscarella, Anna; Negri‐Cesi, P.; Colciago, Alessandra; Celotti, F.; Martini, L.

doi:10.1016/s0039-128x(98)00018-x

Cited by 91 publications

(52 citation statements)

References 72 publications

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“…These enzymes are present in the adrenal gland, ovary, brain and placenta. De novo synthesis of allopregnanolone from cholesterol wholly within the CNS is also possible (Poletti et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on fetal guinea pig brain development.

Kelleher¹,

Palliser²,

Walker³

et al. 2010

Journal of Endocrinology

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Progesterone and its neuroactive metabolite, allopregnanolone, are present in high concentrations during pregnancy, but drop significantly following birth. Allopregnanolone influences foetal arousal and enhances cognitive and behavioural recovery following traumatic brain injury. Inhibition of allopregnanolone synthesis increases cell death in foetal animal brains with experimental hypoxia. We hypothesised that complications during pregnancy, such as early or preterm loss of placental steroids and intrauterine growth restriction (IUGR), would disrupt the foetal neurosteroid system, contributing to poor neurodevelopmental outcomes. This study aimed to investigate the effects of chronic inhibition of allopregnanolone synthesis before term and IUGR on developmental processes in the foetal brain. Guinea pig foetuses were experimentally growth restricted at midgestation and treated with finasteride, an inhibitor of allopregnanolone synthesis. Finasteride treatment reduced foetal brain allopregnanolone concentrations by up to 75% and was associated with a reduction in myelin basic protein (MBP) (PZ0 . 001) and an increase in glial fibrillary acidic protein expression in the subcortical white matter brain region (P!0 . 001). IUGR resulted in decreased MBP expression (P!0 . 01) and was associated with a reduction in the expression of steroidogenic enzyme 5a-reductase (5aR) type 2 in the foetal brain (PZ0 . 061). Brain levels of 5aR1 were higher in male foetuses (PZ0 . 008). Both IUGR and reduced foetal brain concentrations of allopregnanolone were associated with altered expression of myelination and glial cell markers within the developing foetal brain. The potential role of neurosteroids in protecting and regulating neurodevelopmental processes in the foetal brain may provide new directions for treatment of neurodevelopmental disorders in infants who are exposed to perinatal insults and pathologies.

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Section: Introductionmentioning

confidence: 99%

Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on fetal guinea pig brain development.

Kelleher¹,

Palliser²,

Walker³

et al. 2010

Journal of Endocrinology

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“…Two isoforms of 5AR have been identified, differing from each other in chemical characteristics and tissue distribution. In the rat brain, 5AR type 1 is constantly present throughout all developmental stages, whereas the expression of 5AR type 2 in the adult is mainly driven by androgen signaling (Poletti et al, 1998;Torres and Ortega, 2003).…”

Section: Introductionmentioning

confidence: 99%

Antipsychotic-Like Properties of 5-α-Reductase Inhibitors

Bortolato

Frau

Orrù

et al. 2008

Neuropsychopharmacol

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Recent evidence indicates that neuroactive steroids may participate in the pathogenesis of schizophrenia spectrum disorders, yet the mechanisms of this involvement are elusive. As 5-a-reductase (5AR) is the rate-limiting enzyme of one of the two major metabolic pathways in brain steroidogenesis, we investigated the effects of its blockade in several rat models of psychotic-like behavior. The 5AR inhibitor finasteride (FIN, 60 or 100 mg/kg, intraperitoneal, i.p.) dose-and time-dependently antagonized prepulse inhibition (PPI) deficits induced by apomorphine (APO, 0.25 mg/kg, subcutaneous, s.c.) and d-amphetamine (AMPH, 5 mg/kg, s.c.), in a manner analogous to haloperidol (HAL, 0.1 mg/kg, i.p.) and clozapine (CLO, 5 mg/kg, i.p.). Similar results were observed with the other 5AR inhibitors dutasteride (DUT, 40 or 80 mg/kg, i.p.) and SKF 105111 (30 mg/kg, i.p.). FIN (60 or 100 mg/kg, i.p.) also reduced hyperlocomotion induced by AMPH (1 or 3 mg/kg, s.c.) and attenuated stereotyped behaviors induced by APO (0.25 mg/kg, s.c.). Nevertheless, FIN (100 mg/kg, i.p.) did not reverse the PPI disruption induced by the N-methyl-d-aspartate receptor antagonist dizocilpine (0.1 mg/kg, s.c.). FIN (60-300 mg/kg, i.p.) induced no catalepsy in either the bar test or the paw test. Our results suggest that 5AR inhibitors elicit antipsychotic-like effects in animals and may be proposed as a putative novel target in the management of psychotic disorders.

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“…This control progressively disappeared during the first 3 weeks of postnatal life, but pharmacological stimulation of neurosteroidogenesis remained possible in adult animals and enhanced synaptic inhibition to a level comparable with that observed at early developmental stages. In addition, the presence of the enzymes required for the synthesis of 5␣NS has been documented in the spinal cord of the adult rat (Poletti et al, 1998;Patte-Mensah et al, 2003. Therefore, we hypothesized that the production of neurosteroids in the spinal cord might be reactivated in adult animals under particular physiological/pathological situations and could be involved in the control of incoming nociceptive messages.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Pain Upregulates Spinal Inhibition via Endogenous Neurosteroid Production

Poisbeau¹,

Patte‐Mensah²,

Keller³

et al. 2005

J. Neurosci.

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Inhibitory synaptic transmission in the dorsal horn (DH) of the spinal cord plays an important role in the modulation of nociceptive messages because pharmacological blockade of spinal GABA A receptors leads to thermal and mechanical pain symptoms. Here, we show that during the development of thermal hyperalgesia and mechanical allodynia associated with inflammatory pain, synaptic inhibition mediated by GABA A receptors in lamina II of the DH was in fact markedly increased. This phenomenon was accompanied by an upregulation of the endogenous production of 5␣-reduced neurosteroids, which, at the spinal level, led to a prolongation of GABA A receptor-mediated synaptic currents and to the appearance of a mixed GABA/glycine cotransmission. This increased inhibition was correlated with a selective limitation of the inflammation-induced thermal hyperalgesia, whereas mechanical allodynia remained unaffected. Our results show that peripheral inflammation activates an endogenous neurosteroid-based antinociceptive control, which discriminates between thermal and mechanical hyperalgesia.

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5α-Reductase Isozymes in the Central Nervous System

Cited by 91 publications

References 72 publications

Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on fetal guinea pig brain development.

Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on fetal guinea pig brain development.

Antipsychotic-Like Properties of 5-α-Reductase Inhibitors

Inflammatory Pain Upregulates Spinal Inhibition via Endogenous Neurosteroid Production

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