Laura Garay

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Papers by Laura Garay

Exposure to endogenous and exogenous sex hormones and reproductive history influence prognosis in women with ALS

Muscle & Nerve

Introduction/AimsAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a ... more Introduction/AimsAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a higher incidence in men suggesting an influence of sex steroids. Our objective was to investigate past exposure to endogenous and synthetic steroids in female ALS patients and controls.MethodsWe administered a questionnaire to 158 postmenopausal women (75 ALS patients and 83 controls). We calculated reproductive time span (RTS), lifetime endogenous estrogen (LEE) and progesterone exposures (LPE), oral contraceptive pill (OCP) use, and reproductive history.ResultsALS patients showed shorter LEE and LPE, a lower proportion of breast cancer, and 11% showed no history of pregnancies vs. 4% of controls. Odds ratios (ORs) showed that <17 y of LEE and a delayed menarche (>13 y) constitute risk factors for ALS [OR = 2.1 (95% confidence interval {CI}, 1.08–4.2); and OR = 2.4 (95% CI, 1.1–5.1) respectively]. According to Cox survival analysis, for each year the LEE increased over 17 y, it wa...

Tibolone restrains neuroinflammation in mouse experimental autoimmune encephalomyelitis

Journal of Neuroendocrinology, 2021

Multiple sclerosis (MS) is an immune‐mediated and degenerating disease in which myelin sheaths ar... more Multiple sclerosis (MS) is an immune‐mediated and degenerating disease in which myelin sheaths are damaged as a result of chronic progressive inflammation of the central nervous system. Tibolone [(7α,17α)‐17‐hydroxy‐7‐methyl‐19‐norpregn‐5(10)‐en‐20‐in‐3‐one], a synthetic estrogenic compound with tissue‐specific actions and used for menopausal hormone therapy, shows neuroprotective and antioxidant properties both in vivo and in vitro. In the present study, we analyzed whether tibolone plays a therapeutic role in experimental autoimmune encephalomyelitis (EAE) mice, a commonly used model of MS. Female C57BL/6 mice were induced with the myelin oligodendrocyte glycoprotein MOG35–55 and received s.c. tibolone (0.08 mg kg–1) injection every other day from the day of induction until death on the acute phase of the disease. Reactive gliosis, Toll like receptor 4 (TLR4), high mobility group box protein 1 (HMGB1), inflammasome parameters, activated Akt levels and myelin were assessed by a rea...

Sex steroids, neurosteroidogenesis, and inflammation in multiple sclerosis and related animal models

Current Opinion in Endocrine and Metabolic Research, 2021

Multiple sclerosis (MS) and rodent models of the disease including experimental autoimmune enceph... more Multiple sclerosis (MS) and rodent models of the disease including experimental autoimmune encephalomyelitis, cuprizone intoxication, and lysophosphatidyl choline-induced demyelination show altered levels of circulating sex steroids and changes in the biosynthesis of nervous system localized steroidogenesis (neurosteroidogenesis). Therapy with progesterone, estrogens, androgens, or direct stimulation of neurosteroidogenesis shows beneficial effects for brain and spinal cord neuropathology of MS models owing to the reduction of reactive astrocytes and microglia, downregulation of the expression of proinflammatory markers, improved myelin formation from oligodendrocyte precursors, and better clinical scores and behavioral performances. Steroid effectiveness is explained in part by activation of classical nuclear receptors, membrane receptors, and modulation of gamma aminobutyric acid (GABAA) receptors expressed by several cell types from different central nervous system (CNS) regions. Because resolving inflammation is crucial for treatment of MS and related animal models, treatment with natural or synthetic steroids or with molecules targeting neurosteroidogenesis may open further therapeutic opportunities for neuroinflammatory diseases.Fil: Garay, Laura Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Meyer, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Guennoun, Rachida. Inserm; FranciaFil: Schumacher, Michael. Inserm; FranciaFil: Gonzalez Deniselle, Maria Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; ArgentinaFil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentin

Changes in neurosteroidogenesis during demyelination and remyelination in cuprizone treated mice

Journal of neuroendocrinology, Jan 10, 2018

Literature evidence indicates that changes of neurosteroids may be involved in the pathophysiolog... more Literature evidence indicates that changes of neurosteroids may be involved in the pathophysiology of Multiple Sclerosis (MS). The present study assessed if changes of neurosteroidogenesis also occurred in gray and white matter regions of the brain from mice subjected to cuprizone-induced demyelination. To this end, we compared the expression of neurosteroidogenic proteins including steroidogenic acute regulatory protein (StAR), voltage-dependent anion channel (VDAC), 18 Kd translocator protein (TSPO), and neurosteroidogenic enzymes including the side chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase/ isomerase (3β-HSD) and 5α-reductase (5α-R) during the demyelination and remyelination periods. Using immunohistochemistry and qPCR, we demonstrated a decreased expression of StAR, P450scc and 5α-R in consonance with an increase astrocytic and microglial reaction and elevated levels of TNFα during the cuprizone demyelination period in hippocampus, cortex and corpus callos...

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Protective effects of the neurosteroid allopregnanolone in a mouse model of spontaneous motoneuron degeneration

The Journal of Steroid Biochemistry and Molecular Biology, 2017

Highlights 1. Progesterone and allopregnanolone effects were evaluated in a model of motoneuron d... more Highlights 1. Progesterone and allopregnanolone effects were evaluated in a model of motoneuron degeneration. 2. Both steroids increased protective signals such as pAKT and MnSOD in the spinal cord of Wobbler mice. 3. Both steroids decreased death signals such as p75NTR, pJNK, and NOS hyperactivity in Wobblers. 4. Increased BDNF and ChAT and enhanced muscle strength indicate steroid protection. 5. Allopregnanolone, a GABAAR agonist, may become a therapeutic tool for motoneuron degeneration.

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Neurosteroidogenesis and progesterone anti-inflammatory/ neuroprotective effects

Journal of neuroendocrinology, Jan 4, 2017

Progesterone shows anti-inflammatory and promyelinating effects in mice with autoimmune experimen... more Progesterone shows anti-inflammatory and promyelinating effects in mice with autoimmune experimental encephalomyelitis (EAE), a commonly used model for multiple sclerosis (MS). Since neurosteroids have been implicated as protective factors for MS and EAE, we analyzed the expression of neurosteroidogenic enzymes in the compromised spinal cord of EAE mice. EAE was induced in female C57Bl6 mice and killed on day 16 after induction. Progesterone was given by pellet implantation 1 week before EAE induction. Untreated EAE mice showed decreased mRNAs for the steroidogenic acute regulatory protein (Star), voltage-dependent anion channel (VDAC), cholesterol side-chain cleavage (P450scc), 5α-reductase, 3α-hydroxysteroid dehydrogenase (3α-HSOR) and aromatase, whereas changes of 3β-hydroxysteroid dehydrogenase (3β-HSD) were not significant. mRNA of 18 Kd translocator protein (TSPO) was elevated, concomitantly with a reactive microgliosis. EAE mice also showed abnormal mitochondrial ultrastructu...

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Steroid protection in the experimental autoimmune encephalomyelitis model of multiple sclerosis

Neuroimmunomodulation, 2008

Based on evidence that pregnant women with multiple sclerosis (MS) show a decline in the relapse ... more Based on evidence that pregnant women with multiple sclerosis (MS) show a decline in the relapse rate during the third trimester and an increase during the first 3 months postpartum, the suggestion was made that high levels of circulating sex steroids are responsible for pregnancy-mediated neuroprotection. As both estradiol (E(2)) and progesterone exert neuroprotective and myelinating effects on the nervous system, the effects of sex steroids were studied in the experimental autoimmune encephalomyelitis (EAE) model of MS. EAE was induced in female C57BL/6 mice by administration of a myelin oligodendrocyte protein (MOG(40-45)) peptide. Clinical signs of EAE, myelin protein expression and neuronal parameters were determined in mice with or without hormonal treatment. Progesterone given prior to EAE induction attenuated the clinical scores of the disease, slightly delayed disease onset and decreased demyelination foci, according to luxol fast blue staining (LFB), myelin basic protein (...

Efficacy of the selective progesterone receptor agonist Nestorone for chronic experimental autoimmune encephalomyelitis

Journal of Neuroimmunology, 2014

Progesterone plays a protective role in the experimental autoimmune encephalomyelitis (EAE) model... more Progesterone plays a protective role in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Besides spinal cord neuropathology, MS patients present a dysfunctional hippocampus. In this work we studied the therapeutic effects of the progestin Nestorone in the brain of mice with chronic EAE. Nestorone decreased clinical grade and enhanced motor behavior. In addition, it increased cell proliferation and doublecortin positive neuroblasts in the hippocampus, increased GABAergic interneurons and attenuated the number of Iba1 + microglia/macrophages, events possibly linked to enhancement of neurogenesis. Therefore, Nestorone protected against hippocampus abnormalities and improved functional outcomes of EAE mice, suggesting its potential value for MS.

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Effects of progesterone in the spinal cord of a mouse model of multiple sclerosis

The Journal of Steroid Biochemistry and Molecular Biology, 2007

The spinal cord is a target of progesterone (PROG), as demonstrated by the expression of intracel... more The spinal cord is a target of progesterone (PROG), as demonstrated by the expression of intracellular and membrane PROG receptors and by its myelinating and neuroprotective effects in trauma and neurodegeneration. Here we studied PROG effects in mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis characterized by demyelination and immune cell infiltration in the spinal cord. Female C57BL/6 mice were immunized with a myelin oligodendrocyte glycoprotein peptide (MOG 40-54 ). One week before EAE induction, mice received single pellets of PROG weighing either 20 or 100 mg or remained free of steroid treatment. On average, mice developed clinical signs of EAE 9-10 days following MOG administration. The spinal cord white matter of EAE mice showed inflammatory cell infiltration and circumscribed demyelinating areas, demonstrated by reductions of luxol fast blue (LFB) staining, myelin basic protein (MBP) and proteolipid protein (PLP) immunoreactivity (IR) and PLP mRNA expression. In motoneurons, EAE reduced the expression of the alpha 3 subunit of Na,K-ATPase mRNA. In contrast, EAE mice receiving PROG showed less inflammatory cell infiltration, recovery of myelin proteins and normal grain density of neuronal Na,K-ATPase mRNA. Clinically, PROG produced a moderate delay of disease onset and reduced the clinical scores. Thus, PROG attenuated disease severity, and reduced the inflammatory response and the occurrence of demyelination in the spinal cord during the acute phase of EAE.

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Basis of progesterone protection in spinal cord neurodegeneration

The Journal of Steroid Biochemistry and Molecular Biology, 2002

Progesterone neuroprotection has been reported in experimental brain, peripheral nerve and spinal... more Progesterone neuroprotection has been reported in experimental brain, peripheral nerve and spinal cord injury. To investigate for a similar role in neurodegeneration, we studied progesterone effects in the Wobbler mouse, a mutant presenting severe motoneuron degeneration and astrogliosis of the spinal cord. Implant of a single progesterone pellet (20 mg) during 15 days produced substantial changes in Wobbler mice spinal cord. Morphologically, motoneurons of untreated Wobbler mice showed severe vacuolation of intracellular organelles including mitochondria. In contrast, neuropathology was less pronounced in Wobbler mice receiving progesterone, together with a reduction of vacuolated cells and preservation of mitochondrial ultrastructure. Determination of mRNAs for the ␣3 and ␤1 subunits of neuronal Na, K-ATPase, showed that mRNA levels in untreated mice were significantly reduced, whereas progesterone therapy re-established the expression of both subunits. Additionally, progesterone treatment of Wobbler mice attenuated the aberrant expression of the growth-associated protein (GAP-43) mRNA which otherwise occurred in motoneurons of untreated animals. The hormone, however, was without effect on astrocytosis of Wobbler mice, determined by glial fibrillary acidic protein (GFAP)-immunostaining. Lastly, progesterone treatment of Wobbler mice enhanced grip strength and prolonged survival at the end of the 15-day observation period. Recovery of morphology and molecular motoneuron parameters of Wobbler mice receiving progesterone, suggest a new and important role for this hormone in the prevention of spinal cord neurodegenerative disorders.

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Progesterone down-regulates spinal cord inflammatory mediators and increases myelination in experimental autoimmune encephalomyelitis

Neuroscience, 2012

In mice with experimental autoimmune encephalomyelitis (EAE) pretreatment with progesterone impro... more In mice with experimental autoimmune encephalomyelitis (EAE) pretreatment with progesterone improves clinical signs and decreases the loss of myelin basic protein (MBP) and proteolipid protein (PLP) measured by immunohistochemistry and in situ hybridization. Presently, we analyzed if progesterone effects in the spinal cord of EAE mice involved the decreased transcription of local inflammatory mediators and the increased transcription of myelin proteins and myelin transcription factors. C57Bl/6 female mice were divided into controls, EAE and EAE receiving progesterone (100mg implant) 7 days before EAE induction. Tissues were collected on day 17 post-immunization. Real time PCR technology demonstrated that progesterone blocked the EAE-induced increase of the proinflammatory mediators tumor necrosis factor alpha (TNFα) and its receptor TNFR1, the microglial marker CD11b and toll-like receptor 4 (TLR4) mRNAs, and increased mRNA expression of PLP and MBP, the myelin transcription factors NKx2.2 and Olig1 and enhanced CC1+oligodendrocyte density respect of untreated EAE mice. Immunocytochemistry demonstrated decreased Iba1+microglial cells. Confocal microscopy demonstrated that TNFα colocalized with glial-fibrillary acidic protein+astrocytes and OX-42+microglial cells. Therefore, progesterone treatment improved the clinical signs of EAE, decreased inflammatory glial reactivity and increased myelination. Data suggest that progesterone neuroprotection involves the modulation of transcriptional events in the spinal cord of EAE mice.

Progesterone attenuates demyelination and microglial reaction in the lysolecithin-injured spinal cord

Neuroscience, 2011

Progesterone treatment of mice with experimental autoimmune encephalomyelitis has shown beneficia... more Progesterone treatment of mice with experimental autoimmune encephalomyelitis has shown beneficial effects in the spinal cord according to enhanced clinical, myelin and neuronal-related parameters. In the present work, we report progesterone effects in a model of primary demyelination induced by the intraspinal injection of lysophospatidylcholine (LPC). C57Bl6 adult male mice remained steroid-untreated or received a single 100 mg progesterone implant, which increased circulating steroid levels to those of mouse pregnancy. Seven days afterwards mice received a single injection of 1% LPC into the dorsal funiculus of the spinal cord. A week after, anesthetized mice were perfused and paraffin embedded sections of the spinal cord stained for total myelin using Luxol Fast Blue (LFB) histochemistry, for myelin basic protein (MBP) immunohistochemistry and for determination of OX-42+ microglia/macrophages. Cryostat sections were also prepared and stained for oligodendrocyte precursors (NG2+ cells) and mature oligodendrocytes (CC1+ cells). A third batch of spinal cords was prepared for analysis of the microglial marker CD11b mRNA using qPCR. Results showed that progesterone pretreatment of LPC-injected mice decreased by 50% the area of demyelination, evaluated by either LFB staining or MBP immunostaining, increased the density of NG2+ cells and of mature, CC1+ oligodendrocytes and decreased the number of OX-42+ cells, respect of steroid-untreated LPC mice. CD11b mRNA was hyperexpressed in LPC-treated mice, but significantly reduced in LPC-mice receiving progesterone. These results indicated that progesterone antagonized LPC injury, an effect involving (a) increased myelination; (b) stimulation of oligodendrocyte precursors and mature oligodendrocytes, and (c) attenuation of the microglial/macrophage response. Thus, use of a focal demyelination model suggests that progesterone exerts promyelinating and anti-inflammatory effects at the spinal cord level.

Progesterone Neuroprotection in the Wobbler Mouse, a Genetic Model of Spinal Cord Motor Neuron Disease

Neurobiology of Disease, 2002

Motor neuron degeneration characterizes the spinal cord of patients with amyotrophic lateral scle... more Motor neuron degeneration characterizes the spinal cord of patients with amyotrophic lateral sclerosis and the Wobbler mouse mutant. Considering that progesterone (PROG) provides neuroprotection in experimental ischemia and injury, its potential role in neurodegeneration was studied in the murine model. Two-month-old symptomatic Wobbler mice were left untreated or received sc a 20-mg PROG implant for 15 days. Both light and electron microscopy of Wobbler mice spinal cord showed severely affected motor neurons with profuse cytoplasmic vacuolation of the endoplasmic reticulum and/or Golgi apparatus and ruptured mitochondria with damaged cristae, a profile indicative of a type II cytoplasmic form of cell death. In contrast to untreated mice, neuropathology was less severe in Wobbler mice receiving PROG; including a reduction of vacuolation and of the number of vacuolated cells and better conservation of the mitochondrial ultrastructure. In biochemical studies, we determined the mRNA for the ␣3 subunit of Na,K-ATPase, a neuronal enzyme controlling ion fluxes, neurotransmission, membrane potential, and nutrient uptake. In untreated Wobbler mice, mRNA levels in motor neurons were reduced by half compared to controls, whereas PROG treatment of Wobbler mice restored the expression of ␣3 subunit Na,K-ATPase mRNA. Therefore, PROG was able to rescue motor neurons from degeneration, based on recovery of histopathological abnormalities and of mRNA levels of the sodium pump. However, because the gene mutation in Wobbler mice is still unknown, further studies are needed to unveil the action of PROG and the mechanism of neuronal death in this genetic model of neurodegeneration.

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Progesterone Increases the Expression of Myelin Basic Protein and the Number of Cells Showing NG2Immunostaining in the Lesioned Spinal Cord

Journal of Neurotrauma, 2006

It is now widely accepted that progesterone (PROG) brings neuroprotection in lesions of the perip... more It is now widely accepted that progesterone (PROG) brings neuroprotection in lesions of the peripheral and central nervous system. Spinal cord trauma leads to neuronal degeneration, astrogliosis, demyelination, and proliferation of oligodendrocyte-precursor cells (OPCs). In this work, we studied the effects of PROG on myelin-related parameters in rats with complete spinal cord transection (TRX). To this end, sham-operated controls and rats with TRX at thoracic level T10 received vehicle or PROG (4 mg/kg/day) during 3 days. Three variables were measured in the lumbar L4 region below the lesion: (1) expression of myelin basic protein (MBP) at the protein and mRNA levels; (2) density of NG2-immunopositive cells as markers for OPCs; and (3) number of cells immunopositive for RIP, an antibody staining mature oligodendrocytes. TRX decreased MBP immunostaining in the corticospinal tract (CST) and dorsal ascending tract (DAT) but not the ventral funiculus (VF). NG2+ cells, which were detected in low number in controls, increased after TRX in the gray and white matter. RIP-positive cell number, however, remained unchanged. PROG treatment of rats with TRX enhanced the expression of MBP protein and mRNA in CST and DAT, but not VF and highly stimulated the number of cells showing NG2 immunostaining over untreated lesioned rats. Instead, density of RIP positive cells was similar in the PROG-treated and untreated lesioned groups. We propose that PROG effects on expression of MBP and the number of NG2 immunopositive cells may contribute to neuroprotection, as they go in parallel with previous results showing enhanced biochemical and morphological parameters of motoneurons of animals with TRX receiving PROG treatment.

Progesterone Treatment of Spinal Cord Injury: Effects on Receptors, Neurotrophins, and Myelination

Journal of Molecular Neuroscience, 2006

In addition to its traditional role in reproduction, progesterone (PROG) has demonstrated neuropr... more In addition to its traditional role in reproduction, progesterone (PROG) has demonstrated neuroprotective and promyelinating effects in lesions of the peripheral and central nervous systems, including the spinal cord. The latter is a target of PROG, as nuclear receptors, as well as membrane receptors, are expressed by neurons and/or glial cells. When spinal cord injury (SCI) is produced at the thoracic level, several genes become sensitive to PROG in the region caudal to the lesion site. Although the cellular machinery implicated in PROG neuroprotection is only emerging, neurotrophins, their receptors, and signaling cascades might be part of the molecules involved in this process. In rats with SCI, a 3-d course of PROG treatment increased the mRNA of brain-derived neurotrophic factor (BDNF) and BDNF immunoreactivity in perikaryon and processes of motoneurons, whereas chromatolysis was strongly prevented. The increased expression of BDNF correlated with increased immunoreactivity for the BDNF receptor TrkB and for phosphorylated cAMP-responsive element binding in motoneurons. In the same SCI model, PROG restored myelination, according to measurements of myelin basic protein (MBP) and mRNA levels, and further increased the density of NG 2 + -positive oligodendrocyte progenitors. These cells might be involved in remyelination of the lesioned spinal cord. Interestingly, similarities in the regulation of molecular parameters and some cellular events attributed to PROG and BDNF (i.e., choline acetyltransferase, Na,K-ATPase, MBP, chromatolysis) suggest that BDNF and PROG might share intracellular pathways. Furthermore, PROG-induced BDNF might regulate, in a paracrine or autocrine fashion, the function of neurons and glial cells and prevent the generation of damage.

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Pharmacotherapy with 17β-estradiol and progesterone prevents development of mouse experimental autoimmune encephalomyelitis

hmbci, 2010

Background: Pregnant women with multiple sclerosis (MS) show disease remission in the third trime... more Background: Pregnant women with multiple sclerosis (MS) show disease remission in the third trimester concomitant with high circulating levels of sex steroids. Rodent experimental autoimmune encephalomyelitis (EAE) is an accepted model for MS. Previous studies have shown that monotherapy with estrogens or progesterone exert beneficial effects on EAE. The aim of the present study was to determine if estrogen and progesterone cotherapy of C57BL/6 female mice provided substantial protection from EAE. Methods: A group of mice received single pellets of progesterone (100 mg) and 17 β-estradiol (2.5 mg) subcutaneously 1 week before EAE induction, whereas another group were untreated before EAE induction. On day 16 we compared the two EAE groups and control mice in terms of clinical scores, spinal cord demyelination, expression of myelin basic protein and proteolipid protein, macrophage cell infiltration, neuronal expression of brain-derived neurotrophic factor mRNA and protein, and the nu...

Progesterone and cortisol levels in sporadic amyotrophic lateral sclerosis (sALS): correlation with prognostic factors

Hormone Molecular Biology and Clinical Investigation, 2011

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Worse prognostic factors in ... more Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Worse prognostic factors in ALS are: (a) advanced age, (b) bulbar onset, and (c) short time between onset and diagnosis. Progesterone (PROG) has been associated with neuroprotective and promyelinating activities in injury, ischemia and degeneration of the central and peripheral nervous system. Cortisol is connected to the response to stress situations and could contribute to neuronal damage. The goals of this study were: (i) to investigate whether PROG levels are modified by ALS prognostic factors and (ii) to determine whether cortisol follows the same pattern. We determined serum steroid levels in 27 patients with sporadic ALS (sALS) and 21 controls. Both steroid hormones showed significantly increased levels in ALS patients versus controls (mean±SEM: PROG ALS vs. control: 0.54±0.05 vs. 0.39±0.04 ng/mL, p<0.05; cortisol ALS vs. control: 17.02±1.60 vs. 11.83±1.38 μg/dL, p<0.05).

Progesterone neuroprotection in traumatic CNS injury and motoneuron degeneration

Frontiers in Neuroendocrinology, 2009

Studies on the neuroprotective and promyelinating effects of progesterone in the nervous system a... more Studies on the neuroprotective and promyelinating effects of progesterone in the nervous system are of great interest due to their potential clinical connotations. In peripheral neuropathies, progesterone and reduced derivatives promote remyelination, axonal regeneration and the recovery of function. In traumatic brain injury (TBI), progesterone has the ability to reduce edema and inflammatory cytokines, prevent neuronal loss and improve functional outcomes. Clinical trials have shown that shortand long-term progesterone treatment induces a significant improvement in the level of disability among patients with brain injury. In experimental spinal cord injury (SCI), molecular markers of functional motoneurons become impaired, including brain-derived neurotrophic factor (BDNF) mRNA, Na,K-ATPase mRNA, microtubule-associated protein 2 and choline acetyltransferase (ChAT). SCI also produces motoneuron chromatolysis. Progesterone treatment restores the expression of these molecules while chromatolysis subsided. SCI also causes oligodendrocyte loss and demyelination. In this case, a short progesterone treatment enhances proliferation and differentiation of oligodendrocyte progenitors into mature myelin-producing cells, whereas prolonged treatment increases a transcription factor (Olig1) needed to repair injury-induced demyelination. Progesterone neuroprotection has also been shown in motoneuron neurodegeneration. In Wobbler mice spinal cord, progesterone reverses the impaired expression of BDNF, ChAT and Na,K-ATPase, prevents vacuolar motoneuron degeneration and the development of mitochondrial abnormalities, while functionally increases muscle strength and the survival of Wobbler mice. Multiple mechanisms contribute to these progesterone effects, and the role played by classical nuclear receptors, extra nuclear receptors, membrane receptors, and the reduced metabolites of progesterone in neuroprotection and myelin formation remain an exciting field worth of exploration.

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Progesterone restores retrograde labeling of cervical motoneurons in Wobbler mouse motoneuron disease

Experimental Neurology, 2005

The Wobbler mouse, a mutant characterized by motoneuron degeneration in the cervical spinal cord,... more The Wobbler mouse, a mutant characterized by motoneuron degeneration in the cervical spinal cord, has been used to test the efficacy of novel treatments for human motoneuron diseases (HMD). Previous reports have shown that slow axonal transport is impaired in Wobblers and other models of HMD. Since progesterone (PROG) corrects some morphological, molecular, and functional abnormalities of Wobbler mice, we studied if steroid exposure for 8 weeks restored retrograde axonal transport by measuring motoneuron labeling after injection of fluorogold into the limb muscles. The dye was injected into forelimb biceps bracchii and flexor or into the rearlimb gastrocnemius muscles; 6 days later, the number of fluorescent motoneurons and the total number of cresyl violet stained motoneurons were counted in the cervical (C5-T1) or lumbar (L3-L5) spinal cord regions. A pronounced reduction (- 42.2%) of the percent of fluorescent motoneurons in Wobbler mice cervical cord was noted, which was significantly corrected after PROG treatment. In contrast, labeling of lumbar motoneurons was not reduced in Wobbler mice and was not affected by PROG treatment. In no case PROG showed an effect in control mice. Concomitantly, PROG slightly but significantly increased biceps weight of Wobbler mice. Behaviorally, PROG-treated Wobblers performed better on a motor test (hanging time from a horizontal rope) compared to untreated counterparts. We postulate a dual role for PROG in the Wobbler mouse, in part by prevention of motoneuron degeneration and also by enhancement of axonal transport. The latter mechanism could improve the traffic of neurotrophic factors from the forelimb muscles into the ailing motoneurons, improving neuromuscular function in this murine model of HMD.