Abstract
BackgroundSpinal cord edema is a serious complication and pathophysiological change after ischemia reperfusion (IR) injury. It has been demonstrated closely associated with bimodal disruption of blood–spinal cord barrier (BSCB) in our previous work. Aquaporin (AQP)1 plays important but contradictory roles in water homeostasis. Recently, microRNAs (miRs) effectively regulate numerous target mRNAs during ischemia. However, whether miRs are able to protect against dimodal disruption of BSCB by regulating perivascular AQP1 remains to be elucidated. ResultsSpinal water content and EB extravasation were suggested as a bimodal distribution in directly proportion to AQP1, since all maximal changes were detected at 12 and 48 h after reperfusion. Further TEM and double immunofluorescence showed that former disruption of BSCB at 12 h was attributed to cytotoxic edema by up-regulated AQP1 expressions in astrocytes, whereas the latter at 48 h was mixed with vasogenic edema with both endothelial cells and astrocytes involvement. Microarray analysis revealed that at 12 h post-injury, ten miRs were upregulated (>2.0 fold) and seven miRs were downregulated (<0.5 fold) and at 48 h, ten miRs were upregulated and eleven were downregulated compared to Sham-operated controls. Genomic screening and luciferase assays identified that miR-320a was a potential modulator of AQP1 in spinal cord after IR in vitro. In vivo, compared to rats in IR and negative control group, intrathecal infusion of miR-320a mimic attenuated IR-induced lower limb motor function deficits and BSCB dysfunction as decreased EB extravasation and spinal water content through down-regulating AQP1 expressions, whereas pretreated with miR-320a AMO reversed above effects. ConclusionThese findings indicate miR-320a directly and functionally affects spinal cord edema through negatively regulating AQP1 of BSCB after IR.
Highlights
Spinal cord edema is a serious complication and pathophysiological change after ischemia reperfusion (IR) injury
There was evidence to support that microR‐ NAs (miRs)-130a, a strong transcriptional repressor of the AQP4 M1 isoform, could up-regulate transcription of AQP4 M1 transcript and cause a reduction in cerebral infarct and promote recovery [14]. These findings suggested that miRs could be used as potential regulators to modulate AQP1 in spinal cord edema after IR
Pathological changes in blood–spinal cord barrier (BSCB) after IR injury Our recent study has demonstrated that bimodal disruption of BSCB was occurred at 12 and 48 h after injury in a rat model of spinal cord IR injury [1]
Summary
Spinal cord edema is a serious complication and pathophysiological change after ischemia reperfusion (IR) injury. It has been demonstrated closely associated with bimodal disruption of blood–spinal cord barrier (BSCB) in our previous work. In contrast to cerebral edema, contradictory roles of AQP1 in spinal cord edema formation have been described in previous studies [3, 7]. It requires further study to elucidate whether there are two different kinds of tissue edema, cytotoxic and vasogenic edema existing in procedure of spinal cord IR and to further clarify the underlying mechanisms regulating AQP1
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