Anatomical and cellular localization of neuroactive 5α/3α‐reduced steroid‐synthesizing enzymes in the spinal cord

Patte‐Mensah, Christine; Penning, T.M.; Mensah‐Nyagan, Ayikoe Guy

doi:10.1002/cne.20251

Cited by 82 publications

(73 citation statements)

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“…The high V max of 5 -R1 endows it with a great capacity to reduce steroids at 5 , and for this reason 5 -R1 has been associated with purely catabolic actions, protecting neurons from excess of glucocorticoids that may induce apoptotic processes (Mahendroo et al 1997, Poletti et al 1998a. In contrast, a substantially high 5 -R2 mRNA levels was found in spinal cord (SC) (Pozzi et al 2003), an observation perfectly in agreement with recent findings that indicate 5 -R2 immunoreactive material in adult rat SC is much higher than those of 5 -R1 (Patte- Mensah et al 2004).…”

Section: Discussionsupporting

confidence: 91%

“…According to the previous findings observed in the SC (Patte-Mensah et al 2004) the 5 -R2 mRNA levels were not significantly modified two weeks after castration in the prefrontal cortex of female rats. 5 -R2 mRNA is much less regulated by T (5-fold and 26-fold in I and castrated animals, respectively) and DHT (3-fold and 13-fold in I and castrated animals, respectively) in females than in males (Torres & Ortega 2003a).…”

Section: Discussionsupporting

confidence: 76%

“…However, no sex difference was observed in the distribution of 5 -R1 and 5 -R2 immunoreactive elements in the SC of adult female and male rats (Patte-Mensah et al 2004).…”

Section: Discussionmentioning

confidence: 73%

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Steroid 5α-reductase isozymes in the adult female rat brain: central role of dihydrotestosterone

Torres

Ortega

2006

Journal of Molecular Endocrinology

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The enzyme 5 -reductase (5 -R) (EC 1·3·99·5) exists as two isoforms, 5 -R type 1 (5 -R1) and 5 -R type 2 (5 -R2). 5 -R1 has been associated with catabolic functions whereas 5 -R2 has been associated with sexually dimorphic functions of the male. We recently demonstrated that both 5 -R isozymes are present in the central nervous system (CNS) of the adult male rat and are regulated in an opposing way by androgens. This finding raises the question as to whether both isozymes play a role in the sexual dimorphism of the CNS, besides other functions. To test this hypothesis, it is essential to study the regulation of both isozymes by androgens in the female. In this work, we studied the effects of testosterone (T) and dihydrotestosterone (DHT) on mRNA levels of both 5 -R isoforms in the prefrontal cortex of the adult female rat by one-step quantitative RT-PCR coupled with laser-induced fluorescence capillary electrophoresis. Our results demonstrate for the first time that 5 -R2 mRNA is slightly regulated by T and DHT in females. Surprisingly, 5 -R1 mRNA is not regulated by T in the intact female, whereas it is very positively regulated by DHT, a more potent androgen than T. These data indicate the great sexual dimorphism in the CNS with respect to both 5 -R isozymes, and suggest a crucial role of DHT in the sexual dimorphism of the CNS in the female. These results open up a new research line that may lead to a better understanding of the physiology of the CNS.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 76%

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Steroid 5α-reductase isozymes in the adult female rat brain: central role of dihydrotestosterone

Torres

Ortega

2006

Journal of Molecular Endocrinology

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“…These include neuroprotection against ischemia and stroke (Cutler, et al, 2005,Djebaili, et al, 2005,Hoffman, et al, 2003,Lapchak, 2004,Meffre, et al, 2007,Shear, et al, 2002,VanLandingham, et al, 2006, recovery of motor function after spinal cord injury (di Michele, et al, 2000,Fiore, et al, 2004,Labombarda, et al, 2006,Patte-Mensah, et al, 2004,Pomata, et al, 2000, regulation of myelination (Chavez-Delgado, et al, 2005,Gago, et al, 2001,Ghoumari, et al, 2005,Ghoumari, et al, 2003,Le Goascogne, et al, 2000,Schumacher, et al, 2000,Schumacher, et al, 2004, proliferation of neuronal stem cells (Suzuki, et al, 2004,Wang, et al, 2005 , neurogenesis in the hippocampus (Keller, et al, 2004,Suzuki, et al, 2004,Wang, et al, 2005, and induction of analgesia (Pathirathna, et al, 2005,Todorovic, et al, 2004. Many of these actions of neurosteroids are discussed in detail in other papers in this issue.…”

Section: Introductionmentioning

confidence: 99%

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Mellon

Gong

Schonemann

2008

Brain Research Reviews

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The functions for neurosteroids during development and in response to nervous system injury are beginning to be identified. We focused on a mouse model in which we believed neurosteroid production would be altered, and which had a neurodegenerative phenotype. Niemann Pick Type-C (NP-C) is an autosomal recessive neurodegenerative disease caused by mutations in NPC1 (95%) or NPC2 (5%), resulting in lysosomal accumulation of unesterified cholesterol and glycolipids. The NIH mouse model of NP-C has a mutation in the NPC1 gene, and exhibits several pathological features of the most severe NP-C patients. How lysosomal storage and trafficking defects lead to neurodegeneration is unknown. We found that these mice had normal neurosteroidogenic enzyme activity during development, but lost this activity in the early neonatal period, prior to onset of neurological symptoms. Neurons that expressed P450scc, 3ß HSD, as well as those that expressed 3α HSD and 5α reductase were lost in adult NP-C brains, resulting in diminished concentrations of allopregnanolone. We treated NP-C mice with allopregnanolone and found that a single dose in the neonatal period resulted in a doubling of lifespan, substantial delay in onset of neurological symptoms, survival of cerebellar Purkinje and granule cell neurons, and reduction in cholesterol and ganglioside accumulation. The mechanism by which allopregnanolone elicited these effects is unknown. Our in vitro studies showed that Purkinje cell survival promoted by allopregnanolone was lost by treatment with bicuculline, suggesting GABA A receptors may play a role. We treated NP-C mice with a synthetic GABA A neurosteroid, ganaxolone (3α-hydroxy-3β-methyl-5α -pregnan-20-one). Ganaxolone treatment of NP-C mice produced beneficial neurological effects, but these effects were not as robust as those obtained using allopregnanolone. Thus, allopregnanolone may elicit its effects through GABA A receptors and through other mechanisms. Additional studies also suggest that allopregnanolone may elicit its effects through pregnane-X receptors (PXR). Our data suggest that mouse models of neurodegeneration may be beneficial in establishing both physiologic and pharmacologic actions of neurosteroids. These animal models further establish the wide range of functions of these compounds, which may ultimately be useful for treatment of human diseases.

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“…In a recent series of studies, we observed that the rat DH is an active neurosteroidogenic center that contains several sensory neurons expressing the isoenzyme type 2 of 5␣-reductase (5␣-R) and 3␣-hydroxysteroid oxydo-reductase (3␣-HSOR), also called 3␣-hydroxysteroid dehydrogenase (10,11). 5␣-R and 3␣-HSOR are the two key enzymes catalyzing progesterone conversion into dihydroprogesterone (5␣-DHP) and tetrahydroprogesterone (3␣,5␣-THP) or allopregnanolone, which control important functions such as sexual behaviors, neuroprotection, stress, anxiety, analgesia, sleep, and locomotion (12)(13)(14)(15).…”

mentioning

confidence: 99%

Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: A potential component of nociception

Patte‐Mensah

Kibaly

Mensah‐Nyagan

2005

Proc. Natl. Acad. Sci. U.S.A.

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A crucial biochemical reaction in vertebrates is progesterone conversion into neuroactive metabolites such as dihydroprogesterone (5␣-DHP) and tetrahydroprogesterone (3␣,5␣-THP), which regulate several neurobiological processes, including stress, depression, neuroprotection, and analgesia. 3␣,5␣-THP is a potent stimulator of type A receptors of GABA, the main inhibitory neurotransmitter. Here, we show that in the spinal sensory circuit progesterone conversion into 5␣-DHP and 3␣,5␣-THP is inhibited dose-dependently by substance P (SP), a major mediator of painful signals. We developed a triple-labeling approach coupled with multichannel confocal microscope analysis, which revealed that, in the spinal cord (SC), SP-releasing afferents project on sensory neurons expressing simultaneously neurokinin 1 receptors (rNK1) and key enzymes catalyzing progesterone metabolism. Evidence for a potent inhibitory effect of SP on 5␣-DHP and 3␣,5␣-THP formation in the SC was provided by combining pulse-chase experiments using neurosteroid ͉ pain ͉ spinal cord ͉ steroids ͉ nervous system T he spinal cord (SC) is a pivotal structure controlling many neurophysiological activities, including somatosensory transmission, locomotion, reflexes, and neurovegetative functions. Primary sensory inputs arising from receptors in various areas of the body are integrated in multisynaptic relays in the SC that convey these inputs toward the brain (1, 2). A variety of molecules, including glutamate, substance P (SP), neurotrophins, calcitonin-gene related peptide, and adenosine triphosphate, are thought to be involved in the central transmission of sensory messages (2, 3). Among these neuromodulators, SP, the role of which is clearly established and well documented, is considered as a key neuropeptide mediating nociceptive message transmission from peripheral afferents to sensory neurons located in the SC dorsal horn (DH) (4-6). In particular, it has been shown that projection neurons in lamina I of rat DH expressing neurokinin 1 receptors (rNK1s) are selectively innervated by SP-containing afferents and respond to noxious stimulation (7). Direct structural-functional evidence for SP-mediated nociceptive transmission has also been provided in cats by multidisciplinary studies that combined various approaches, including intracellular recording from DH neurons in vivo, characterization of these neurons on the basis of their responses to peripheral noxious stimulation, cellular labeling by horseradish peroxidase, and electron microscopic identification of synaptic contacts (6-9). Moreover, intrathecal injection of SP conjugated to the cytotoxin saporin selectively destroyed DH neurons bearing rNK1 and strongly reduced hyperalgesia after capsaicin treatment, indicating that spinal rNK1 neurons are important for the development of hyperalgesia (4, 5). However, intracellular changes or neurochemical modifications that spinal rNK1 neurons undergo during nociception are poorly characterized. This situation hampers the understanding of spinal mechanisms in...

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Anatomical and cellular localization of neuroactive 5α/3α‐reduced steroid‐synthesizing enzymes in the spinal cord

Cited by 82 publications

References 62 publications

Steroid 5α-reductase isozymes in the adult female rat brain: central role of dihydrotestosterone

Steroid 5α-reductase isozymes in the adult female rat brain: central role of dihydrotestosterone

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: A potential component of nociception

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