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1.
Hum Mol Genet ; 22(25): 5096-106, 2013 Dec 20.
Article in English | MEDLINE | ID: mdl-23900073

ABSTRACT

Increased mitochondrial mass, commonly termed mitochondrial proliferation, is frequently observed in many human diseases directly or indirectly involving mitochondrial dysfunction. Mitochondrial proliferation is thought to counterbalance a compromised energy metabolism, yet it might also be detrimental through alterations of mitochondrial regulatory functions such as apoptosis, calcium metabolism or oxidative stress. Here, we show that prominent mitochondrial proliferation occurs in Cramping mice, a model of hereditary neuropathy caused by a mutation in the dynein heavy chain gene Dync1h1. The mitochondrial proliferation correlates with post-prandial induction of full-length (FL) and N-terminal truncated (NT) isoforms of the transcriptional co-activator PGC-1α. The selective knock-out of FL-PGC-1α isoform, preserving expression and function of NT-PGC-1α, led to a complete reversal of mitochondrial proliferation. Moreover, FL-PGC-1α ablation potently exacerbated the mitochondrial dysfunction and led to severe weight loss. Finally, FL-PGC-1α ablation triggered pronounced locomotor dysfunction, tremors and inability to rear in Cramping mice. In summary, endogenous FL-PGC-1α activates mitochondrial proliferation and salvages neurological and metabolic health upon disease. NT-PGC-1α cannot fulfil this protective action. Activation of this endogenous salvage pathway might thus be a valuable therapeutic target for diseases involving mitochondrial dysfunction.


Subject(s)
Energy Metabolism/genetics , Mitochondria/metabolism , Protein Isoforms/genetics , Transcription Factors/genetics , Animals , Apoptosis/genetics , Cell Proliferation , Cytoplasmic Dyneins/genetics , Disease Models, Animal , Humans , Mice , Mice, Knockout , Mitochondria/genetics , Mitochondria/pathology , Oxidative Stress/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Phenotype , Protein Isoforms/metabolism , Transcription Factors/metabolism
2.
Hum Mol Genet ; 22(17): 3477-84, 2013 Sep 01.
Article in English | MEDLINE | ID: mdl-23669350

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a devastating, adult-onset neurodegenerative disorder of the upper and lower motor systems. It leads to paresis, muscle wasting and inevitably to death, typically within 3-5 years. However, disease onset and survival vary considerably ranging in extreme cases from a few months to several decades. The genetic and environmental factors underlying this variability are of great interest as potential therapeutic targets. In ALS, men are affected more often and have an earlier age of onset than women. This gender difference is recapitulated in transgenic rodent models, but no underlying mechanism has been elucidated. Here we report that SNPs in the brain-specific promoter region of the transcriptional co-activator PGC-1α, a master regulator of metabolism, modulate age of onset and survival in two large and independent ALS populations and this occurs in a strictly male-specific manner. In complementary animal studies, we show that deficiency of full-length (FL) Pgc-1α leads to a significantly earlier age of onset and a borderline shortened survival in male, but not in female ALS-transgenic mice. In the animal model, FL Pgc-1α-loss is associated with reduced mRNA levels of the trophic factor Vegf-A in males, but not in females. In summary, we indentify PGC-1α as a novel and clinically relevant disease modifier of human and experimental ALS and report a sex-dependent effect of PGC-1α in this neurodegenerative disorder.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Adult , Age of Onset , Aged , Animals , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Transgenic , Middle Aged , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Polymorphism, Single Nucleotide , Sex Characteristics , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
3.
J Neural Transm (Vienna) ; 120(5): 785-98, 2013 May.
Article in English | MEDLINE | ID: mdl-23143281

ABSTRACT

The dynactin p150glued subunit, encoded by the gene DCTN1 is part of the dynein-dynactin motor protein complex responsible for retrograde axonal transport. This subunit is a candidate modifier for neurodegenerative diseases, in particular motoneuron and extrapyramidal diseases. Based on an extensive screening effort of all 32 exons in more than 2,500 ALS/MND patients, patients suffering from Parkinsonian Syndromes and controls, we investigated 24 sequence variants of p150 in cell-based studies. We used both non-neuronal cell lines and primary rodent spinal motoneurons and report on cell biological abnormalities in five of these sequence alterations and also briefly report on the clinical features. Our results suggest the presence of biological changes caused by some p150 mutants pointing to a potential pathogenetic significance as modifier of the phenotype of the human disease.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Microtubule-Associated Proteins/genetics , Motor Neurons/metabolism , Parkinsonian Disorders/genetics , Parkinsonian Disorders/pathology , Adaptor Proteins, Signal Transducing , Amyotrophic Lateral Sclerosis/pathology , Animals , Apoptosis/drug effects , Apoptosis/genetics , Autophagy-Related Proteins , Carrier Proteins/metabolism , Cell Cycle Proteins/metabolism , Cells, Cultured , Chlorocebus aethiops , Dynactin Complex , Embryo, Mammalian , Female , Green Fluorescent Proteins/genetics , Humans , Male , Microscopy, Electron, Transmission , Microtubule-Associated Proteins/metabolism , Microtubules/metabolism , Motor Neurons/pathology , Motor Neurons/ultrastructure , Mutation/genetics , Pregnancy , Proteasome Endopeptidase Complex/metabolism , Protein Binding , Rats , Rats, Sprague-Dawley , Retrospective Studies , Spinal Cord/cytology , Time Factors
4.
Mol Neurodegener ; 6(1): 26, 2011 Apr 26.
Article in English | MEDLINE | ID: mdl-21521523

ABSTRACT

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. ALS patients, as well as animal models such as mice overexpressing mutant SOD1s, are characterized by increased energy expenditure. In mice, this hypermetabolism leads to energy deficit and precipitates motor neuron degeneration. Recent studies have shown that mutations in the gene encoding the dynein heavy chain protein are able to extend lifespan of mutant SOD1 mice. It remains unknown whether the protection offered by these dynein mutations relies on a compensation of energy metabolism defects. RESULTS: SOD1(G93A) mice were crossbred with mice harboring the dynein mutant Cramping allele (Cra/+ mice). Dynein mutation increased adipose stores in compound transgenic mice through increasing carbohydrate oxidation and sparing lipids. Metabolic changes that occurred in double transgenic mice were accompanied by the normalization of the expression of key mRNAs in the white adipose tissue and liver. Furthermore, Dynein Cra mutation rescued decreased post-prandial plasma triglycerides and decreased non esterified fatty acids upon fasting. In SOD1(G93A) mice, the dynein Cra mutation led to increased expression of IGF-1 in the liver, increased systemic IGF-1 and, most importantly, to increased spinal IGF-1 levels that are potentially neuroprotective. CONCLUSIONS: These findings suggest that the protection against SOD1(G93A) offered by the Cramping mutation in the dynein gene is, at least partially, mediated by a reversal in energy deficit and increased IGF-1 availability to motor neurons.

5.
Biochim Biophys Acta ; 1812(1): 59-69, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20887786

ABSTRACT

The molecular motor dynein is regulated by the huntingtin protein, and Huntington's disease (HD) mutations of huntingtin disrupt dynein motor activity. Besides abnormalities in the central nervous system, HD animal models develop prominent peripheral pathology, with defective brown tissue thermogenesis and dysfunctional white adipocytes, but whether this peripheral phenotype is recapitulated by dynein dysfunction is unknown. Here, we observed prominently increased adiposity in mice harboring the legs at odd angles (Loa/+) or the Cramping mutations (Cra/+) in the dynein heavy chain gene. In Cra/+ mice, hyperadiposity occurred in the absence of energy imbalance and was the result of impaired norepinephrine-stimulated lipolysis. A similar phenotype was observed in 3T3L1 adipocytes upon chemical inhibition of dynein showing that loss of functional dynein leads to impairment of lipolysis. Ex vivo, dynein mutant adipose tissue displayed increased reactive oxygen species production that was, at least partially, responsible for the decreased cellular responses to norepinephrine and subsequent defect in stimulated lipolysis. Dynein mutation also affected norepinephrine efficacy to elicit a thermogenic response and led to morphological abnormalities in brown adipose tissue and cold intolerance in dynein mutant mice. Interestingly, protein levels of huntingtin were decreased in dynein mutant adipose tissue. Collectively, our results provide genetic evidence that dynein plays a key role in lipid metabolism and thermogenesis through a modulation of oxidative stress elicited by norepinephrine. This peripheral phenotype of dynein mutant mice is similar to that observed in various animal models of HD, lending further support for a functional link between huntingtin and dynein.


Subject(s)
Adipose Tissue, Brown/metabolism , Adipose Tissue, White/metabolism , Cytoplasmic Dyneins/genetics , Energy Metabolism/genetics , Mutation , 3T3-L1 Cells , Adrenergic alpha-Agonists/pharmacology , Animals , Blotting, Western , Cytoplasmic Dyneins/metabolism , Female , Gene Expression , Humans , Huntingtin Protein , Huntington Disease/genetics , Huntington Disease/metabolism , Lipolysis/drug effects , Lipolysis/genetics , Male , Mice , Mice, Mutant Strains , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Norepinephrine/pharmacology , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Oxidative Stress/drug effects , Receptors, Adrenergic, beta-2/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Thermogenesis/genetics
6.
Hum Mol Genet ; 19(22): 4385-98, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20807776

ABSTRACT

The molecular motor dynein and its associated regulatory subunit dynactin have been implicated in several neurodegenerative conditions of the basal ganglia, such as Huntington's disease (HD) and Perry syndrome, an atypical Parkinson-like disease. This pathogenic role has been largely postulated from the existence of mutations in the dynactin subunit p150(Glued). However, dynactin is also able to act independently of dynein, and there is currently no direct evidence linking dynein to basal ganglia degeneration. To provide such evidence, we used here a mouse strain carrying a point mutation in the dynein heavy chain gene that impairs retrograde axonal transport. These mice exhibited motor and behavioural abnormalities including hindlimb clasping, early muscle weakness, incoordination and hyperactivity. In vivo brain imaging using magnetic resonance imaging showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signalling, decreased dopamine D1 and D2 receptor binding in positron emission tomography SCAN and prominent astrocytosis were observed, although there was no neuronal loss either in the striatum or substantia nigra. In vitro, dynein mutant striatal neurons displayed strongly impaired neuritic morphology. Altogether, these findings provide a direct genetic evidence for the requirement of dynein for the morphology and function of striatal neurons. Our study supports a role for dynein dysfunction in the pathogenesis of neurodegenerative disorders of the basal ganglia, such as Perry syndrome and HD.


Subject(s)
Corpus Striatum/pathology , Dyneins/genetics , Neurons/metabolism , Point Mutation , Animals , Atrophy , Behavior, Animal/physiology , Cells, Cultured , Corpus Striatum/metabolism , Dopamine/genetics , Dopamine/metabolism , Dynactin Complex , Embryo, Mammalian , Heterozygote , Huntington Disease/genetics , Huntington Disease/metabolism , Huntington Disease/physiopathology , Male , Mice , Mice, Inbred C3H , Microtubule-Associated Proteins/genetics , Nerve Degeneration/genetics , Nerve Degeneration/metabolism , Nerve Degeneration/pathology , Neurites/metabolism , Neurites/pathology , Neurons/pathology , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism , Substantia Nigra/metabolism , Substantia Nigra/pathology , Substantia Nigra/physiopathology
7.
Amyotroph Lateral Scler ; 11(1-2): 38-45, 2010.
Article in English | MEDLINE | ID: mdl-20184514

ABSTRACT

The development of therapeutics for ALS/MND is largely based on work in experimental animals carrying human SOD mutations. However, translation of apparent therapeutic successes from in vivo to the human disease has proven difficult and a considerable amount of financial resources has been apparently wasted. Standard operating procedures (SOPs) for preclinical animal research in ALS/MND are urgently required. Such SOPs will help to establish SOPs for translational research for other neurological diseases within the next few years. To identify the challenges and to improve the research methodology, the European ALS/MND group held a meeting in 2006 and published guidelines in 2007 (1). A second international conference to improve the guidelines was held in 2009. These second and improved guidelines are dedicated to the memory of Sean F. Scott.


Subject(s)
Amyotrophic Lateral Sclerosis/drug therapy , Disease Models, Animal , Drug Evaluation, Preclinical/methods , Drug Evaluation, Preclinical/standards , Guidelines as Topic , Animals , Consensus
8.
Am J Pathol ; 176(3): 1409-20, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20075202

ABSTRACT

Transgenic mice expressing human mutated superoxide dismutase 1 (SOD1) linked to familial forms of amyotrophic lateral sclerosis are frequently used as a disease model. We used the SOD1G93A mouse in a cross-breeding strategy to study the function of physiological prion protein (Prp). SOD1G93APrp-/- mice exhibited a significantly reduced life span, and an earlier onset and accelerated progression of disease, as compared with SOD1G93APrp+/+ mice. Additionally, during disease progression, SOD1G93APrp-/- mice showed impaired rotarod performance, lower body weight, and reduced muscle strength. Histologically, SOD1G93APrp-/- mice showed reduced numbers of spinal cord motor neurons and extended areas occupied by large vacuoles early in the course of the disease. Analysis of spinal cord homogenates revealed no differences in SOD1 activity. Using an unbiased proteomic approach, a marked reduction of glial fibrillary acidic protein and enhanced levels of collapsing response mediator protein 2 and creatine kinase were detected in SOD1G93APrp-/- versus SOD1G93A mice. In the course of disease, Bcl-2 decreases, nuclear factor-kappaB increases, and Akt is activated, but these changes were largely unaffected by Prp expression. Exclusively in double-transgenic mice, we detected a significant increase in extracellular signal-regulated kinase 2 activation at clinical onset. We propose that Prp has a beneficial role in the SOD1G93A amyotrophic lateral sclerosis mouse model by influencing neuronal and/or glial factors involved in antioxidative defense, rather than anti-apoptotic signaling.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Neuroprotective Agents/metabolism , Prions/metabolism , Amyotrophic Lateral Sclerosis/enzymology , Amyotrophic Lateral Sclerosis/pathology , Animals , Brain/enzymology , Brain/pathology , Breeding , Cell Count , DNA/metabolism , Disease Models, Animal , Disease Progression , Enzyme Activation , Female , Glial Fibrillary Acidic Protein/metabolism , Humans , Male , Mice , Mice, Transgenic , Mitogen-Activated Protein Kinase 1/metabolism , Motor Neurons/pathology , Prion Proteins , Spinal Cord/enzymology , Spinal Cord/pathology , Superoxide Dismutase/genetics , Superoxide Dismutase-1 , Survival Analysis , Transgenes/genetics , Vacuoles/metabolism
9.
Exp Neurol ; 215(1): 146-52, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18952079

ABSTRACT

In neurons, cytoplasmic dynein functions as a molecular motor responsible for retrograde axonal transport. An impairment of axonal transport is thought to play a key role in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis, the most frequent motor neuron disease in the elderly. In this regard, previous studies described two heterozygous mouse strains bearing missense point mutations in the dynein heavy chain 1 gene that were reported to display late-onset progressive motor neuron degeneration. Here we show, however, that one of these mutant strains, the so-called Cra mice does not suffer from motor neuron loss, even in aged animals. Consistently, we did not observe electrophysiological or biochemical signs of muscle denervation, indicative of motor neuron disease. The "hindlimb clasping" phenotype of Cra mice could rather be due to the prominent degeneration of sensory neurons associated with a loss of muscle spindles. Altogether, these findings show that dynein heavy chain mutation triggers sensory neuropathy rather than motor neuron disease.


Subject(s)
Dyneins/genetics , Mutation/genetics , Sensation Disorders/genetics , Sensation Disorders/physiopathology , Age Factors , Analysis of Variance , Animals , Benzofurans , Choline O-Acetyltransferase/metabolism , Cytoplasmic Dyneins , Disease Models, Animal , Electromyography/methods , Mice , Mice, Inbred C3H , Mice, Mutant Strains , Motor Neuron Disease/genetics , Motor Neuron Disease/physiopathology , Motor Neurons/pathology , Muscle Denervation/methods , Muscle, Skeletal/physiology , Neuromuscular Junction/pathology , Sensation Disorders/pathology , Spinal Nerve Roots/pathology , Superoxide Dismutase/genetics , Superoxide Dismutase-1
10.
Exp Neurol ; 206(2): 288-95, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17597611

ABSTRACT

In amyotrophic lateral sclerosis (ALS), an involvement of the immune system in the degenerative processes has been shown in both humans and the transgenic SOD1-G93A mice. We previously showed that Glatiramer acetate (also known as copolymer-1; COP-1; Copaxone) improves motor function and extends survival times in an inbred strain of ALS mice probably by interacting with pro-inflammatory T(H) lymphocytes. In the course of this study we tested whether these beneficial effects could be reproduced by repeated vaccination of animals with COP-1 without co-administration of complete Freund's adjuvant. In an outbred strain we could not demonstrate a positive effect of COP-1 on survival times, but found a significant improvement of motor performance during the late stage of disease and a moderate decrease of the production of the inflammatory cytokines interferon-gamma and IL-4 by T lymphocytes isolated from the mice's spleen. In conclusion, the effects of COP-1 in the applied hybrid strain displaying a faster disease progression were less pronounced than in the earlier tested inbred strain of ALS mice.


Subject(s)
Amyotrophic Lateral Sclerosis/drug therapy , Myelitis/drug therapy , Peptides/pharmacology , Superoxide Dismutase/genetics , T-Lymphocytes/drug effects , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/immunology , Animals , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Disease Progression , Female , Gene Dosage/genetics , Glatiramer Acetate , Humans , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Male , Mice , Mice, Transgenic , Myelitis/genetics , Myelitis/immunology , Paralysis/drug therapy , Paralysis/immunology , Paralysis/prevention & control , Peptides/therapeutic use , Superoxide Dismutase-1 , Survival Rate , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Treatment Outcome
11.
Neurochem Res ; 32(3): 415-21, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17268853

ABSTRACT

The work is a continuation of studies on tau expression and alternative splicing in the central nervous system of transgenic mice harboring human SOD1 with G93A amyotrophic lateral sclerosis (ALS)-associated mutation. Since age is an important risk factor for ALS, we expanded the studies into younger animals (age 5 and 25 days). We also included cerebellum, a structure not studied in the context of neurodegeneration in ALS. We found decreased total tau-mRNA expression in hippocampus but not in cortex and spinal cord of young transgenics, and a lack of exon 10 in 5-day-old mice. In cerebellum, the total tau-mRNA expression was increased in transgenic animals during the whole period of life, however at the symptomatic stage of ALS (age 120 days) the level of protein was decreased. It can be concluded that the SOD1 G93A mutation causes early alterations of tau expression in cns, which are not exclusively restricted to the upper and lower motor neuron.


Subject(s)
Motor Neuron Disease/genetics , tau Proteins/genetics , Aging/genetics , Alternative Splicing , Animals , Cerebellum/growth & development , Cerebellum/metabolism , Disease Models, Animal , Gene Expression Regulation, Developmental , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , RNA, Messenger/genetics , RNA, Messenger/isolation & purification , Reverse Transcriptase Polymerase Chain Reaction , Superoxide Dismutase/genetics , Superoxide Dismutase-1
12.
Neurochem Res ; 31(5): 597-602, 2006 May.
Article in English | MEDLINE | ID: mdl-16770730

ABSTRACT

Tau is a protein involved in regulation of microtubule stability, axonal differentiation and transport. Alteration of retrograde transport may lead to motor neuron degeneration. Thus alternative mRNA splicing and expression of tau isoforms were studied in a transgenic mouse model harboring the human SOD1 G93A mutation. The studies were performed on cortex, hippocampus and spinal cord of 64- and 120-day-old animals (presymptomatic and symptomatic stage) and wild type controls. Exon 10 was found in all studied tissues. The 2N isoform containing exons 2 and 3 (+2+3) and the 1N (+2-3) predominated over the 0N (-2-3) in brain regions of the studied mice. The 2N expression was significantly lower in cortex and hippocampus of symptomatic animals compared to analogue control tissues. The decrease in 2N expression resulted in lower levels of total tau mRNA and tau protein. No changes in tau expression were observed in spinal cord of studied animals.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Protein Isoforms/metabolism , tau Proteins/metabolism , Alternative Splicing , Animals , Cerebral Cortex/metabolism , Disease Models, Animal , Exons , Hippocampus/metabolism , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Protein Isoforms/genetics , Spinal Cord/metabolism , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , Superoxide Dismutase-1 , tau Proteins/genetics
13.
J Neurosci Res ; 71(6): 819-25, 2003 Mar 15.
Article in English | MEDLINE | ID: mdl-12605408

ABSTRACT

Defective glutamate uptake has been implicated as a pathogenic event of neuronal damage related to cerebral ischemia and hypoxia. In several models of ischemia-hypoxia, a reduced immunoreactivity and altered RNA expression of excitatory amino acid transporter 2 (EAAT2), the major excitatory amino acid transporter, have been reported. However, the gene regulation of EAAT2 under these conditions is incompletely understood. In this study, we investigated alternative splicing of EAAT2 in an in vivo mouse model of chemical hypoxia as induced by 3-nitropropionic acid (3-NP). The neurotoxin 3-NP is an inhibitor of mitochondrial energy production. Furthermore, it is known to inhibit glutamate reuptake directly, representing at least one of the mechanisms responsible for 3-NP-induced neurodegeneration. Here we report an expression analysis of five known (mEAAT2/5UT1-5) and two novel (mEAAT2/5UT6, -7) 5' splice variants of EAAT2 using semiquantitative PCR. The RNA expression was studied at 2, 12, 24, 48, and 72 hr and 7 days after 3-NP administration. mEAAT2/5UT4 and mEAAT2/5UT5 were up-regulated in the frontal cortex and down-regulated in the hippocampus 12-72 hr after chemical hypoxia. In the cerebellum, there was an increased expression of mEAAT2/5UT4 and a down-regulation of mEAAT2/5UT5. mEAAT2/5UT3 show a different regional expression pattern, being regulated in the cerebellum only. mEAAT2/5UT1-7 encoded distinct 5' regulatory sequences, including conserved elements of translational control. It is easily conceivable that expression alterations of 5' splice variants of EAAT2 are related to glutamate transporter malfunction after chemical hypoxia. Our findings contribute to the hypothesis that RNA splicing events can serve as a molecular mechanism of posthypoxic gene regulation.


Subject(s)
Alternative Splicing/genetics , Brain/physiology , Excitatory Amino Acid Transporter 2/metabolism , Gene Expression Regulation , Hypoxia, Brain/metabolism , Animals , Cloning, Molecular , Convulsants/pharmacology , Excitatory Amino Acid Transporter 2/genetics , Hypoxia, Brain/chemically induced , Hypoxia, Brain/genetics , Male , Mice , Nitro Compounds , Polymerase Chain Reaction , Propionates/pharmacology , RNA, Messenger/metabolism , Recombination, Genetic
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