Abstract
BackgroundMicroglia are the primary immune cells of the spinal cord that are activated in response to ischemia/reperfusion (IR) injury and release various neurotrophic and/or neurotoxic factors to determine neuronal survival. Among them, matrix metalloproteinase-9 (MMP-9), which cleaves various components of the extracellular matrix in the basal lamina and functions as part of the blood spinal cord barrier (BSCB), is considered important for regulating inflammatory responses and microenvironmental homeostasis of the BSCB in the pathology of ischemia. Sevoflurane has been reported to protect against neuronal apoptosis during cerebral IR. However, the effects of sevoflurane preconditioning on spinal cord IR injury remain unclear. In this study, we investigated the role of sevoflurane on potential genetic roles of microglial MMP-9 in tight junction protein breakdown, opening of the BSCB, and subsequent recruitment of microglia to apoptotic spinal cord neurons.ResultsThe results showed significant upregulation of MMP-9 in rats with IR-induced inflammation of the BSCB compared to that of the sham group, manifested as dysfunctional BSCB with increased Evans blue extravasation and reduced expression of occludin protein. Increased MMP-9 expression was also observed to facilitate invasion and migration of activated microglia, imaging as high Iba-1 expression, clustered to neurons in the injured spinal cord, as shown by double immunofluorescence, and increased proinflammatory chemokine production (CXCL10, CCL2). Further, sevoflurane preconditioning markedly improved motor function by ameliorating neuronal apoptosis, as shown by reduced TUNEL-positive cell counts and expression of cleaved caspase-3. These protective effects were probably responsible for downregulation of MMP-9 and maintenance of normal expression of occludin protein indicating BSCB integrity from inflammatory damage, which was confirmed by decreased protein levels of Iba-1 and MMP-9, as well as reduced production of proinflammatory chemokines (CXCL10, CCL2) and proinflammatory cytokines (IL-1β). Intrathecal injection of specific siRNAs targeting MMP-9 had similar protective effects to those of sevoflurane preconditioning.ConclusionsPreconditioning with 2.4% sevoflurane attenuated spinal cord IR injury by inhibiting recruitment of microglia and secretion of MMP-9; thus inhibiting downstream effects on inflammatory damage to BSCB integrity and neuronal apoptosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-014-0069-7) contains supplementary material, which is available to authorized users.
Highlights
Spinal cord ischemia/reperfusion (IR) injury is a wellrecognized clinical problem resulting in motor and sensory dysfunction that is characterized as temporary or permanent ischemia of the spinal cord following reperfusion in a setting of shock or thoracoabdominal aorta surgery [1]
This suggests that the neuroprotective effects of sevoflurane preconditioning, in part, contributed to the inhibition of residual immune cell activation and Matrix metalloproteinase (MMP)-9 expression in the injured region. (D) Histogram for quantification of colocalized cells. (E) Histogram for quantification of Ionized calcium-binding adaptor molecule 1 (Iba-1)-positive cells localized around Neuronal nuclei (NeuN)-positive cells of lamina IX
Consistent with previous research in our laboratory [16,19], the present study demonstrated that spinal cord IR injury induced by 14-min aortic arch occlusion produced extensive neuronal apoptosis manifesting as severe hind-limb motor functional deficits, along with increased blood spinal cord barrier (BSCB) leakage
Summary
Spinal cord ischemia/reperfusion (IR) injury is a wellrecognized clinical problem resulting in motor and sensory dysfunction that is characterized as temporary or permanent ischemia of the spinal cord following reperfusion in a setting of shock or thoracoabdominal aorta surgery [1]. Accumulating evidence suggests that the extracellular matrix and tight junction complexes serve several important physiological functions, including defense and homeostatic balance between the spinal cord and systemic circulation, aberrant decomposition of which could cause neurotoxic effects [5,6]. Matrix metalloproteinase-9 (MMP-9), which cleaves various components of the extracellular matrix in the basal lamina and functions as part of the blood spinal cord barrier (BSCB), is considered important for regulating inflammatory responses and microenvironmental homeostasis of the BSCB in the pathology of ischemia. We investigated the role of sevoflurane on potential genetic roles of microglial MMP-9 in tight junction protein breakdown, opening of the BSCB, and subsequent recruitment of microglia to apoptotic spinal cord neurons
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