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

Vanessa H Brait,Hyun Ah Kim,Melanie A Pritchard,Alicia Corlett,Christopher G Sobey,Grant R Drummond,Brad R S Broughton,John Thundyil,Katherine R Martin,Thiruma V Arumugam,Renping Zhou

doi:10.1371/journal.pone.0047841

Abstract

Background and PurposeThe 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.MethodsTransient 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.ResultsIn 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.ConclusionsOver-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.

Highlights

Stroke is the second cause of death worldwide, accounting for,10% of all deaths, and is a major cause of long-term disability [1]
Over-expression of Down syndrome candidate region 1 (DSCR1) improves stroke outcome Systolic blood pressure (BP) was similar in naıve DSCR1-TG and WT mice (TG, 12963 mmHg; WT, 12164 mmHg; n = 10–13)
Whereas hippocampal lesions were evident in 37/53 (70%) of sections examined from 11 WT mice, no hippocampal lesions were observed in .50 sections from 11 DSCR1-TG mice

Summary

Introduction

Stroke is the second cause of death worldwide, accounting for ,10% of all deaths, and is a major cause of long-term disability [1]. After an ischemic event the brain tissue in the penumbra undergoes a series of complex neurochemical changes termed the ‘‘ischemic cascade’’, which is characterised by a depletion of energy within the cells followed by the disruption of ion homeostasis, release of glutamate, calcium channel dysfunction, oxidative stress and the induction of inflammatory responses. This complex series of events can lead to cell death through both necrosis and apoptosis [3]. We compared stroke outcome in wildtype (WT) and transgenic (DSCR1-TG) mice which over-express isoform 1 of human DSCR1

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Conclusion