Steroids, spinal cord and pain sensation.

During the whole life, the nervous system is continuously submitted to the actions of different categories of hormones, including steroids. Therefore, the interactions between hormonal compounds and neural tissues are subjected to intense investigations. While a majority of studies focus on the brain, the spinal cord (SC) has received little attention, although this structure is also an important part of the central nervous system, controlling motor and sensory functions. To point out the importance of interactions between hormones and the SC in the regulation of neurobiological activities, we recapitulated and discussed herein various key data, revealing that the pivotal role played by the SC in nociception and pain modulation, directly depends on the SC ability to metabolize and synthesize steroidal molecules. The paper suggests that future investigations aiming to develop effective strategies against chronic pain, must integrate regulatory effects exerted by hormonal steroids on the SC activity, as well as the actions of endogenous neurosteroids locally synthesized in spinal neural networks.journal article2011 Oct 01importe

Comparative Analysis of Gelsemine and Gelsemium sempervirens Activity on Neurosteroid Allopregnanolone Formation in the Spinal Cord and Limbic System

Centesimal dilutions (5, 9 and 15 cH) of Gelsemium sempervirens are claimed to be capable of exerting anxiolytic and analgesic effects. However, basic results supporting this assertion are rare, and the mechanism of action of G. sempervirens is completely unknown. To clarify the point, we performed a comparative analysis of the effects of dilutions 5, 9 and 15 cH of G. sempervirens or gelsemine (the major active principle of G. sempervirens) on allopregnanolone (3α,5α-THP) production in the rat limbic system (hippocampus and amygdala or H-A) and spinal cord (SC). Indeed, H-A and SC are two pivotal structures controlling, respectively, anxiety and pain that are also modulated by the neurosteroid 3α,5α-THP. At the dilution 5 cH, both G. sempervirens and gelsemine stimulated [3H]progesterone conversion into [3H]3α,5α-THP by H-A and SC slices, and the stimulatory effect was fully (100%) reproducible in all assays. The dilution 9 cH of G. sempervirens or gelsemine also stimulated 3α,5α-THP formation in H-A and SC but the reproducibility rate decreased to 75%. At 15 cH of G. sempervirens or gelsemine, no effect was observed on 3α,5α-THP neosynthesis in H-A and SC slices. The stimulatory action of G. sempervirens and gelsemine (5 cH) on 3α,5α-THP production was blocked by strychnine, the selective antagonist of glycine receptors. Altogether, these results, which constitute the first basic demonstration of cellular effects of G. sempervirens, also offer interesting possibilities for the improvement of G. sempervirens-based therapeutic strategies

Neurosteroid 3α-androstanediol efficiently counteracts paclitaxel-induced peripheral neuropathy and painful symptoms.

Painful peripheral neuropathy belongs to major side-effects limiting cancer chemotherapy. Paclitaxel, widely used to treat several cancers, induces neurological symptoms including burning pain, allodynia, hyperalgesia and numbness. Therefore, identification of drugs that may effectively counteract paclitaxel-induced neuropathic symptoms is crucial. Here, we combined histopathological, neurochemical, behavioral and electrophysiological methods to investigate the natural neurosteroid 3α-androstanediol (3α-DIOL) ability to counteract paclitaxel-evoked peripheral nerve tissue damages and neurological symptoms. Prophylactic or corrective 3α-DIOL treatment (4 mg/kg/2 days) prevented or suppressed PAC-evoked heat-thermal hyperalgesia, cold-allodynia and mechanical allodynia/hyperalgesia, by reversing to normal, decreased thermal and mechanical pain thresholds of PAC-treated rats. Electrophysiological studies demonstrated that 3α-DIOL restored control values of nerve conduction velocity and action potential peak amplitude significantly altered by PAC-treatment. 3α-DIOL also repaired PAC-induced nerve damages by restoring normal neurofilament-200 level in peripheral axons and control amount of 2',3'-cyclic-nucleotide-3'-phosphodiesterase in myelin sheaths. Decreased density of intraepidermal nerve fibers evoked by PAC-therapy was also counteracted by 3α-DIOL treatment. More importantly, 3α-DIOL beneficial effects were not sedation-dependent but resulted from its neuroprotective ability, nerve tissue repairing capacity and long-term analgesic action. Altogether, our results showing that 3α-DIOL efficiently counteracted PAC-evoked painful symptoms, also offer interesting possibilities to develop neurosteroid-based strategies against chemotherapy-induced peripheral neuropathy. This article shows that the prophylactic or corrective treatment with 3α-androstanediol prevents or suppresses PAC-evoked painful symptoms and peripheral nerve dysfunctions in rats. The data suggest that 3α-androstanediol-based therapy may constitute an efficient strategy to explore in humans for the eradication of chemotherapy-induced peripheral neuropathy.journal articleresearch support, non-u.s. gov't20132013 11 15importe

Local modulation of steroid action: rapid control of enzymatic activity.

peer reviewedEstrogens can induce rapid, short-lived physiological and behavioral responses, in addition to their slow, but long-term, effects at the transcriptional level. To be functionally relevant, these effects should be associated with rapid modulations of estrogens concentrations. 17beta-estradiol is synthesized by the enzyme aromatase, using testosterone as a substrate, but can also be degraded into catechol-estrogens via hydroxylation by the same enzyme, leading to an increase or decrease in estrogens concentration, respectively. The first evidence that aromatase activity (AA) can be rapidly modulated came from experiments performed in Japanese quail hypothalamus homogenates. This rapid modulation is triggered by calcium-dependent phosphorylations and was confirmed in other tissues and species. The mechanisms controlling the phosphorylation status, the targeted amino acid residues and the reversibility seem to vary depending of the tissues and is discussed in this review. We currently do not know whether the phosphorylation of the same amino acid affects both aromatase and/or hydroxylase activities or whether these residues are different. These processes provide a new general mechanism by which local estrogen concentration can be rapidly altered in the brain and other tissues

Alzheimer's Disease, Oestrogen and Mitochondria: an Ambiguous Relationship

Hormonal deficit in post-menopausal women has been proposed to be one risk factor in Alzheimer's disease (AD) since two thirds of AD patients are women. However, large treatment trials showed negative effects of long-term treatment with oestrogens in older women. Thus, oestrogen treatment after menopause is still under debate, and several hypotheses trying to explain the failure in outcome are under discussion. Concurrently, it was shown that amyloid-beta (Aβ) peptide, the main constituent of senile plaques, as well as abnormally hyperphosphorylated tau protein, the main component of neurofibrillary tangles, can modulate the level of neurosteroids which notably represent neuroactive steroids synthetized within the nervous system, independently of peripheral endocrine glands. In this review, we summarize the role of neurosteroids especially that of oestrogen in AD and discuss their potentially neuroprotective effects with specific regard to the role of oestrogens on the maintenance and function of mitochondria, important organelles which are highly vulnerable to Aβ- and tau-induced toxicity. We also discuss the role of Aβ-binding alcohol dehydrogenase (ABAD), a mitochondrial enzyme able to bind Aβ peptide thereby modifying mitochondrial function as well as oestradiol levels suggesting possible modes of interaction between the three, and the potential therapeutic implication of inhibiting Aβ-ABAD interactio

Age-related vulnerability of pattern separation in C57BL/6J mice

International audienceAging is associated with impaired performance in behavioral pattern separation (PS) tasks based on similarities in object features and in object location. These deficits have been attributed to functional alterations in the dentate gyrus (DG)-CA3 region. Animal studies suggested a role of adult-born DG neurons in PS performance. The present study investigated the effect of aging in C57BL/6J mice performing PS tasks based on either object features or object location. At the age of 18 months or more, performance was severely impaired in both tasks. Spatial PS performance declined gradually over adult lifespan from 3 to 21 months. Subchronic treatment with the cognitive enhancer D-serine fully rescued spatial PS performance in 18-month-old mice and induced a modest increase in the number of 4-week-old adult-born cells in the DG. Performance of mice in these PS tasks shows an age-dependence which appears to translate well to that found in humans. This model should help in deciphering physiological changes underlying PS deficits and in identifying future therapeutic targets

HS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer's disease-related tau pathology

Heparan sulphate (glucosamine) 3-O-sulphotransferase 2 (HS3ST2, also known as 3OST2) is an enzyme predominantly expressed in neurons wherein it generates rare 3-O-sulphated domains of unknown functions in heparan sulphates. in Alzheimer's disease, heparan sulphates accumulate at the intracellular level in disease neurons where they co-localize with the neurofibrillary pathology, while they persist at the neuronal cell membrane in normal brain. However, it is unknown whether HS3ST2 and its 3-O-sulphated heparan sulphate products are involved in the mechanisms leading to the abnormal phosphorylation of tau in Alzheimer's disease and related tauopathies. Here, we first measured the transcript levels of all human heparan sulphate sulphotransferases in hippocampus of Alzheimer's disease (n = 8; 76.8 +/- 3.5 years old) and found increased expression of HS3ST2 (P < 0.001) compared with control brain (n = 8; 67.8 +/- 2.9 years old). Then, to investigate whether the membrane-associated 3-O-sulphated heparan sulphates translocate to the intracellular level under pathological conditions, we used two cell models of tauopathy in neuro-differentiated SH-SY5Y cells: a tau mutation-dependent model in cells expressing human tau carrying the P-301L mutation hTau P-301L, and a tau mutation-independent model in where tau hyperphosphorylation is induced by oxidative stress. Confocal microscopy, fluorescence resonance energy transfer, and western blot analyses showed that 3-O-sulphated heparan sulphates can be internalized into cells where they interact with tau, promoting its abnormal phosphorylation, but not that of p38 or NF-kappa B p65. We showed, in vitro, that the 3-O-sulphated heparan sulphates bind to tau, but not to GSK3B, protein kinase A or protein phosphatase 2, inducing its abnormal phosphorylation. Finally, we demonstrated in a zebrafish model of tauopathy expressing the hTau P-301L, that inhibiting hs3st2 (also known as 3ost2) expression results in a strong inhibition of the abnormally phosphorylated tau epitopes in brain and in spinal cord, leading to a complete recovery of motor neuronal axons length (n = 25; P < 0.005) and of the animal motor response to touching stimuli (n = 150; P < 0.005). Our findings indicate that HS3ST2 centrally participates to the molecular mechanisms leading the abnormal phosphorylation of tau. By interacting with tau at the intracellular level, the 3-O-sulphated heparan sulphates produced by HS3ST2 might act as molecular chaperones allowing the abnormal phosphorylation of tau. We propose HS3ST2 as a novel therapeutic target for Alzheimer's disease.Association France Alzheimer & Maladies ApparenteesSATT Idf InnovCONACyT, MexicoFrench Ministry of Higher Education and ResearchInstitute de Recherche ServierUniv Paris Est, CNRS, Lab Cell Growth Tissue Repair & Regenerat CRRET, UPEC,EA 4397,ERL 9215, F-94000 Creteil, FranceUPMC, Univ Paris 04, Inst Cerveau & Moelle Epiniere, CNRS,UMR 7225,INSERM,U1127,UM75, Paris, FranceHop Robert Debre, INSERM, UMR 1141, F-75019 Paris, FranceSorbonne Paris Cite, Univ Paris Diderot, Paris, FranceUniversidade Federal de São Paulo, Aging & Neurodegenerat Dis Brain Bank Invest Lab, BR-04023062 São Paulo, BrazilGrp Hosp Pitie Salpetriere, Biochim Malad Neurometab, F-75013 Paris, FranceRadboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, NL-6525 ED Nijmegen, NetherlandsUniv Strasbourg, INSERM, U1119, FMTS, F-67000 Strasbourg, FranceUniversidade Federal de São Paulo, Aging & Neurodegenerat Dis Brain Bank Invest Lab, BR-04023062 São Paulo, BrazilCONACyT, Mexico: 308978Web of Scienc

The small GTPase RhoA regulates the expression and function of the sodium channel Nav1.5 in breast cancer cells.

Voltage-gated Na+ channels (VGSCs) are highly expressed in several types of carcinomas including breast, prostate and lung cancers as well as in mesothelioma and cervical cancers. Although the VGSCs activity is considered crucial for the potentiation of cancer cell migration and invasion, the mechanisms responsible for their functional expression and regulation in cancer cells remain unclear. In the present study, the role of the small GTPase RhoA in the regulation of expression and function of the Nav1.5 channel in the breast cancer cell lines MDA-MB 231 and MCF-7 was investigated. RhoA silencing significantly reduced both Nav1.5 channel expression and sodium current indicating that RhoA exerts a stimulatory effect on the synthesis of an active form of Nav1.5 channel in cancer cells. The inhibition of Nav1.5 expression dramatically reduced both cell invasion and proliferation. In addition, a decrease of RhoA protein levels induced by Nav1.5 silencing was observed. Altogether, these findings revealed: i) the key role of the small GTPase RhoA in upregulation of Nav1.5 channel expression and tumor aggressiveness, and ii) the existence of a positive feedback of Nav1.5 channels on RhoA protein levels.journal articleresearch support, non-u.s. gov't2014 Feb2013 12 10importe

Neuroactive steroids in depression and anxiety disorders: Clinical studies

Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3 alpha-reduced pregnane steroids are potent positive allosteric modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor. During major depression, there is a disequilibrium of 3 alpha-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment, we studied the impact of nonpharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation, nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroid concentrations observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder, changes in neuroactive steroid composition have been observed opposite to those seen in depression. However, during experimentally induced panic induction either with cholecystokinine-tetrapeptide or sodium lactate, there was a pronounced decline in the concentrations of 3 alpha-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3 alpha,5 alpha-tetrahydrodeoxycorticosterone. The modulation of GABA(A) receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds. Copyright (c) 2006 S. Karger AG, Basel