Research reportHypoxia-inducible factor-1α is involved in isoflurane-induced blood-brain barrier disruption in aged rats model of POCD
Introduction
Postoperation cognitive dysfunction (POCD) is a common complication affecting the nervous system, resulting in significant long-term morbidities and compromising quality of life, especially in older patients undergoing surgery [1]. Our previous studies and other etiological research showed that the inhaled anesthetic isoflurane produced persistent deficits in aged animals [2], [3], [4] and in aged patients [5]. The underlying mechanisms of these adverse effects may include neuroinflammation [3], transient blood–brain barrier (BBB) disruption [6], and Aβ accumulation [2], etc. Among those possibilities, BBB disruption, which results in aberrant brain homeostasis and neuronal dysfunction, can increase the risk for subsequent development of POCD [7]. However, the precise mechanisms responsible for isoflurane-induced disruption of the BBB remain largely to be determined.
Hypoxia-inducible factor 1-alpha (HIF-1α) is a transcription factor that activates genes involved in cellular adaptation to hypoxia and in vascularization [8]. Recent reports showed that isoflurane temporally increased HIF-1α protein accumulation in vivo and in vitro [9], [10]. Among the genes regulated by HIF-1α, vascular endothelial growth factor (VEGF) is known as the master regulator of angiogenesis [11], and, in acute stages, it also increases vascular permeability through activation of matrix metalloproteinases (MMPs) [12], [13]. Previous findings showed that MMPs attack the collagen and tight junctions (TJs) of cerebral endothelial cells, inducing BBB disruption [14], [15]. However, the molecular mechanisms involved in POCD have not been described.
Based on this background information, we hypothesized that HIF-1α and VEGF are involved in isoflurane-induced BBB disruption. Therefore, the purpose of this study was to determine whether HIF-1α plays a role in isoflurane-induced BBB disruption and whether the HIF-1α inhibitor, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1), can improve isoflurane-induced cognitive deficits by preventing BBB disruption in the hippocampus of aged rats. To further explore the mechanisms underlying vascular leakage potentially induced by HIF-1α/VEGF-MMPs during isoflurane-induced cognitive dysfunction, we observed BBB ultrastructure, quantified BBB permeability, and monitored levels of structural proteins in brain vessels. In addition, we used the Morris water maze (MWM) test to assess learning and memory functions in the aged rats after those exposures.
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Animals
All experiments were performed using aged male Sprague–Dawley rats (20monthsold; 500–600 g) in the laboratory animal facility of Peking University. Animals were kept on a 12:12 h light: dark cycle, with access to food and water ad libitum. The experimental protocol was approved by the Peking University Biomedical Ethics Committee Experimental Animal Ethics Branch (Approval No. LA 2012-38).
Isoflurane exposure caused upregulation of HIF-1α and VEGF, effects attenuated by YC-1
Our findings verified that isoflurane exposure and YC-1 administration to aged rats impacted expression of HIF-1a and its downstream target gene, VEGF. Immunofluorescence was performed after 4 h isoflurane or control gas exposures. The results showed that levels of HIF-1α and VEGF were significantly increased in the nucleus of neurons in the hippocampal CA1 region (arrowheads) after 4 h isoflurane exposure, compared with in the control group (Fig. 1). These changes were suppressed by the HIF-1α
Discussion
In the present study, isoflurane induced downregulation of collagen type IV and occludin expression, concurrent with BBB disruption and spatial learning and memory deficits, were partially rescued by administration of a HIF-1α inhibitor. Our results demonstrated that HIF-1α inhibition could mitigate cognitive impairment induced by isoflurane exposure by improving the BBB structural and functional integrity.
HIF-1α is a ubiquitously expressed transcription factor that has been shown to activate a
Conclusions
We demonstrated that isoflurane-induced spatial learning and memory impairment in aged rats were associated with inhibition of the HIF-1α/VEGF-MMPs signaling pathway. Suppressing HIF-1α/VEGF expression could attenuate the disturbances in BBB ultrastructure and permeability in the hippocampus by decreasing MMP-2 expression, which reversed the loss of occludin and collagen type IV proteins in the brain vessels. These data suggested that regulation of HIF-1α activities a potential target for
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (No. 81371205, 81571036 and 81171015), the National Basic Research Program of China (973 Program, No. 2012CB911004).
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These authors collaborated to this work and they are co-corresponders for this article.