Steroid profiling in male wobbler mouse, a model of Amyotrophic Lateral Sclerosis

The Wobbler mouse is an animal model for human motoneuron diseases, especially amyotrophic lateral sclerosis (ALS), used in the investigation of both pathology and therapeutic treatment. ALS is a fatal neurodegenerative disease, characterized by the selective and progressive death of motoneurons, leading to progressive paralysis. Previous limited studies have reported steroidal hormone dysregulation in Wobbler mouse and in ALS patients, suggesting endocrine dysfunctions which may be involved in the pathogenesis of the disease. In this study, we established a steroid profiling in brain, spinal cord, plasma, adrenal glands, and testes in 2-month-old male Wobbler mice and their littermates by gas chromatography coupled to mass spectrometry. Our results show in Wobbler mice the following: 1) a marked up-regulation of corticosterone levels in adrenal glands, plasma, spinal cord regions (cervical, thoracic, lumbar) and brain; 2) a strong decrease in T levels in the testis, plasma, spinal cord, and brain; and 3) increased levels of progesterone and especially of its reduced metabolites 5α-dihydroprogesterone, allopregnanolone, and 20α-dihydroprogesterone in the brain, spinal cord, and adrenal glands. Furthermore, Wobbler mice showed a hypothalamic-pituitary-gonadal hypoactivity. Interestingly, plasma concentrations of corticosterone and T correlate well with their respective levels in cervical spinal cord in both control and Wobbler mice. T down-regulation is probably the consequence of adrenal hyperactivity, and the up-regulation of progesterone and its reduced metabolites may correspond to an endogenous protective mechanism in response to motoneuron degeneration. Our findings suggest that increased levels of corticosterone and decreased levels of T in plasma could be a signature of motoneuron degeneration.Fil: Gonzalez Deniselle, Maria Claudia. Universidad de Buenos Aires. Facultad de Medicina; Argentina. 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: Liere, Philippe. Inserm; Francia. Université Paris Saclay; FranciaFil: Pianos, Antoine. Inserm; Francia. Université Paris Saclay; FranciaFil: 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: Aprahamian, Fanny. Inserm; Francia. Université Paris Saclay; FranciaFil: Cambourg, Annie. Inserm; Francia. Université Paris Saclay; FranciaFil: Di Giorgio, Noelia Paula. 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: Schumacher, Michael. Inserm; Francia. Université Paris Saclay; Francia. Universite Paris Sud; FranciaFil: 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; ArgentinaFil: Guennoun, Rachida. Université Paris Saclay; Francia. Inserm; Francia. Universite Paris Sud; Franci

Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases

Glucocorticoids are crucial for stress-coping, resilience, and adaptation. However, if the stress hormones become dysregulated, the vulnerability to stress-related diseases is enhanced. In this brief review, we discuss the role of glucocorticoids in the pathogenesis of neurodegenerative disorders in both human and animal models, and focus in particular on amyotrophic lateral sclerosis (ALS). For this purpose, we used the Wobbler animal model, which mimics much of the pathology of ALS including a dysfunctional hypothalamic–pituitary–adrenal axis. We discuss recent studies that demonstrated that the pathological cascade characteristic for motoneuron degeneration of ALS is mimicked in the genetically selected Wobbler mouse and can be attenuated by treatment with the selective glucocorticoid receptor antagonist (GRA) CORT113176. In long-term treatment (3 weeks) GRA attenuated progression of the behavioral, inflammatory, excitatory, and cell-death-signaling pathways while increasing the survival signal of serine–threonine kinase (pAkt). The action mechanism of the GRA may be either by interfering with GR deactivation or by restoring the balance between pro- and anti-inflammatory signaling pathways driven by the complementary mineralocorticoid receptor (MR)- and GR-mediated actions of corticosterone. Accordingly, GR antagonism may have clinical relevance for the treatment of neurodegenerative diseases.Fil: 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; 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; Francia. Université Paris Sud; Francia. Université Paris Saclay; FranciaFil: Schumacher, Michael. Inserm; Francia. Université Paris Sud; Francia. Université Paris Saclay; FranciaFil: Hunt, Hazel. Corcepts Therapeutics; Estados UnidosFil: Belanoff, Joseph. Corcepts Therapeutics; Estados UnidosFil: de Kloet, E. Ronald. Leiden University. Leiden University Medical Center.; Países BajosFil: Gonzalez Deniselle, Maria Claudia. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; Argentina. 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; Argentin

Progesterone protective effects in neurodegeneration and neuroinflamation

Progesterone is a neuroprotective, promyelinating and antiinflammatory  factor for the nervous system. Here we discuss progesterone effects in models of  motoneuron degeneration and neuroinflammation. In neurodegeneration of the  Wobbler mouse, a subset of spinal cord motoneurons showed increased activity of  nitric oxide synthase (NOS), increased intramitochondrial NOS, decreased activity of  respiratory chain complexes and decreased activity and protein expression of Mnsuperoxide  dismutase type 2 (MnSOD2). Clinically, Wobblers suffered several  degrees of motor impairment. Progesterone treatment restored the expression of  neuronal markers, decreased the activity of NOS and enhanced complex I  respiratory activity and MnSOD2. Long-term treatment with progesterone increased  muscle strength, biceps weight and survival. Collectively, these data supported that  progesterone prevented neurodegeneration. To study progesterone effects in  neuroinflammation, we employed mice with experimental autoimmune  encephalomyelitis (EAE). EAE mice spinal cord showed increased mRNA levels of  the inflammatory mediators tumour necrosis factor α (TNFα) and its receptor TNFR1,  the microglial marker CD11b, iNOS and the toll-like receptor 4 (TLR4). Progesterone  pretreatment of EAE mice blocked the proinflammatory mediators, decreased Iba1+  microglial cells and attenuated clinical signs of EAE. Therefore, reactive glial cells  became targets of progesterone anti-inflammatory effects. These results open the  ground for testing the usefulness of neuroactive steroids for neurological disorders.Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Gonzalez Deniselle, Maria Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Garay, Laura Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Meyer, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Gargiulo Monachelli, Gisella Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Guennoun, Rachida. Inserm; Francia. Universite Paris Sud; FranciaFil: Schumacher, M.. Inserm; Francia. Universite Paris Sud; FranciaFil: Carreras, Maria Cecilia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Poderoso, Juan José. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo; Argentin

Progesterone receptors: a key for neuroprotection in experimental stroke

Progesterone receptors (PR) are expressed throughout the brain. However, their functional significance remains understudied. Here we report a novel role of PR as crucial mediators of neuroprotection using a model of transient middle cerebral artery occlusion and PR knockout mice. Six hours after ischemia, we observed a rapid increase in progesterone and 5-dihydroprogesterone, the endogenous PR ligands, a process that may be a part of the natural neuroprotective mechanisms. PR deficiency, and even haploinsufficiency, increases the susceptibility of the brain to stroke damage. Within a time window of 24 h, PR-dependent signaling of endogenous brain progesterone limits the extent of tissue damage and the impairment of motor functions. Longer-term improvement requires additional treatment with exogenous progesterone and is also PR dependent. The potent and selective PR agonist Nestorone is also effective. In contrast to progesterone, levels of the neurosteroid allopregnanolone, which modulates -aminobutyric acid type A receptors, did not increase after stroke, but its administration protected both wild-type and PR-deficient mice against ischemic damage. These results show that 1) PR are linked to signaling pathways that influence susceptibility to stroke, and 2) PR are direct key targets for both endogenous neuroprotection and for therapeutic strategies after stroke, and they suggest a novel indication for synthetic progestins already validated for contraception. Although allopregnanolone may not be an endogenous neuroprotective agent, its administration protects the brain against ischemicdamageby signaling mechanisms not involving PR. Collectively, our data clarify the relative roles of PR and allopregnanolone in neuroprotection after stroke.Fil: Liu, Ailing. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; FranciaFil: Margaill, Isabelle. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; Francia. University Paris Descartes; FranciaFil: Zhang, Shaodong. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; FranciaFil: Labombarda, Maria Florencia. 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: Coqueran, Bérard. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; FranciaFil: Delespierre, Brigitte. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Liere, Philippe. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Marchand Leroux, Catherine. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Paris V; FranciaFil: O’Malley, Bert W.. Baylor College of Medicine;Fil: Lydon, John P.. Baylor College of Medicine;Fil: 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; ArgentinaFil: Sitruk Ware, Regine. The Rockefeller University; Estados UnidosFil: Mattern, Claudia. MetP Pharma AG; SuizaFil: Plotkine, Michel. Universite de Paris V; FranciaFil: Schumacher, Michael. Institut National de la Santé et de la Recherche Médicale; Francia. Université Paris Sud; FranciaFil: Guennoun, Rachida. Université Paris Sud; Francia. Institut National de la Santé et de la Recherche Médicale; Franci

Progesterone in the Brain: Hormone, Neurosteroid and Neuroprotectant

Progesterone has a broad spectrum of actions in the brain. Among these, the neuroprotective effects are well documented. Progesterone neural effects are mediated by multiple signaling pathways involving binding to specific receptors (intracellular progesterone receptors (PR); membrane-associated progesterone receptor membrane component 1 (PGRMC1); and membrane progesterone receptors (mPRs)) and local bioconversion to 3α,5α-tetrahydroprogesterone (3α,5α-THPROG), which modulates GABAA receptors. This brief review aims to give an overview of the synthesis, metabolism, neuroprotective effects, and mechanism of action of progesterone in the rodent and human brain. First, we succinctly describe the biosynthetic pathways and the expression of enzymes and receptors of progesterone; as well as the changes observed after brain injuries and in neurological diseases. Then, we summarize current data on the differential fluctuations in brain levels of progesterone and its neuroactive metabolites according to sex, age, and neuropathological conditions. The third part is devoted to the neuroprotective effects of progesterone and 3α,5α-THPROG in different experimental models, with a focus on traumatic brain injury and stroke. Finally, we highlight the key role of the classical progesterone receptors (PR) in mediating the neuroprotective effects of progesterone after stroke

Recepteurs de la progesterone dans l'hypothalamus et l'hypophyse de l'embryon de poulet: ontogenie et regulation

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

La progestérone dans le cerveau sain et après traumatisme (sites membranaires, synthèse, métabolites et effets)

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Cerebroprotection by progesterone following ischemic stroke: Multiple effects and role of the neural progesterone receptors

International audienceTreatment with progesterone limits brain damage after stroke. However, the cellular bases of the cerebroprotective effects of progesterone are not well documented. The aims of this study were to determine neural cells and functions that are affected by progesterone treatment and the role of neural progesterone receptors (PR) after stroke. Adult male PRNesCre mice, selectively lacking PR in the central nervous system, and their control PRloxP/loxP littermates were subjected to transient ischemia by middle cerebral artery occlusion (MCAO) for 30 min. Mice received either progesterone (8 mg/kg) or vehicle at 1-, 6- and 24- hrs post-MCAO and outcomes were analyzed at 48 h post-MCAO. In PRloxP/loxP mice, progesterone exerted multiple effects on different neural cell types, improved motor functional outcomes and reduced total infarct volumes. In the peri-infarct, progesterone increased the density of neurons (NeuN+ cells), of cells of the oligodendroglial lineage (Olig2+ cells) and of oligodendrocyte progenitors (OP, NG2+ cells). Progesterone decreased the density of activated astrocytes (GFAP+ cells) and reactive microglia (Iba1+ cells) coexpressing the mannose receptor type 1 CD206 marker. Progesterone also reduced the expression of aquaporin 4 (AQP4), the water channel involved in both edema formation and resorption. The beneficial effects of progesterone were not observed in PRNesCre mice. Our findings show that progesterone treatment exerts beneficial effects on neurons, oligodendroglial cells and neuroinflammatory responses via PR. These findings demonstrate that progesterone is a pleiotropic cerebroprotective agent and that neural PR represent a therapeutic target for stroke cerebroprotection

Progesterone: therapeutic opportunities for neuroprotection and myelin repair

Progesterone and its metabolites promote the viability of neurons in the brain and spinal cord. Their neuroprotective effects have been documented in different lesion models, including traumatic brain injury (TBI), experimentally induced ischemia, spinal cord lesions and a genetic model of motoneuron disease. Progesterone plays an important role in developmental myelination and in myelin repair, and the aging nervous system appears to remain sensitive to some of progesterone's beneficial effects. Thus, the hormone may promote neuroregeneration by several different actions by reducing inflammation, swelling and apoptosis, thereby increasing the survival of neurons, and by promoting the formation of new myelin sheaths. Recognition of the important pleiotropic effects of progesterone opens novel perspectives for the treatment of brain lesions and diseases of the nervous system. Over the last decade, there have been a growing number of studies showing that exogenous administration of progesterone or some of its metabolites can be successfully used to treat traumatic brain and spinal cord injury, as well as ischemic stroke. Progesterone can also be synthesized by neurons and by glial cells within the nervous system. This finding opens the way for a promising therapeutic strategy, the use of pharmacological agents, such as ligands of the translocator protein (18 kDa) (TSPO; the former peripheral benzodiazepine receptor or PBR), to locally increase the synthesis of steroids with neuroprotective and neuroregenerative properties. A concept is emerging that progesterone may exert different actions and use different signaling mechanisms in normal and injured neural tissue.Fil: Schumacher, Michael. Inserm; Francia. Universite Paris Sud; FranciaFil: Guennoun, Rachida. Inserm; Francia. Universite Paris Sud; FranciaFil: Stein, Donald G.. University of Emory; Estados UnidosFil: de Nicola, Alejandro Federico. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. 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; Argentin