Over-Expression of DSCR1 Protects against Post-Ischemic Neuronal Injury

Autor: Katherine R. Martin, John Thundyil, Christopher G. Sobey, Thiruma V. Arumugam, Bradley Rs Broughton, Alicia Corlett, Melanie April Pritchard, Vanessa H Brait, Grant R Drummond, Helena Kim
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Male
Time Factors
Mouse
lcsh:Medicine
Gene Expression
Muscle Proteins
Apoptosis
Hippocampal formation
Cardiovascular
Mice
0302 clinical medicine
Edema
Molecular Cell Biology
lcsh:Science
Cells
Cultured
0303 health sciences
Multidisciplinary
Microglia
Reverse Transcriptase Polymerase Chain Reaction
Intracellular Signaling Peptides and Proteins
Brain
Animal Models
Immunohistochemistry
Stroke
DNA-Binding Proteins
medicine.anatomical_structure
Neurology
Neutrophil Infiltration
Ischemic Attack
Transient
Reperfusion Injury
Medicine
Cytokines
medicine.symptom
Inflammation Mediators
Research Article
Brain Infarction
medicine.medical_specialty
Cerebrovascular Diseases
Immunoblotting
Ischemia
Inflammation
Mice
Transgenic
Biology
Molecular Genetics
03 medical and health sciences
Model Organisms
Downregulation and upregulation
Internal medicine
medicine
Genetics
Animals
Humans
030304 developmental biology
Ischemic Stroke
lcsh:R
medicine.disease
Calcineurin
Mice
Inbred C57BL
Endocrinology
Glucose
Cellular Neuroscience
Brain Injuries
Immunology
Genetics of Disease
Mice
Inbred CBA
lcsh:Q
Gene Function
Molecular Neuroscience
Reperfusion injury
030217 neurology & neurosurgery
Neuroscience
Zdroj: PLoS ONE
PLoS ONE, Vol 7, Iss 10, p e47841 (2012)
ISSN: 1932-6203
Popis: Background and Purpose: The Down syndrome candidate region 1 (DSCR1) gene is located on human chromosome 21 and its protein is over-expressed in brains of Down syndrome individuals. DSCR1 can modulate the activity of calcineurin, a phosphatase abundant in the brain, but its influence on stroke outcome is not clear. We compared stroke outcome in wildtype (WT) and transgenic (DSCR1-TG) mice which over-express isoform 1 of human DSCR1. Methods: Transient cerebral ischemia was produced by occlusion of the middle cerebral artery for 0.5 h. After 23.5 h reperfusion, we assessed neurological impairment, brain infarct and edema volume, leukocyte infiltration and markers of inflammation. Intrinsic resistance to apoptosis following glucose deprivation was also assessed in primary cultures of WT and DSCR1-TG neurons. Results: In contrast to WT, DSCR1-TG mice had an improved neurological deficit score, greater grip strength, attenuated infarct volume and brain swelling, and lacked hippocampal lesions after stroke. Expression of mouse DSCR1-1, but not DSCR1-4, mRNA and protein was increased by ischemia in both WT and DSCR1-TG. Brain calcineurin activity was increased to a similar degree after ischemia in each genotype. DSCR1-TG mice had fewer infiltrating neutrophils and activated microglia compared with WT, in association with an attenuated upregulation of several pro-inflammatory genes. Neurons from DSCR1-TG mice were more resistant than WT neurons to apoptotic cell death following 24 h of glucose deprivation. Conclusions: Over-expression of DSCR1 in mice improves outcome following stroke. Mechanisms underlying this protection may involve calcineurin-independent, anti-inflammatory and anti-apoptotic effects mediated by DSCR1 in neurons.
Databáze: OpenAIRE
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