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  1. Maria Meyer, Maria Claudia Gonzalez Deniselle, Hazel Hunt, Ronald E Kloet and Alejandro F De Nicola.
    The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice.. The Journal of steroid biochemistry and molecular biology 143C:40–48, February 2014.
    Abstract Mutant Wobbler mice are models for human amyotrophic lateral sclerosis (ALS). In addition to spinal cord degeneration, Wobbler mice show high levels of blood corticosterone, hyperactivity of the hypothalamic-pituitary-adrenal axis and abnormalities of the hippocampus. Hypersecretion of glucocorticoids increase hippocampus vulnerability, a process linked to an enriched content of glucocorticoid receptors (GR). Hence, we studied if a selective GR antagonist (CORT108297) with null affinity for other steroid receptors restored faulty hippocampus parameters of Wobbler mice. Three months old genotyped Wobbler mice received s.c. vehicle or CORT108297 during 4 days. We compared the response of doublecortin (DCX)+ neuroblasts in the subgranular layer of the dentate gyrus (DG), NeuN+ cells in the hilus of the DG, glial fibrillary acidic protein (GFAP)+ astrocytes and the phenotype of Iba1+ microglia in CORT108297-treated and vehicle-treated Wobblers. The number of DCX+ cells in Wobblers was lower than in control mice, whereas CORT108297 restored this parameter. After CORT108297 treatment, Wobblers showed diminished astrogliosis, and changed the phenotype of Iba1+ microglia from an activated to a quiescent form. These changes occurred without alterations in the hypercorticosteronemia or the number of NeuN+ cells of the Wobblers. In a separate experiment employing control NFR/NFR mice, treatment with corticosterone for 5 days reduced DCX+ neuroblasts and induced astrocyte hypertrophy, whereas treatment with CORT108297 antagonized these effects. Normalization of neuronal progenitors, astrogliosis and microglial phenotype by CORT108297 indicates the usefulness of this antagonist to normalize hippocampus parameters of Wobbler mice. Thus, CORT108297 opens new therapeutic options for the brain abnormalities of ALS patients and hyperadrenocorticisms.
    URL, DOI BibTeX

    @article{Meyer2014,
    	abstract = "Mutant Wobbler mice are models for human amyotrophic lateral sclerosis (ALS). In addition to spinal cord degeneration, Wobbler mice show high levels of blood corticosterone, hyperactivity of the hypothalamic-pituitary-adrenal axis and abnormalities of the hippocampus. Hypersecretion of glucocorticoids increase hippocampus vulnerability, a process linked to an enriched content of glucocorticoid receptors (GR). Hence, we studied if a selective GR antagonist (CORT108297) with null affinity for other steroid receptors restored faulty hippocampus parameters of Wobbler mice. Three months old genotyped Wobbler mice received s.c. vehicle or CORT108297 during 4 days. We compared the response of doublecortin (DCX)+ neuroblasts in the subgranular layer of the dentate gyrus (DG), NeuN+ cells in the hilus of the DG, glial fibrillary acidic protein (GFAP)+ astrocytes and the phenotype of Iba1+ microglia in CORT108297-treated and vehicle-treated Wobblers. The number of DCX+ cells in Wobblers was lower than in control mice, whereas CORT108297 restored this parameter. After CORT108297 treatment, Wobblers showed diminished astrogliosis, and changed the phenotype of Iba1+ microglia from an activated to a quiescent form. These changes occurred without alterations in the hypercorticosteronemia or the number of NeuN+ cells of the Wobblers. In a separate experiment employing control NFR/NFR mice, treatment with corticosterone for 5 days reduced DCX+ neuroblasts and induced astrocyte hypertrophy, whereas treatment with CORT108297 antagonized these effects. Normalization of neuronal progenitors, astrogliosis and microglial phenotype by CORT108297 indicates the usefulness of this antagonist to normalize hippocampus parameters of Wobbler mice. Thus, CORT108297 opens new therapeutic options for the brain abnormalities of ALS patients and hyperadrenocorticisms.",
    	author = "Meyer, Maria and {Gonzalez Deniselle}, Maria Claudia and Hunt, Hazel and de Kloet, E Ronald and {De Nicola}, Alejandro F",
    	doi = "10.1016/j.jsbmb.2014.02.007",
    	issn = "1879-1220",
    	journal = "The Journal of steroid biochemistry and molecular biology",
    	month = "feb",
    	pages = "40--48",
    	pmid = 24565565,
    	title = "{The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24565565",
    	volume = "143C",
    	year = 2014
    }
    
  2. Matthew C Evans, Pieter J Gaillard, Marco Boer, Chantal Appeldoorn, Rick Dorland, Nicola R Sibson, Martin R Turner, Daniel C Anthony and Helen B Stolp.
    CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis.. Acta neuropathologica communications 2:66, January 2014.
    Abstract BACKGROUND: Hallmarks of CNS inflammation, including microglial and astrocyte activation, are prominent features in post-mortem tissue from amyotrophic lateral sclerosis (ALS) patients and in mice overexpressing mutant superoxide dismutase-1 (SOD1G93A). Administration of non-targeted glucocorticoids does not significantly alter disease progression, but this may reflect poor CNS delivery. Here, we sought to discover whether CNS-targeted, liposomal encapsulated glucocorticoid would inhibit the CNS inflammatory response and reduce motor neuron loss. SOD1G93A mice were treated with saline, free methylprednisolone (MP, 10 mg/kg/week) or glutathione PEGylated liposomal MP (2B3-201, 10 mg/kg/week) and compared to saline treated wild-type animals. Animals were treated weekly with intravenous injections for 9 weeks from 60 days of age. Weights and motor performance were monitored during this period. At the end of the experimental period (116 days) mice were imaged using T2-weighted MRI for brainstem pathology; brain and spinal cord tissue were then collected for histological analysis. RESULTS: All SOD1G93A groups showed a significant decrease in motor performance, compared to baseline, from \~100 days. SOD1G93A animals showed a significant increase in signal intensity on T2 weighted MR images, which may reflect the combination of neuronal vacuolation and glial activation in these motor nuclei. Treatment with 2B3-201, but not free MP, significantly reduced T2 hyperintensity observed in SOD1G93A mice. Compared to saline-treated and free-MP-treated SOD1G93A mice, those animals given 2B3-201 displayed significantly improved histopathological outcomes in brainstem motor nuclei, which included reduced gliosis and neuronal loss. CONCLUSIONS: In contrast to previous reports that employed free steroid preparations, CNS-targeted anti-inflammatory agent 2B3-201 (liposomal methylprednisolone) has therapeutic potential, reducing brainstem pathology in the SOD1G93A mouse model of ALS. 2B3-201 reduced neuronal loss and vacuolation in brainstem nuclei, and reduced activation preferentially in astrocytes compared with microglia. These data also suggest that other previously ineffective therapies could be of therapeutic value if delivered specifically to the CNS.
    URL, DOI BibTeX

    @article{Evans2014,
    	abstract = "BACKGROUND: Hallmarks of CNS inflammation, including microglial and astrocyte activation, are prominent features in post-mortem tissue from amyotrophic lateral sclerosis (ALS) patients and in mice overexpressing mutant superoxide dismutase-1 (SOD1G93A). Administration of non-targeted glucocorticoids does not significantly alter disease progression, but this may reflect poor CNS delivery. Here, we sought to discover whether CNS-targeted, liposomal encapsulated glucocorticoid would inhibit the CNS inflammatory response and reduce motor neuron loss. SOD1G93A mice were treated with saline, free methylprednisolone (MP, 10 mg/kg/week) or glutathione PEGylated liposomal MP (2B3-201, 10 mg/kg/week) and compared to saline treated wild-type animals. Animals were treated weekly with intravenous injections for 9 weeks from 60 days of age. Weights and motor performance were monitored during this period. At the end of the experimental period (116 days) mice were imaged using T2-weighted MRI for brainstem pathology; brain and spinal cord tissue were then collected for histological analysis. RESULTS: All SOD1G93A groups showed a significant decrease in motor performance, compared to baseline, from \~{}100 days. SOD1G93A animals showed a significant increase in signal intensity on T2 weighted MR images, which may reflect the combination of neuronal vacuolation and glial activation in these motor nuclei. Treatment with 2B3-201, but not free MP, significantly reduced T2 hyperintensity observed in SOD1G93A mice. Compared to saline-treated and free-MP-treated SOD1G93A mice, those animals given 2B3-201 displayed significantly improved histopathological outcomes in brainstem motor nuclei, which included reduced gliosis and neuronal loss. CONCLUSIONS: In contrast to previous reports that employed free steroid preparations, CNS-targeted anti-inflammatory agent 2B3-201 (liposomal methylprednisolone) has therapeutic potential, reducing brainstem pathology in the SOD1G93A mouse model of ALS. 2B3-201 reduced neuronal loss and vacuolation in brainstem nuclei, and reduced activation preferentially in astrocytes compared with microglia. These data also suggest that other previously ineffective therapies could be of therapeutic value if delivered specifically to the CNS.",
    	author = "Evans, Matthew C and Gaillard, Pieter J and de Boer, Marco and Appeldoorn, Chantal and Dorland, Rick and Sibson, Nicola R and Turner, Martin R and Anthony, Daniel C and Stolp, Helen B",
    	doi = "10.1186/2051-5960-2-66",
    	issn = "2051-5960",
    	journal = "Acta neuropathologica communications",
    	month = "jan",
    	pages = 66,
    	pmid = 24923195,
    	title = "{CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24923195",
    	volume = 2,
    	year = 2014
    }
    
  3. Antonella Caccamo, David X Medina and Salvatore Oddo.
    Glucocorticoids exacerbate cognitive deficits in TDP-25 transgenic mice via a glutathione-mediated mechanism: implications for aging, stress and TDP-43 proteinopathies.. The Journal of neuroscience : the official journal of the Society for Neuroscience 33(3):906–13, 2013.
    Abstract The accumulation of TDP-43 (transactive response DNA-binding protein 43) and its 25 kDa C-terminal fragment (TDP-25) is a hallmark of several neurodegenerative disorders, including frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). The majority of FTLD-TDP cases are due to loss of function mutations in the gene encoding progranulin, a secreted growth factor. In ALS, specific mutations in the gene encoding TDP-43 have been linked to the disease pathogenesis. In both cases, however, the penetrance of the mutations greatly increases during aging, suggesting that other genetic or environmental factors may facilitate the development of the disease. Using transgenic mice that overexpress the 25 kDa C-terminal fragment of TDP-43, here we show that glucocorticoids, stress hormones known to increase the brain susceptibility to neurotoxic insults, increase the levels of soluble TDP-25 and exacerbate cognitive deficits, without altering full-length TDP-43 levels. Additionally, we show that the mechanism underlying the glucocorticoid-mediated increase in TDP-25 levels is coupled to changes in the glutathione redox state. Glutathione is an antioxidant involved in protecting cells from damage caused by reactive oxygen species; notably, alterations in the ratio of reduced to oxidized glutathione, which is the primary determinant of the cellular redox state, are associated with aging and neurodegeneration. We show that restoring the ratio of reduced to oxidized glutathione blocks the glucocorticoid effects on TDP-25. These data show that glucocorticoids potentiate the neurotoxic action of TDP-25 by increasing its levels and clearly indicate the role of cellular oxidative damage in this process.
    URL, DOI BibTeX

    @article{Caccamo2013,
    	abstract = "The accumulation of TDP-43 (transactive response DNA-binding protein 43) and its 25 kDa C-terminal fragment (TDP-25) is a hallmark of several neurodegenerative disorders, including frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). The majority of FTLD-TDP cases are due to loss of function mutations in the gene encoding progranulin, a secreted growth factor. In ALS, specific mutations in the gene encoding TDP-43 have been linked to the disease pathogenesis. In both cases, however, the penetrance of the mutations greatly increases during aging, suggesting that other genetic or environmental factors may facilitate the development of the disease. Using transgenic mice that overexpress the 25 kDa C-terminal fragment of TDP-43, here we show that glucocorticoids, stress hormones known to increase the brain susceptibility to neurotoxic insults, increase the levels of soluble TDP-25 and exacerbate cognitive deficits, without altering full-length TDP-43 levels. Additionally, we show that the mechanism underlying the glucocorticoid-mediated increase in TDP-25 levels is coupled to changes in the glutathione redox state. Glutathione is an antioxidant involved in protecting cells from damage caused by reactive oxygen species; notably, alterations in the ratio of reduced to oxidized glutathione, which is the primary determinant of the cellular redox state, are associated with aging and neurodegeneration. We show that restoring the ratio of reduced to oxidized glutathione blocks the glucocorticoid effects on TDP-25. These data show that glucocorticoids potentiate the neurotoxic action of TDP-25 by increasing its levels and clearly indicate the role of cellular oxidative damage in this process.",
    	author = "Caccamo, Antonella and Medina, David X and Oddo, Salvatore",
    	doi = "10.1523/JNEUROSCI.3314-12.2013",
    	issn = "1529-2401",
    	journal = "The Journal of neuroscience : the official journal of the Society for Neuroscience",
    	keywords = "Aging,Aging: metabolism,Animals,Brain,Brain: drug effects,Brain: metabolism,Brain: pathology,DNA-Binding Proteins,DNA-Binding Proteins: genetics,DNA-Binding Proteins: metabolism,Dexamethasone,Dexamethasone: pharmacology,Dexamethasone: therapeutic use,Glucocorticoids,Glucocorticoids: pharmacology,Glucocorticoids: therapeutic use,Glutathione,Glutathione Disulfide,Glutathione Disulfide: metabolism,Glutathione: metabolism,Maze Learning,Maze Learning: drug effects,Maze Learning: physiology,Mice,Mice, Transgenic,Reactive Oxygen Species,Reactive Oxygen Species: metabolism,TDP-43 Proteinopathies,TDP-43 Proteinopathies: drug therapy,TDP-43 Proteinopathies: metabolism,TDP-43 Proteinopathies: pathology",
    	month = "",
    	number = 3,
    	pages = "906--13",
    	pmid = 23325230,
    	title = "{Glucocorticoids exacerbate cognitive deficits in TDP-25 transgenic mice via a glutathione-mediated mechanism: implications for aging, stress and TDP-43 proteinopathies.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23325230",
    	volume = 33,
    	year = 2013
    }
    
  4. Jonathan A Fidler, Christopher M Treleaven, Ashley Frakes, Thomas J Tamsett, Mary McCrate, Seng H Cheng, Lamya S Shihabuddin, Brian K Kaspar and James C Dodge.
    Disease progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25(12):4369–77, December 2011.
    Abstract Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron cell loss, muscular atrophy, and a shortened life span. Survival is highly variable, as some patients die within months, while others live for many years. Exposure to stress or the development of a nonoptimal stress response to disease might account for some of this variability. We show in the SOD1(G93A) mouse model of ALS that recurrent exposure to restraint stress led to an earlier onset of astrogliosis and microglial activation within the spinal cord, accelerated muscular weakness, and a significant decrease in median survival (105 vs. 122 d) when compared to nonstressed animals. Moreover, during normal disease course, ALS mice display a cacostatic stress response by developing an aberrant serum corticosterone circadian rhythm. Interestingly, we also found that higher corticosterone levels were significantly correlated with both an earlier onset of paralysis (males: r(2)=0.746; females: r(2)=0.707) and shorter survival times (males: r(2)=0.680; females: r(2)=0.552) in ALS mice. These results suggest that stress is capable of accelerating disease progression and that strategies that modulate glucocorticoid metabolism might be a viable treatment approach for ALS.
    URL, DOI BibTeX

    @article{Fidler2011,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron cell loss, muscular atrophy, and a shortened life span. Survival is highly variable, as some patients die within months, while others live for many years. Exposure to stress or the development of a nonoptimal stress response to disease might account for some of this variability. We show in the SOD1(G93A) mouse model of ALS that recurrent exposure to restraint stress led to an earlier onset of astrogliosis and microglial activation within the spinal cord, accelerated muscular weakness, and a significant decrease in median survival (105 vs. 122 d) when compared to nonstressed animals. Moreover, during normal disease course, ALS mice display a cacostatic stress response by developing an aberrant serum corticosterone circadian rhythm. Interestingly, we also found that higher corticosterone levels were significantly correlated with both an earlier onset of paralysis (males: r(2)=0.746; females: r(2)=0.707) and shorter survival times (males: r(2)=0.680; females: r(2)=0.552) in ALS mice. These results suggest that stress is capable of accelerating disease progression and that strategies that modulate glucocorticoid metabolism might be a viable treatment approach for ALS.",
    	author = "Fidler, Jonathan A and Treleaven, Christopher M and Frakes, Ashley and Tamsett, Thomas J and McCrate, Mary and Cheng, Seng H and Shihabuddin, Lamya S and Kaspar, Brian K and Dodge, James C",
    	doi = "10.1096/fj.11-190819",
    	issn = "1530-6860",
    	journal = "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: etiology,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Animals,Corticosterone,Corticosterone: blood,Corticosterone: metabolism,Corticosterone: pharmacology,Disease Models, Animal,Disease Progression,Female,Humans,Male,Mice,Mice, Mutant Strains,Mice, Transgenic,Models, Biological,Mutant Proteins,Mutant Proteins: genetics,Mutant Proteins: metabolism,Restraint, Physical,Restraint, Physical: adverse effects,Stress, Physiological,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism",
    	month = "dec",
    	number = 12,
    	pages = "4369--77",
    	pmid = 21876068,
    	title = "{Disease progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3236626\&tool=pmcentrez\&rendertype=abstract",
    	volume = 25,
    	year = 2011
    }
    
  5. Christoph Boehmer, Monica Palmada, Jeyaganesh Rajamanickam, Roman Schniepp, Susan Amara and Florian Lang.
    Post-translational regulation of EAAT2 function by co-expressed ubiquitin ligase Nedd4-2 is impacted by SGK kinases.. Journal of neurochemistry 97(4):911–21, 2006.
    Abstract The human excitatory amino acid transporter (EAAT)2 is the major glutamate carrier in the mammalian CNS. Defective expression of the transporter results in neuroexcitotoxicity that may contribute to neuronal disorders such as amyotrophic lateral sclerosis (ALS). The serum and glucocorticoid inducible kinase (SGK) 1 is expressed in the brain and is known to interact with the ubiquitin ligase Nedd4-2 to modulate membrane transporters and ion channels. The present study aimed to investigate whether SGK isoforms and the related kinase, protein kinase B (PKB), regulate EAAT2. Expression studies in Xenopus oocytes demonstrated that glutamate-induced inward current (IGLU) was stimulated by co-expression of SGK1, SGK2, SGK3 or PKB. IGLU is virtually abolished by Nedd4-2, an effect abrogated by additional co-expression of either kinase. The kinases diminish the effect through Nedd4-2 phosphorylation without altering Nedd4-2 protein abundance. SGKs increase the transporter maximal velocity without significantly affecting substrate affinity. Similar to glutamate-induced currents, [3H] glutamate uptake and cell surface abundance of the transporter were increased by the SGK isoforms and down-regulated by the ubiquitin ligase Nedd4-2. In conclusion, all three SGK isoforms and PKB increase EAAT2 activity and plasma membrane expression and thus, may participate in the regulation of neuroexcitability.
    URL, DOI BibTeX

    @article{Boehmer2006,
    	abstract = "The human excitatory amino acid transporter (EAAT)2 is the major glutamate carrier in the mammalian CNS. Defective expression of the transporter results in neuroexcitotoxicity that may contribute to neuronal disorders such as amyotrophic lateral sclerosis (ALS). The serum and glucocorticoid inducible kinase (SGK) 1 is expressed in the brain and is known to interact with the ubiquitin ligase Nedd4-2 to modulate membrane transporters and ion channels. The present study aimed to investigate whether SGK isoforms and the related kinase, protein kinase B (PKB), regulate EAAT2. Expression studies in Xenopus oocytes demonstrated that glutamate-induced inward current (IGLU) was stimulated by co-expression of SGK1, SGK2, SGK3 or PKB. IGLU is virtually abolished by Nedd4-2, an effect abrogated by additional co-expression of either kinase. The kinases diminish the effect through Nedd4-2 phosphorylation without altering Nedd4-2 protein abundance. SGKs increase the transporter maximal velocity without significantly affecting substrate affinity. Similar to glutamate-induced currents, [3H] glutamate uptake and cell surface abundance of the transporter were increased by the SGK isoforms and down-regulated by the ubiquitin ligase Nedd4-2. In conclusion, all three SGK isoforms and PKB increase EAAT2 activity and plasma membrane expression and thus, may participate in the regulation of neuroexcitability.",
    	author = "Boehmer, Christoph and Palmada, Monica and Rajamanickam, Jeyaganesh and Schniepp, Roman and Amara, Susan and Lang, Florian",
    	doi = "10.1111/j.1471-4159.2006.03629.x",
    	issn = "0022-3042",
    	journal = "Journal of neurochemistry",
    	keywords = "Animals,Catalytic Domain,Catalytic Domain: drug effects,Catalytic Domain: physiology,Down-Regulation,Down-Regulation: drug effects,Down-Regulation: physiology,Endosomal Sorting Complexes Required for Transport,Excitatory Amino Acid Transporter 2,Excitatory Amino Acid Transporter 2: metabolism,Female,Glutamic Acid,Glutamic Acid: metabolism,Glutamic Acid: pharmacology,Humans,Immediate-Early Proteins,Immediate-Early Proteins: metabolism,Membrane Potentials,Membrane Potentials: drug effects,Membrane Potentials: physiology,Oocytes,Oocytes: drug effects,Oocytes: enzymology,Phosphorylation,Phosphorylation: drug effects,Protein Isoforms,Protein Isoforms: metabolism,Protein Processing, Post-Translational,Protein Processing, Post-Translational: physiology,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: metabolism,Proto-Oncogene Proteins c-akt,Proto-Oncogene Proteins c-akt: metabolism,Ubiquitin,Ubiquitin-Protein Ligases,Ubiquitin-Protein Ligases: metabolism,Ubiquitin: metabolism,Up-Regulation,Up-Regulation: drug effects,Up-Regulation: physiology,Xenopus laevis",
    	month = "",
    	number = 4,
    	pages = "911--21",
    	pmid = 16573659,
    	title = "{Post-translational regulation of EAAT2 function by co-expressed ubiquitin ligase Nedd4-2 is impacted by SGK kinases.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/16573659",
    	volume = 97,
    	year = 2006
    }
    
  6. Bodo Schoenebeck, Verian Bader, Xin Ran Zhu, Beate Schmitz, Hermann Lübbert and Christine C Stichel.
    Sgk1, a cell survival response in neurodegenerative diseases.. Molecular and cellular neurosciences 30(2):249–64, 2005.
    Abstract Serum and glucocorticoid-regulated kinase 1 (sgk1) belongs to a family of serine/threonine kinases that is under acute transcriptional control by serum and glucocorticoids. An expanding set of receptors and cellular stress pathways has been shown to enhance sgk1 expression, which is implicated in the regulation of ion channel conductance, cell volume, cell cycle progression, and apoptosis. Recent evidence for the involvement of sgk1 in the early pathogenesis of MPTP-induced Parkinson's disease (PD) prompted us to investigate in more detail its expression and role in animal models of different neurodegenerative diseases. Here, we show that transcription of sgk1 is increased in several animal models of PD and a transgenic model of amyotrophic lateral sclerosis (ALS). The upregulation of sgk1 strongly correlates with the occurrence of cell death. Furthermore, we provide evidence that the Forkhead transcription factor FKHRL1 and some of the voltage-gated potassium channels are physiological substrates of sgk1 in vivo. Using a small interfering RNA approach to silence sgk1 transcripts in vitro, we give evidence that sgk1 exerts a protective role in oxidative stress situations. These findings underline a key role for sgk1 in the molecular pathway of cell death, in which sgk1 seems to exert a protective role.
    URL, DOI BibTeX

    @article{Schoenebeck2005,
    	abstract = "Serum and glucocorticoid-regulated kinase 1 (sgk1) belongs to a family of serine/threonine kinases that is under acute transcriptional control by serum and glucocorticoids. An expanding set of receptors and cellular stress pathways has been shown to enhance sgk1 expression, which is implicated in the regulation of ion channel conductance, cell volume, cell cycle progression, and apoptosis. Recent evidence for the involvement of sgk1 in the early pathogenesis of MPTP-induced Parkinson's disease (PD) prompted us to investigate in more detail its expression and role in animal models of different neurodegenerative diseases. Here, we show that transcription of sgk1 is increased in several animal models of PD and a transgenic model of amyotrophic lateral sclerosis (ALS). The upregulation of sgk1 strongly correlates with the occurrence of cell death. Furthermore, we provide evidence that the Forkhead transcription factor FKHRL1 and some of the voltage-gated potassium channels are physiological substrates of sgk1 in vivo. Using a small interfering RNA approach to silence sgk1 transcripts in vitro, we give evidence that sgk1 exerts a protective role in oxidative stress situations. These findings underline a key role for sgk1 in the molecular pathway of cell death, in which sgk1 seems to exert a protective role.",
    	author = {Schoenebeck, Bodo and Bader, Verian and Zhu, Xin Ran and Schmitz, Beate and L\"{u}bbert, Hermann and Stichel, Christine C},
    	doi = "10.1016/j.mcn.2005.07.017",
    	issn = "1044-7431",
    	journal = "Molecular and cellular neurosciences",
    	keywords = "Animals,Cell Death,Cell Survival,Cell Survival: drug effects,Cell Survival: physiology,Exons,Humans,Immediate-Early Proteins,Immediate-Early Proteins: genetics,Immediate-Early Proteins: physiology,Mice,Mice, Knockout,Mice, Transgenic,Motor Neuron Disease,Motor Neuron Disease: genetics,Motor Neuron Disease: physiopathology,Neurodegenerative Diseases,Neurodegenerative Diseases: genetics,Neurodegenerative Diseases: physiopathology,Polymerase Chain Reaction,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: genetics,Protein-Serine-Threonine Kinases: physiology,RNA, Messenger,RNA, Messenger: genetics,Tropolone,Tropolone: analogs \& derivatives,Tropolone: toxicity,Ubiquitin-Protein Ligases,Ubiquitin-Protein Ligases: deficiency,Ubiquitin-Protein Ligases: genetics",
    	month = "",
    	number = 2,
    	pages = "249--64",
    	pmid = 16125969,
    	title = "{Sgk1, a cell survival response in neurodegenerative diseases.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/16125969",
    	volume = 30,
    	year = 2005
    }
    
  7. M C González Deniselle, S L González, A E Lima, G Wilkin and A F De Nicola.
    The 21-aminosteroid U-74389F attenuates hyperexpression of GAP-43 and NADPH-diaphorase in the spinal cord of wobbler mouse, a model for amyotrophic lateral sclerosis.. Neurochemical research 24(1):1–8, January 1999.
    Abstract The wobbler mouse suffers an autosomal recessive mutation producing severe neurodegeneration and astrogliosis in spinal cord. It has been considered a model for amyotrophic lateral sclerosis. We have studied in these animals the expression of two proteins, the growth-associated protein (GAP-43) and the NADPH-diaphorase, the nitric oxide synthesizing enzyme, employing immunocytochemistry and histochemistry. We found higher expression of GAP-43 immunoreactivity in dorsal horn, Lamina X, corticospinal tract and ventral horn motoneurons in wobbler mice compared to controls. Weak NADPH-diaphorase activity was present in control motoneurons, in contrast to intense labeling of the wobbler group. No differences in diaphorase activity was measured in the rest of the spinal cord between control and mutant mice. A group of animals received subcutaneously for 4 days a 50 mg pellet of U-74389F, a glucocorticoid-derived 21-aminosteroid with antioxidant properties but without glucocorticoid activity. U-74389F slightly attenuated GAP-43 immunostaining in dorsal regions of the spinal cord from wobblers but not in controls. However, in motoneurons of wobbler mice number of GAP-43 immunopositive neurons, cell processes and reaction intensity were reduced by U-74389F. The aminosteroid reduced by 50% motoneuron NADPH-diaphorase activity. Hyperexpression of GAP-43 immunoreactivity in wobbler mice may represent an exaggerated neuronal response to advancing degeneration or muscle denervation. It may also be linked to increased nitric oxide levels. U-74389F may stop neurodegeneration and/or increase muscle trophism and stop oxidative stress, consequently GAP-43 hyperexpression was attenuated. Wobbler mice may be important models to evaluate the use of antioxidant steroid therapy with a view to its use in human motoneuron disease.
    URL BibTeX

    @article{GonzalezDeniselle1999,
    	abstract = "The wobbler mouse suffers an autosomal recessive mutation producing severe neurodegeneration and astrogliosis in spinal cord. It has been considered a model for amyotrophic lateral sclerosis. We have studied in these animals the expression of two proteins, the growth-associated protein (GAP-43) and the NADPH-diaphorase, the nitric oxide synthesizing enzyme, employing immunocytochemistry and histochemistry. We found higher expression of GAP-43 immunoreactivity in dorsal horn, Lamina X, corticospinal tract and ventral horn motoneurons in wobbler mice compared to controls. Weak NADPH-diaphorase activity was present in control motoneurons, in contrast to intense labeling of the wobbler group. No differences in diaphorase activity was measured in the rest of the spinal cord between control and mutant mice. A group of animals received subcutaneously for 4 days a 50 mg pellet of U-74389F, a glucocorticoid-derived 21-aminosteroid with antioxidant properties but without glucocorticoid activity. U-74389F slightly attenuated GAP-43 immunostaining in dorsal regions of the spinal cord from wobblers but not in controls. However, in motoneurons of wobbler mice number of GAP-43 immunopositive neurons, cell processes and reaction intensity were reduced by U-74389F. The aminosteroid reduced by 50\% motoneuron NADPH-diaphorase activity. Hyperexpression of GAP-43 immunoreactivity in wobbler mice may represent an exaggerated neuronal response to advancing degeneration or muscle denervation. It may also be linked to increased nitric oxide levels. U-74389F may stop neurodegeneration and/or increase muscle trophism and stop oxidative stress, consequently GAP-43 hyperexpression was attenuated. Wobbler mice may be important models to evaluate the use of antioxidant steroid therapy with a view to its use in human motoneuron disease.",
    	author = "{Gonz\'{a}lez Deniselle}, M C and Gonz\'{a}lez, S L and Lima, A E and Wilkin, G and {De Nicola}, A F",
    	issn = "0364-3190",
    	journal = "Neurochemical research",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Animals,Antioxidants,Antioxidants: pharmacology,Dihydrolipoamide Dehydrogenase,Dihydrolipoamide Dehydrogenase: biosynthesis,Dihydrolipoamide Dehydrogenase: genetics,Disease Models, Animal,Female,GAP-43 Protein,GAP-43 Protein: biosynthesis,GAP-43 Protein: genetics,Gene Expression Regulation,Gene Expression Regulation: drug effects,Humans,Male,Mice,Mice, Neurologic Mutants,Motor Neurons,Motor Neurons: cytology,Motor Neurons: metabolism,Motor Neurons: pathology,Pregnatrienes,Pregnatrienes: pharmacology,Spinal Cord,Spinal Cord: cytology,Spinal Cord: metabolism,Spinal Cord: pathology",
    	month = "jan",
    	number = 1,
    	pages = "1--8",
    	pmid = 9973230,
    	title = "{The 21-aminosteroid U-74389F attenuates hyperexpression of GAP-43 and NADPH-diaphorase in the spinal cord of wobbler mouse, a model for amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/9973230",
    	volume = 24,
    	year = 1999
    }
    
  8. M C Deniselle, S Lavista-Llanos, M G Ferrini, A E Lima, A G Roldán and A F De Nicola.
    In vitro differences between astrocytes of control and wobbler mice spinal cord.. Neurochemical research 24(12):1535–41, 1999.
    Abstract The Wobbler mouse, a model of amyotrophic lateral sclerosis (ALS), presents motorneuron degeneration and pronounced astrogliosis in the spinal cord. We have studied factors controlling astrocyte proliferation in cultures derived from Wobbler and control mice spinal cord. Basal rate of [3H]thymidine incorporation was 15 times lower in Wobbler astrocytes. While in control cultured cells interleukin-1alpha (IL-1) and corticosterone (CORT) significantly increased proliferation, both agents were inactive in Wobbler astrocytes. The lack of response to CORT was not due to the absence of glucocorticoid receptors, because similar receptor amounts were found in Wobbler and control astrocytes. In contrast to IL-1 and CORT, transforming growth factor-beta1 (TGF-beta1) substantially increased proliferation of Wobbler astrocytes but not of control cells. Differences in response to TGF-beta1 were also obtained by measuring glial fibrillary acidic protein (GFAP) immunoreaction intensity, which was substantially higher in Wobbler astrocytes. Thus, abnormal responses to different mitogens characterized Wobbler astrocytes in culture. We suggest that TGF-beta1 may play a role in the reactive gliosis and GFAP hyperexpression found in the degenerating spinal cord of this model of ALS.
    URL BibTeX

    @article{Deniselle1999,
    	abstract = "The Wobbler mouse, a model of amyotrophic lateral sclerosis (ALS), presents motorneuron degeneration and pronounced astrogliosis in the spinal cord. We have studied factors controlling astrocyte proliferation in cultures derived from Wobbler and control mice spinal cord. Basal rate of [3H]thymidine incorporation was 15 times lower in Wobbler astrocytes. While in control cultured cells interleukin-1alpha (IL-1) and corticosterone (CORT) significantly increased proliferation, both agents were inactive in Wobbler astrocytes. The lack of response to CORT was not due to the absence of glucocorticoid receptors, because similar receptor amounts were found in Wobbler and control astrocytes. In contrast to IL-1 and CORT, transforming growth factor-beta1 (TGF-beta1) substantially increased proliferation of Wobbler astrocytes but not of control cells. Differences in response to TGF-beta1 were also obtained by measuring glial fibrillary acidic protein (GFAP) immunoreaction intensity, which was substantially higher in Wobbler astrocytes. Thus, abnormal responses to different mitogens characterized Wobbler astrocytes in culture. We suggest that TGF-beta1 may play a role in the reactive gliosis and GFAP hyperexpression found in the degenerating spinal cord of this model of ALS.",
    	author = "Deniselle, M C and Lavista-Llanos, S and Ferrini, M G and Lima, A E and Rold\'{a}n, A G and {De Nicola}, A F",
    	issn = "0364-3190",
    	journal = "Neurochemical research",
    	keywords = "Animals,Astrocytes,Astrocytes: cytology,Astrocytes: drug effects,Astrocytes: metabolism,Cell Division,Cell Division: drug effects,Cells, Cultured,Corticosterone,Corticosterone: pharmacology,Female,Glial Fibrillary Acidic Protein,Glial Fibrillary Acidic Protein: metabolism,Gliosis,Gliosis: genetics,Gliosis: pathology,Interleukin-1,Interleukin-1: pharmacology,Kinetics,Male,Mice,Mice, Inbred Strains,Mice, Neurologic Mutants,Motor Neuron Disease,Motor Neuron Disease: genetics,Motor Neuron Disease: pathology,Neuroprotective Agents,Neuroprotective Agents: pharmacology,Pregnatrienes,Pregnatrienes: pharmacology,Receptors, Glucocorticoid,Receptors, Glucocorticoid: metabolism,Reference Values,Spinal Cord,Spinal Cord: cytology,Spinal Cord: drug effects,Spinal Cord: metabolism,Thymidine,Thymidine: metabolism,Transforming Growth Factor beta,Transforming Growth Factor beta: pharmacology",
    	month = "",
    	number = 12,
    	pages = "1535--41",
    	pmid = 10591403,
    	title = "{In vitro differences between astrocytes of control and wobbler mice spinal cord.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/10591403",
    	volume = 24,
    	year = 1999
    }
    
  9. M C González Deniselle, S González, G Piroli, M Ferrini, A E Lima and A F De Nicola.
    Glucocorticoid receptors and actions in the spinal cord of the Wobbler mouse, a model for neurodegenerative diseases.. The Journal of steroid biochemistry and molecular biology 60(3-4):205–13, February 1997.
    Abstract We have studied glucocorticoid receptors (GR) and actions in the spinal cord of the Wobbler mouse, a model for amyotrophic lateral sclerosis and infantile spinal muscular atrophy. Basal and stress levels of circulating corticosterone (CORT) were increased in Wobbler mice. Single point binding assays showed that cytosolic type II GR in the spinal cord of Wobbler mice of both sexes were slightly reduced compared with normal littermates. Saturation analysis further demonstrated a non-significant reduction in Bmax with increased Kd. In the hippocampus, however, we found down-regulation of GR, a probable response to increased CORT levels. We also found that the basal activity of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, was higher in Wobbler mice than in control animals. Both groups showed a two-fold stimulation of ODC activity after treatment with dexamethasone (DEX). Additionally, Wobbler mice presented with an intense proliferation of astrocytes immunoreactive (ir) for glial fibrillary acidic protein (GFAP) in grey and white matter of the spinal cord. The enhanced GFAP-ir was attenuated after four days of treatment with a corticosterone (CORT) pellet implant, producing a pharmacological increase in peripheral circulating CORT. Taking into consideration the content of GR and the changes in ODC activity and GFAP-ir brought about by glucocorticoids, we suggest that Wobbler mice are hormone responsive. Further elucidation of glucocorticoid effects in this model may be relevant for understanding the possible use of hormones in human neurodegenerative diseases.
    URL BibTeX

    @article{GonzalezDeniselle1997,
    	abstract = "We have studied glucocorticoid receptors (GR) and actions in the spinal cord of the Wobbler mouse, a model for amyotrophic lateral sclerosis and infantile spinal muscular atrophy. Basal and stress levels of circulating corticosterone (CORT) were increased in Wobbler mice. Single point binding assays showed that cytosolic type II GR in the spinal cord of Wobbler mice of both sexes were slightly reduced compared with normal littermates. Saturation analysis further demonstrated a non-significant reduction in Bmax with increased Kd. In the hippocampus, however, we found down-regulation of GR, a probable response to increased CORT levels. We also found that the basal activity of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, was higher in Wobbler mice than in control animals. Both groups showed a two-fold stimulation of ODC activity after treatment with dexamethasone (DEX). Additionally, Wobbler mice presented with an intense proliferation of astrocytes immunoreactive (ir) for glial fibrillary acidic protein (GFAP) in grey and white matter of the spinal cord. The enhanced GFAP-ir was attenuated after four days of treatment with a corticosterone (CORT) pellet implant, producing a pharmacological increase in peripheral circulating CORT. Taking into consideration the content of GR and the changes in ODC activity and GFAP-ir brought about by glucocorticoids, we suggest that Wobbler mice are hormone responsive. Further elucidation of glucocorticoid effects in this model may be relevant for understanding the possible use of hormones in human neurodegenerative diseases.",
    	author = "{Gonz\'{a}lez Deniselle}, M C and Gonz\'{a}lez, S and Piroli, G and Ferrini, M and Lima, A E and {De Nicola}, A F",
    	issn = "0960-0760",
    	journal = "The Journal of steroid biochemistry and molecular biology",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Animals,Astrocytes,Astrocytes: cytology,Cell Division,Corticosterone,Corticosterone: blood,Dexamethasone,Dexamethasone: metabolism,Disease Models, Animal,Female,Glial Fibrillary Acidic Protein,Glial Fibrillary Acidic Protein: analysis,Glucocorticoids,Glucocorticoids: metabolism,Lumbosacral Region,Male,Mice,Mice, Mutant Strains,Neck,Ornithine Decarboxylase,Ornithine Decarboxylase: analysis,Receptors, Glucocorticoid,Receptors, Glucocorticoid: metabolism,Sex Factors,Spinal Cord,Spinal Cord: enzymology,Spinal Cord: metabolism,Spinal Cord: pathology,Spinal Muscular Atrophies of Childhood,Spinal Muscular Atrophies of Childhood: metabolism",
    	month = "feb",
    	number = "3-4",
    	pages = "205--13",
    	pmid = 9191978,
    	title = "{Glucocorticoid receptors and actions in the spinal cord of the Wobbler mouse, a model for neurodegenerative diseases.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/9191978",
    	volume = 60,
    	year = 1997
    }
    
  10. M C Gonzalez Deniselle, S L Gonzalez, G G Piroli, A E Lima and A F De Nicola.
    The 21-aminosteroid U-74389F increases the number of glial fibrillary acidic protein-expressing astrocytes in the spinal cord of control and Wobbler mice.. Cellular and molecular neurobiology 16(1):61–72, 1996.
    Abstract 1. Wobbler mice suffer an autosomal recessive mutation producing severe motoneuron degeneration and dense astrogliosis, with increased levels of glial fibrillary acidic protein (GFAP) in the spinal cord and brain stem. They have been considered animal models of amyotrophic lateral sclerosis and infantile spinal muscular atrophy. 2. Using Wobbler mice and normal littermates, we investigated the effects of the membrane-active steroid Lazaroid U-74389F on the number of GFAP-expressing astrocytes and glucocorticoid receptors (GR). Lazaroids are inhibitors of oxygen radical-induced lipid peroxidation, and proved beneficial in cases of CNS injury and ischemia. 3. Four days after pellet implantation of U-74389F into Wobbler mice, hyperplasia and hypertophy of GFAP-expressing astrocytes were apparent in the spinal cord ventral and dorsal horn, areas showing already intense astrogliosis in untreated Wobbler mice. In control mice, U-74389F also produced astrocyte hyperplasia and hypertophy in the dorsal horn and hyperplasia in the ventral-lateral funiculi of the cord. 4. Given in vivo U-74389F did not change GR in spinal cord of Wobbler or control mice, in line with the concept that it is active in membranes but does not bind to GR. Besides, U-74390F did not compete for [3H]dexamethasone binding when added in vitro. 5. The results suggest that stimulation of proliferation and size of GFAP-expressing astrocytes by U-74389F may be a novel mechanism of action of this compound. The Wobbler mouse may be a valuable animal model for further pharmacological testing of glucocorticoid and nonglucocorticoid steroids in neurodegenerative diseases.
    URL BibTeX

    @article{GonzalezDeniselle1996,
    	abstract = "1. Wobbler mice suffer an autosomal recessive mutation producing severe motoneuron degeneration and dense astrogliosis, with increased levels of glial fibrillary acidic protein (GFAP) in the spinal cord and brain stem. They have been considered animal models of amyotrophic lateral sclerosis and infantile spinal muscular atrophy. 2. Using Wobbler mice and normal littermates, we investigated the effects of the membrane-active steroid Lazaroid U-74389F on the number of GFAP-expressing astrocytes and glucocorticoid receptors (GR). Lazaroids are inhibitors of oxygen radical-induced lipid peroxidation, and proved beneficial in cases of CNS injury and ischemia. 3. Four days after pellet implantation of U-74389F into Wobbler mice, hyperplasia and hypertophy of GFAP-expressing astrocytes were apparent in the spinal cord ventral and dorsal horn, areas showing already intense astrogliosis in untreated Wobbler mice. In control mice, U-74389F also produced astrocyte hyperplasia and hypertophy in the dorsal horn and hyperplasia in the ventral-lateral funiculi of the cord. 4. Given in vivo U-74389F did not change GR in spinal cord of Wobbler or control mice, in line with the concept that it is active in membranes but does not bind to GR. Besides, U-74390F did not compete for [3H]dexamethasone binding when added in vitro. 5. The results suggest that stimulation of proliferation and size of GFAP-expressing astrocytes by U-74389F may be a novel mechanism of action of this compound. The Wobbler mouse may be a valuable animal model for further pharmacological testing of glucocorticoid and nonglucocorticoid steroids in neurodegenerative diseases.",
    	author = "{Gonzalez Deniselle}, M C and Gonzalez, S L and Piroli, G G and Lima, A E and {De Nicola}, A F",
    	issn = "0272-4340",
    	journal = "Cellular and molecular neurobiology",
    	keywords = "Adrenalectomy,Amyotrophic Lateral Sclerosis,Animals,Astrocytes,Astrocytes: drug effects,Astrocytes: metabolism,Astrocytes: pathology,Binding, Competitive,Cell Division,Cell Division: drug effects,Corticosterone,Corticosterone: blood,Dexamethasone,Dexamethasone: metabolism,Disease Models, Animal,Female,Genes, Recessive,Glial Fibrillary Acidic Protein,Glial Fibrillary Acidic Protein: analysis,Glial Fibrillary Acidic Protein: biosynthesis,Homozygote,Male,Mice,Mice, Neurologic Mutants,Muscular Atrophy, Spinal,Pregnatrienes,Pregnatrienes: pharmacology,Receptors, Glucocorticoid,Receptors, Glucocorticoid: analysis,Receptors, Glucocorticoid: biosynthesis,Reference Values,Spinal Cord,Spinal Cord: drug effects,Spinal Cord: metabolism,Spinal Cord: pathology",
    	month = "",
    	number = 1,
    	pages = "61--72",
    	pmid = 8714560,
    	title = "{The 21-aminosteroid U-74389F increases the number of glial fibrillary acidic protein-expressing astrocytes in the spinal cord of control and Wobbler mice.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/8714560",
    	volume = 16,
    	year = 1996
    }